Grupos Investigadores

Miembros del Grupo

Colaboradores
Naiara
Aramendía Blázquez
Laura
Blanco Fernández
Laura
Gutiérrez Arrondo
Beatriz
Gómez Napal
Andrea
Jiménez Paternain
Jaione
Larraiotz Senosiáin
Aitziber
López López
Judith
Martínez Cascales
Cristina
Moleiro López
Andreína
Taveras Báez

Líneas de Investigación

  • Entender los mecanismos tumorales e inmunes de trasformación del mieloma indolente a mieloma activo, con vistas a proporcionar biomarcadores que faciliten la intervención precoz y personalizada de la enfermad
  • Establecer modelos de riesgo basados en biomarcadores mínimamente invasivos para el diagnóstico diferencial entre las gammapatías monoclonales con y sin significado clínico
  • Identificar los mecanismos de respuesta y resistencia, así como de infecciones, para adaptar el tratamientos con las nuevas inmunoterapias según el perfil inmune de los pacientes con mieloma múltiple

Palabras Clave

  • Biomarcadores
  • Clínica
  • Detección
  • Enfermedad mínima residual
  • Gammopatías
  • Inmunoterapia
  • Mecanismos
  • Mieloma
  • Resistencia al tratamiento
  • Rutina diagnóstica
  • Transformación

Publicaciones Científicas desde 2018

  • Autores: Ruiz-Pablos, M. (Autor de correspondencia); Paiva, Bruno; Zabaleta Azpiroz, Aintzane
    Revista: JOURNAL OF TRANSLATIONAL MEDICINE
    ISSN: 1479-5876 Vol.21 N° 1 2023 págs. 633
    Resumen
    Both myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) and long COVID (LC) are characterized by similar immunological alterations, persistence of chronic viral infection, autoimmunity, chronic inflammatory state, viral reactivation, hypocortisolism, and microclot formation. They also present with similar symptoms such as asthenia, exercise intolerance, sleep disorders, cognitive dysfunction, and neurological and gastrointestinal complaints. In addition, both pathologies present Epstein-Barr virus (EBV) reactivation, indicating the possibility of this virus being the link between both pathologies. Therefore, we propose that latency and recurrent EBV reactivation could generate an acquired immunodeficiency syndrome in three steps: first, an acquired EBV immunodeficiency develops in individuals with weak EBV HLA-II haplotypes, which prevents the control of latency I cells. Second, ectopic lymphoid structures with EBV latency form in different tissues (including the CNS), promoting inflammatory responses and further impairment of cell-mediated immunity. Finally, immune exhaustion occurs due to chronic exposure to viral antigens, with consolidation of the disease. In the case of LC, prior to the first step, there is the possibility of previous SARS-CoV-2 infection in individuals with weak HLA-II haplotypes against this virus and/or EBV.
  • Autores: Ludwig, H.; Terpos, E.; van de Donk, Niels ; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.24 N° 6 2023 págs. e255 - e269
    Resumen
    T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.
  • Autores: Dimopoulos, M. A.; Merlini, G.; Bridoux, F.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.24 N° 7 2023 págs. e293 - e311
    Resumen
    Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment.
  • Autores: Bouza, E. (Autor de correspondencia); Martin, M.; Alés, J. E.; et al.
    Revista: REVISTA ESPAÑOLA DE QUIMIOTERAPIA
    ISSN: 0214-3429 Vol.36 N° 1 2023 págs. 1 - 25
    Resumen
    We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.
  • Autores: Terpos, E. (Autor de correspondencia); Musto, P.; Engelhardt, M.; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.37 N° 6 2023 págs. 1175 - 1185
    Resumen
    In the post-pandemic COVID-19 period, human activities have returned to normal and COVID-19 cases are usually mild. However, patients with multiple myeloma (MM) present an increased risk for breakthrough infections and severe COVID-19 outcomes, including hospitalization and death. The European Myeloma Network has provided an expert consensus to guide patient management in this era. Vaccination with variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4/5 strains, is essential as novel strains emerge and become dominant in the community. Boosters should be administered every 6-12 months after the last vaccine shot or documented COVID-19 infection (hybrid immunity). Booster shots seem to overcome the negative effect of anti-CD38 monoclonal antibodies on humoral responses; however, anti-BCMA treatment remains an adverse predictive factor for humoral immune response. Evaluation of the immune response after vaccination may identify a particularly vulnerable subset of patients who may need additional boosters, prophylactic therapies and prevention measures. Pre-exposure prophylaxis with tixagevimab/cilgavimab is not effective against the new dominant variants and thus is no longer recommended. Oral antivirals (nirmatrelvir/ritonavir and molnupiravir) and remdesivir are effective against Omicron subvariants BA.2.12.1, BA.4, BA.5, BQ.1.1 and/or XBB.1.5 and should be administered in MM patients at the time of a positive COVID-19 test or within 5 days post symptoms onset. Convalescent plasma seems to have low value in the post-pandemic era. Prevention measures during SARS-CoV-2 outbreaks, including mask wearing and avoiding crowded places, seem prudent to continue for MM patients.
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); Towle, K.; Cope, S.; et al.
    Revista: LEUKEMIA AND LYMPHOMA
    ISSN: 1042-8194 Vol.64 N° 11 2023 págs. 1864 - 1869
  • Autores: Ocio, E. M. M. (Autor de correspondencia); Bringhen, S.; Martínez-López, J.; et al.
    Revista: HEMASPHERE
    ISSN: 2572-9241 Vol.7 N° 2 2023 págs. e829
  • Autores: Simoes Pinto, Cátia Patricia; Villar Fernández, Sara; Ariceta Ganuza, Beñat; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN: 0007-1048 Vol.201 N° 6 2023 págs. 1239 - 1244
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); San Miguel Izquierdo, Jesús
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 9 2023 págs. 1789 - 1790
  • Autores: Moreau, P. (Autor de correspondencia); Chari, A.; Oriol, A.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.13 N° 1 2023 págs. 33
  • Autores: Garcés Latre, Juan José; San Miguel Izquierdo, Jesús; Paiva, Bruno
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 3 2023 págs. 710 - 711
  • Autores: Treon, S. P. (Autor de correspondencia); Patterson, C. J.; Garcia Sanz, R.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 59 - 64
  • Autores: Hillengass, J.; Martin, T.; Puig, N.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° 4 2023 págs. 244 - 248
  • Autores: Paiva, Bruno (Autor de correspondencia); Calasanz Abinzano, María José
    Revista: BLOOD
    ISSN: 0006-4971 Vol.141 N° 13 2023 págs. 1500 - 1502
  • Autores: D'Sa, S. (Autor de correspondencia); Matous, J. V.; Advani, R.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 80 - 89
    Resumen
    The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.
  • Autores: Garcia-Sanz, R. (Autor de correspondencia); Varettoni, M.; Jimenez, C.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 90 - 96
    Resumen
    Apart from the MYD88L265P mutation, extensive information exists on the molecular mechanisms in Waldenstrom's Macroglobulinemia and its potential utility in the diagnosis and treatment tailoring. However, no consensus recommendations are yet available. Consensus Panel 3 (CP3) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current molecular necessities and best way to access the minimum data required for a correct diagnosis and monitoring. Key recommendations from IWWM-11 CP3 included: (1) molecular studies are warranted for patients in whom therapy is going to be started; such studies should also be done in those whose bone marrow (BM) material is sampled based on clinical issues; (2) molecular studies considered essential for these situations are those that clarify the status of 6q and 17p chromosomes, and MYD88, CXCR4, and TP53 genes. These tests in other situations, and/or other tests, are considered optional; (3) independently of the use of more sensitive and/or specific techniques, the minimum requirements are allele specific polymerase chain reaction for MYD88L265P and CXCR4S338X using whole BM, and fluorescence in situ hybridization for 6q and 17p and sequencing for CXCR4 and TP53 using CD19+ enriched BM; (4) these requirements refer to all patients; therefore, sample should be sent to specialized centers.& COPY; 2023 Elsevier Inc. All rights reserved.
  • Autores: Lesokhin, A. M. (Autor de correspondencia); Tomasson, M. H.; Arnulf, B.; et al.
    Revista: NATURE MEDICINE
    ISSN: 1078-8956 Vol.29 N° 9 2023 págs. 2259 - 2267
    Resumen
    Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ¿complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ¿6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3-4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3-4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359 .
  • Autores: Buskea, C. (Autor de correspondencia); Castillo, J. J.; Abeykoonc, J. P.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 73 - 79
    Resumen
    Consensus Panel 1 (CP1) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with updating guidelines for the management of symptomatic, treatment-naïve patients with WM. The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function. For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable. Covalent BTK inhibitors (cBTKi) offer a continuous, generally well-tolerated alternative for the primary treatment of WM patients, particularly those unsuitable for CIT. In a Phase III randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM. While the overall findings of a prospective, randomized trial updated at IWWM-11 did not show superiority of fixed duration rituximab maintenance over observation following attainment of a major response to Benda-R induction, a subset analysis showed benefit in patients >65 years and those with a high IPPSWM score. Whenever possible, the mutational status of MYD88 and CXCR4 should be determined before treatment initiation, as alterations in these 2 genes predict sensitivity towards cBTKi activity. Treatment approaches for WM-associated cryoglobulins, cold agglutinins, AL amyloidosis, Bing-Neel syndrome (BNS), peripheral neuropathy, and hyperviscosity syndrome follow the common principle of reducing tumor and abnormal protein burden rapidly and deeply to improve symptoms. In BNS, ibrutinib can be highly active and produce durable responses. In contrast, cBTKi are not recommended for treating AL amyloidosis. The panel emphasized that continuous improvement of treatment options for symptomatic, treatment-naïve WM patients critically depends on the participation of patients in clinical trials, whenever possible.
  • Autores: Ocio, E. M. (Autor de correspondencia); Perrot, A.; Bories, P.; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.37 N° 7 2023 págs. 1521 - 1529
    Resumen
    Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10(-5) sensitivity). Grade >= 3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
  • Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Dhakal, B.; Yong, K.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.389 N° 4 2023 págs. 335 - 347
    Resumen
    BACKGROUND Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR-T cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies.
  • Autores: Terpos, E. (Autor de correspondencia); Branagan, A. R.; Garcia-Sanz, R.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 107 - 112
    Resumen
    Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.
  • Autores: Weisel, K. (Autor de correspondencia); Dimopoulos, M. A.; San Miguel Izquierdo, Jesús; et al.
    Revista: HEMASPHERE
    ISSN: 2572-9241 Vol.7 N° 3 2023 págs. e843
    Resumen
    Triplet regimens containing immunomodulatory drugs and proteasome inhibitors (PIs) have improved outcomes and extended survival for patients with relapsed/refractory multiple myeloma (RRMM). We evaluated updated health-related quality of life (HRQoL) findings from the phase 2 ELOQUENT-3 clinical trial (NCT02654132) after 4 years of treatment with elotuzumab plus pomalidomide and dexamethasone (EPd) and assessed the impact of the addition of elotuzumab on patients' HRQoL. HRQoL was assessed as an exploratory endpoint using the MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM), which evaluates symptom severity, symptom interference, and HRQoL, and the 3-level EQ-5D, a patient-reported measure of health utility and general health. Statistical analyses included descriptive responder, longitudinal mixed-model, and time-to-first-deterioration (TTD) analyses using prespecified minimally important differences and responder definitions. Of 117 randomized patients, 106 (EPd, n = 55; pomalidomide and dexamethasone [Pd], n = 51) were eligible for inclusion in HRQoL analyses. Completion rates at almost all on-treatment visits were >= 80%. The proportion of patients treated with EPd who improved or maintained stable HRQoL until cycle 13 ranged from 82% to 96% for MDASI-MM total symptom score and 64% to 85% for MDASI-MM symptom interference. Across measurements, there were no clinically meaningful differences in changes from baseline between treatment arms, and TTD was not significantly different for EPd versus Pd. In conclusion, HRQoL was not impacted by the addition of elotuzumab to Pd and did not significantly deteriorate in patients with RRMM previously treated with lenalidomide and a PI in ELOQUENT-3.
  • Autores: Cohen, A. D.; Victoria, M. M.; Cohen, Y. C.; et al.
    Revista: BLOOD
    ISSN: 1528-0020 Vol.141 N° 3 2023 págs. 219 - 230
    Resumen
    B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADC), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non¿cellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC-exposed; 7 BsAb-exposed; 1 in the ADC group also had prior BsAb exposure); 16 (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7/20 (35%) patients were MRD-negative (7/10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% CI) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1/2); 4 had immune effector cell-associated neurotoxicity syndrome (2 grade 3/4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment-related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who have exhausted other therapies.
  • Autores: Tam, C. S. (Autor de correspondencia); Kapoor, P.; Castillo, J. J.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 118 - 124
    Resumen
    Recent advances in the understanding of Waldenstrom macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (>= VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.
  • Autores: Merlini, G. (Autor de correspondencia); Sarosiek, S.; Benevolo, G.; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 113 - 117
    Resumen
    Consensus Panel 6 (CP6) of the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM-11) was tasked with reviewing the state of the art for diagnosis, prognosis, and therapy of AL amyloidosis associated with Waldenström macroglobulinemia (WM). Since significant advances have been made in the management of AL amyloidosis an update for this rare disease associated with WM was necessary. The key recommendations from IWWM-11 CP6 included: (1) The need to improve the diagnostic process by recognizing red flags and using biomarkers and imaging; (2) The essential tests for appropriate workup; (3) The diagnostic flowchart, including mandatory amyloid typing, that improves the differential diagnosis with transthyretin amyloidosis; (4) Criteria for therapy response assessment; (5) State of the art of the treatment including therapy of wild type transthyretin amyloidosis associated with WM.
  • Autores: Rodríguez Otero, Paula; Ailawadhi, S.; Arnulf, B.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.388 N° 11 2023 págs. 1002 - 1014
    Resumen
    BackgroundSurvival is poor among patients with triple-class-exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma.MethodsIn this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150x10(6) to 450x10(6) CAR-positive T cells) or one of five standard regimens. The primary end point was progression-free survival. Key secondary end points were overall response (partial response or better) and overall survival. Safety was assessed.ResultsA total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P < 0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P < 0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher.ConclusionsIde-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports.
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Dytfeld, D.; Grosicki, S.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 3 2023 págs. 568 - 578
    Resumen
    Purpose: In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results. Methods: Patients with RRMM who had received ¿ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically. Results: A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected. Conclusion: EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.
  • Autores: Delforge, M. (Autor de correspondencia); Rodríguez Otero, Paula; Shah, N.; et al.
    Revista: LEUKEMIA RESEARCH
    ISSN: 0145-2126 Vol.129 2023 págs. 107074
    Resumen
    Objective: To understand the long-term experience of patients receiving ide-cel chimeric antigen receptor T (CAR T) cell therapy for relapsed or refractory multiple myeloma in the pivotal phase 2 KarMMa trial.Methods: This qualitative study analyzed semi-structured patient interviews 6-24 months after ide-cel infusion. Thematic analysis with quantitative and longitudinal analyses explored patient perceptions of ide-cel treatment experience, advantages and disadvantages, and long-term health-related quality of life impact. Patient journeys were developed from narrative analysis of perceived treatment benefits with known remission length.Results: Interviews with 45 patients 6-24 months postinfusion were analyzed; all reported >= 1 ide-cel treatment advantage, most often related to efficacy (n = 42/45, 93%), few or no side effects (n = 35/45, 78%), and avoidance of other treatments (n = 34/45, 76%). Patients generally reported 6-month improvements in physical health, functioning, emotional well-being, social life, and outlook on the future; these improvements mostly remained stable through 18 and 24 months. The most common patient journeys comprised physical, func-tioning, or emotional benefit with remission < 2 years.Conclusions: Longitudinal analysis of patient experiences showed sustained benefits and preference for ide-cel up to 24 months after treatment.Trial Registration Number and Date: NCT03361748. December 5, 2017.
  • Autores: Treona, S. P. (Autor de correspondencia); Tedeschi, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: SEMINARS IN HEMATOLOGY
    ISSN: 0037-1963 Vol.60 N° 2 2023 págs. 97 - 106
    Resumen
    Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.
  • Autores: Burgos Rodríguez, Leire; Tamariz Amador, Luis Esteban; Puig, N.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023 págs. 3019 - 3031
    Resumen
    PURPOSEThe existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated.PATIENTS AND METHODSAn algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis.RESULTSPatients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival.CONCLUSIONWe developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.
  • Autores: Schjesvold, F. (Autor de correspondencia); Paiva, Bruno; Ribrag, V.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° 1 2023 págs. e59 - e70
    Resumen
    This phase IB/II trial evaluated safety and efficacy of cobimetinib alone and in novel combinations with veneto-clax with/without atezolizumab in patients with relapsed/refractory multiple myeloma. Forty-nine patients were enrolled. Cobimetinib alone and in combination with venetoclax with/without atezolizumab was determined to be safe and tolerable; anti-tumor activity was moderate overall but higher in patients with translocation t(11;14). Introduction: Mitogen-activated protein kinase pathway mutations are present in > 50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combi-nation with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with veneto-clax (ven) with/without atezolizumab (atezo) in patients with R/R MM. Patients and Methods: Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1-21 (n = 6), cobi 40 mg/day on days 1-21 + ven 800 mg/day on days 1-28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels. Results: Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade >= 3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14) + . Biomarker analysis demon-strated non-t(11;14) patient selection with NRAS /KRAS /BRAF mutation or high BCL-2/BCL-2-L1 ratio ( > 52% of the study population) could enrich for responders to the cobi-ven combination. Conclusions: Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14) + MM, supporting a biomar ker-dr iven approach for ven in MM.
  • Autores: Jelinek, T.; Bezdekova, R.; Zihala, D.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 7 2023 págs. 1383 - 1392
    Resumen
    PURPOSEPrimary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by >= 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to >= 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels.METHODSWe assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis.RESULTSNewly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs.CONCLUSIONOur study uncovers that >= 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.
  • Autores: Paiva, Bruno (Autor de correspondencia); Manrique Sáenz de Tejada, Irene; Dimopoulos, M. A.; et al.
    Revista: BLOOD
    ISSN: 1528-0020 Vol.141 N° 6 2023 págs. 579 - 591
    Resumen
    Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized, placebo-controlled, phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS]: 38.6 vs 15.6 months in MRD- vs MRD+ patients, HR 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD- status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD- status vs those converting from MRD- to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median 18.8 vs 11.6 months, HR 0.65) or at the 14-month landmark (median 16.8 vs 10.6 months, HR 0.65); no difference was observed in patients who were MRD-. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single timepoint MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant endpoint during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status.
  • Autores: Paiva, Bruno; Manrique Sáenz de Tejada, Irene; Rytlewski, J.; et al.
    Revista: BLOOD CANCER DISCOVERY
    ISSN: 2643-3230 Vol.4 N° 5 2023 págs. 365 - 373
    Resumen
    The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus 10-6 logarithmic range and reappearance of normal plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality.SIGNIFICANCE: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion.
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Oriol, A.; Nahi, H.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 8 2023 págs. 1590 - 1599
    Resumen
    Purpose: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS). Methods: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ¿ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression. Results: Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ¿ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (¿ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%). Conclusion: D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).
  • Autores: Schinke, C. D.; Touzeau, C.; Minnema, M. C.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023 págs. 82 - 83
  • Autores: Usmani, S. Z.; Karlin, L.; Benboubker, L.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° Supl. 1 2023 págs. S477
  • Autores: Dholaria, B.; Weisel, K.; Mateos, M. V.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° Supl. 1 2023 págs. S476 - S477
  • Autores: Patel, K.; Rodríguez Otero, Paula; Manier, S.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° Supl. 1 2023 págs. S497 - S498
  • Autores: Lonial, S.; Quach, H.; Dimopoulos, M. A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023
  • Autores: Rodríguez Otero, Paula; Schinke, C.; Chari, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° Supl. 1 2023 págs. S480
  • Autores: Dhakal, B.; Yong, K.; Harrison, S. J.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 17 2023 págs. 81 - 82
  • Autores: Delforge, M.; Patel, K. K.; Eliason, L.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023
  • Autores: Cohen, Y. C.; Morillo, D.; Gatt, M. E.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023
  • Autores: Cohen, Y.; Morillo, D.; Gatt, M.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° Supl. 1 2023 págs. S478 - S479
  • Autores: Usmani, S. Z.; Mielnik, M.; Byun, J. M.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023
  • Autores: Quach, H.; Bahlis, N. J.; Rodríguez Otero, Paula; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023
  • Autores: Bahlis, N. J.; Quach, H.; Weisel, K.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 16 2023
  • Autores: Mohty, M.; Tomasson, M. H.; Arnulf, B.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.23 N° Supl. 1 2023 págs. S493 - S494
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); San Miguel Izquierdo, Jesús
    Revista: HEMATOLOGY
    ISSN: 1520-4391 Vol.2022 N° 1 2022 págs. 180 - 189
    Resumen
    Despite sig nifi cant improve ment in the treat ment of mul ti ple mye loma (MM), a cure remains elu sive, and patients fail-ing proteasome inhib i tors, immu no mod u la tory drugs, and anti - CD38 mono clo nal antibodies remain a chal lenge due to a lack of stan dard of care treat ment and a dis mal sur vival rate. The devel op ment of T -cell redirecting ther a pies, includ-ing bispecific T -cell engagers and chi me ric anti gen recep tor (CAR) T cells, have transformed the out come of tri ple - class exposed relapsed and refrac tory MM (RRMM). B -cell mat u ra tion anti gen (BCMA) has proven to be an impor tant tar get in MM, and BCMA -directed CAR T cells have shown unprec e dented effi cacy with a prolonged dura tion of response in a pop u la tion with advanced RRMM, lead ing to the approval of 2 dif fer ent BCMA CAR T -cell prod ucts. Still, and in con trast to prior expe ri ence in the field of CD19 - directed CARs, no pla teau has been seen in the sur vival curves, and relapses con tinue to occur. Therefore, fur ther improve ment is needed. Early use in the course of the dis ease as well as of next -generation CARs may further augment the efficacy of these therapies. In this review we address current state-of-the-art approved BCMA -directed CAR T -cell ther apy in RRMM, as well as poten tial future devel op ments focused on opti miz ing patient care and novel CAR designs.
  • Autores: Facón, T.; San Miguel Izquierdo, Jesús; Dimopoulos, M. A.; et al.
    Revista: ADVANCES IN THERAPY
    ISSN: 0741-238X Vol.39 N° 5 2022 págs. 1976 - 1992
    Resumen
    Introduction Many treatment regimens have been evaluated in transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). The objective of this study was to compare the efficacy of relevant therapies for the treatment of TIE patients with NDMM. Methods Progression-free survival (PFS) and overall survival (OS) from large randomised controlled trials (RCTs) evaluating different treatment options for TIE patients with NDMM were compared in a network meta-analysis (NMA). The NMA includes recent primary and long-term OS readouts from SWOG S0777, ENDURANCE, MAIA, and ALCYONE. Relevant trials were identified through a systematic literature review. Relative efficacy measures (i.e., hazard ratios [HRs] for PFS and OS) were extracted and synthesised in random-effects NMAs. Results A total of 122 publications describing 45 unique RCTs was identified. Continuous lenalidomide/dexamethasone (Rd) was selected as the referent comparator. Daratumumab-containing treatments (daratumumab/lenalidomide/dexamethasone [D-Rd], daratumumab/bortezomib/melphalan/prednisone [D-VMP]) and bortezomib/lenalidomide/dexamethasone (VRd) had the highest probabilities of being more effective than Rd continuous for PFS (HR: D-Rd, 0.53; D-VMP, 0.57, VRd, 0.77) and OS (HR: D-Rd, 0.68; VRd, 0.77, D-VMP, 0.78). D-Rd had the highest chance of being ranked as the most effective treatment with respect to PFS and OS. Results using a smaller network focusing on only those regimens that are relevant in Europe were consistent with the primary analysis. Conclusions These comparative effectiveness data may help inform treatment selection in TIE patients with NDMM.
  • Autores: Raje, N. S. (Autor de correspondencia); Anaissie, E.; Kumar, S. K.; et al.
    Revista: THE LANCET. HAEMATOLOGY
    ISSN: 2352-3026 Vol.9 N° 2 2022 págs. E143 - E161
    Resumen
    Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.
  • Autores: Ríos-Tamayo, R. (Autor de correspondencia); Paiva, Bruno; Lahuerta, J. J.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 21 2022 págs. 5247
    Resumen
    Simple Summary Monoclonal gammopathy of clinical significance (MGCS) refers to a recently coined term describing a complex and heterogeneous group of nonmalignant monoclonal gammopathies. These patients are characterized by the presence of a commonly small clone and the occurrence of symptoms that may be associated with the clone or with the monoclonal protein through diverse mechanisms. This is an evolving, challenging, and rapidly changing field. Patients are classified according to the key organ or system involved, with kidneys, skin, nerves, and eyes being the most frequently affected. However, multiorgan involvement may be the most relevant clinical feature at the presentation or during the course. This review delves into the definition, history, differential diagnosis, classification, prognosis, and treatment of this group of entities by analyzing the evidence accumulated to date from a critical perspective. Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult to approach from a practical clinical perspective. Several points should be addressed in order to move further toward a better understanding. Overall, these entities are only partially included in the international classifications of diseases. Its definition and classification remain ambiguous. Remarkably, its real incidence is unknown, provided that a diagnostic biopsy is mandatory in most cases. In fact, amyloidosis AL is the final diagnosis in a large percentage of patients with renal significance. On the other hand, many of these young entities are syndromes that are based on a dynamic set of diagnostic criteria, challenging a timely diagnosis. Moreover, a specific risk score for progression is lacking. Despite the key role of the clinical laboratory in the diagnosis and prognosis of these patients, information about laboratory biomarkers is limited. Besides, the evidence accumulated for many of these entities is scarce. Hence, national and international registries are stimulated. In particular, IgM MGCS deserves special attention. Until now, therapy is far from being standardized, and it should be planned on a risk and patient-adapted basis. Finally, a comprehensive and coordinated multidisciplinary approach is needed, and specific clinical trials are encouraged.
  • Autores: Ocio, E. M. (Autor de correspondencia); Perrot, A.; Bories, P.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 N° 6 2022 págs. 425
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Moreau, P.; Terpos, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 9 2022 págs. 988
  • Autores: Facon, T.; San Miguel Izquierdo, Jesús; Dimopoulos, M. A.; et al.
    Revista: ADVANCES IN THERAPY
    ISSN: 0741-238X Vol.39 N° 8 2022 págs. 3868 - 3869
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Moreau, P.; Terpos, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 1 2022 págs. 117
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); San Miguel Izquierdo, Jesús
    Revista: THE LANCET. HAEMATOLOGY
    ISSN: 2352-3026 Vol.9 N° 11 2022 págs. E799 - E801
  • Autores: Richardson, P. G. (Autor de correspondencia); Schjesvold, F.; Weisel, K.; et al.
    Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
    ISSN: 0902-4441 Vol.108 N° 1 2022 págs. 73 - 83
    Resumen
    Objective We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse. Methods OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS). Results Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged <= 65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports. Conclusions These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.
  • Autores: Rodríguez Díaz, Saray; Celay Leoz, Ion; Goicoechea Oroz, Ibai; et al.
    Revista: SCIENCE ADVANCES
    ISSN: 2375-2548 Vol.8 N° 3 2022 págs. eabl4644
    Resumen
    Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
  • Autores: Tamariz Amador, Luis Esteban (Autor de correspondencia); Rodríguez Otero, Paula (Autor de correspondencia); Jiménez-Ubieto, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2669 Vol.22 N° 9 2022 págs. e844 - e852
    Resumen
    Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a ¿resistance¿ parameter that reflects the stagnation in the response after an initial descent. Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P =.02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P =.02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P <.002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies.
  • Autores: Mateos, M. V. (Autor de correspondencia); Hernández, M. T.; Salvador, C.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.174 2022 págs. 243 - 250
    Resumen
    SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary endpoint was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363). Findings: After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18 -0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96). Interpretation: This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS. Funding: Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain.
  • Autores: Puig, N.; Contreras, M. T.; Agullo, C.; et al.
    Revista: BLOOD ADVANCES
    ISSN: 2473-9529 Vol.6 N° 11 2022 págs. 3234 - 3239
    Resumen
    Monitoring of the monoclonal protein (M-protein) by electrophoresis and/or immunofixation (IFE) has long been used to assess treatment response in multiple myeloma (MM). However, with the use of highly effective therapies, the M-protein becomes frequently undetectable, and more sensitive methods had to be explored. We applied IFE and mass spectrometry (EXENT&FLC-MS) in serum samples from newly diagnosed MM patients enrolled in the PETHEMA/GEM2012MENOS65 obtained at baseline (n = 223), and after induction (n = 183), autologous stem cell transplantation (n = 173), and consolidation (n = 173). At baseline, the isotypes identified with both methods fully matched in 82.1% of samples; in the rest but 2 cases, EXENT&FLC-MS provided additional information to IFE with regards to the M-protein(s). Overall, the results of EXENT&FLC-MS and IFE were concordant in >80% of cases, being most discordances due to EXENT&FLC-MS+ but IFE- cases. After consolidation, IFE was not able to discriminate 2 cohorts with different median progression-free survival (PFS), but EXENT&FLC-MS did so; furthermore, among IFE- patients, EXENT&FLC-MS identified 2 groups with significantly different median PFS (P = .0008). In conclusion, compared with IFE, EXENT&FLC-MS is more sensitive to detect the M-protein of patients with MM, both at baseline and during treatment, and provides a more accurate prediction of patients' outcome. This trial was registered at www.clinicaltrials.gov as #NCT01916252.
  • Autores: Richardson, P. G. (Autor de correspondencia); Perrot, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.23 N° 3 2022 págs. 416 - 427
    Resumen
    Background: The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis. Methods: In this randomised, multicentre, open-label, phase 3 study adult patients (aged ¿18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (<75 vs ¿75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ¿75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting. Findings: Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection). Interpretation: Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing. Funding: Sanofi.
  • Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Avet-Loiseau, H.; Paiva, Bruno; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.139 N° 4 2022 págs. 492 - 501
    Resumen
    In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/ lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/ melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10(-5)) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting >= 6 and >= 12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting >= 6 and >= 12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting >= 6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and >= 12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes.
  • Autores: Rosa-Rosa, J. M. (Autor de correspondencia); Cuenca, I.; Medina, A.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 20 2022 págs. 5169
    Resumen
    Simple Summary Multiple Myeloma (MM) is considered an incurable chronic disease, which prognosis depends on the presence of different genomic alterations. To accomplish a complete molecular diagnosis in a single essay, we have designed and validated a capture-based NGS approach to reliably identify pathogenic mutations (SNVs and indels), genomic alterations (CNVs and chromosomic translocations), and IGH rearrangements. We have observed a good correlation of the results obtained using our capture panel with data obtained by both FISH and WES techniques. In this study, the molecular classification performed using our approach was significantly associated with the stratification and outcome of MM patients. Additionally, this panel has been proven to detect specific IGH rearrangements that could be used as biomarkers in patient follow-ups through minimal residual disease (MRD) assays. In conclusion, we think that MM patients could benefit from the use of this capture-based NGS approach with a more accurate, single-essay molecular diagnosis. Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival (p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes (p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients.
  • Autores: Dhakal, B.; Shah, N.; Kansagra, A.; et al.
    Revista: TRANSPLANTATION AND CELLULAR THERAPY
    ISSN: 2666-6375 Vol.28 N° 6 2022 págs. 284 - 293
    Resumen
    Over the past decade, therapeutic options in multiple myeloma (MM) have changed dramatically. Given the unprecedented efficacy of novel agents, the role of hematopoietic cell transplantation (HCT) in MM remains under scrutiny. Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape. The American Society for Transplantation and Cellular Therapy convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of autologous (auto-HCT), allogeneic (allo-HCT) and CAR T-cell therapy for patients with newly diag-nosed (NDMM) and relapsed/refractory MM (RRMM). The RAND-modified Delphi method was used to generate consensus statements. Twenty consensus statements were generated. The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial. For patients not undergoing auto-HCT upfront, the panel recommended its use in first relapse. Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients. In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy. The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial. The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.
  • Autores: Cavo, M. (Autor de correspondencia); San Miguel Izquierdo, Jesús; Usmani, S. Z.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.139 N° 6 2022 págs. 835 - 844
    Resumen
    We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (>= CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10(-5) sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received <= 2 prior lines of therapy (<= 2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved >= CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM <= 2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that >= CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching >= CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support >= CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM.
  • Autores: Chari, A. (Autor de correspondencia); Minnema, M.C.; Berdeja, J.G.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.387 N° 24 2022 págs. 2232 - 2244
    Resumen
    BACKGROUND G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells. METHODS In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 mu g per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 mu g per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study. RESULTS At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 mu g per kilogram weekly [30 patients] and 800 mu g per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-mu g dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-mu g dose level) and 4.2 months (in those who had received it at the 800-mu g dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively. CONCLUSIONS Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, .)
  • Autores: Garcés Latre, Juan José; Cedena, M. T.; Puig, N.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 27 2022 págs. 3151 - 3161
    Resumen
    PURPOSE Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined. PATIENTS AND METHODS CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment. RESULTS CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS. CONCLUSION Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of >= 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.
  • Autores: Delforge, M. (Autor de correspondencia); Shah, N. (Autor de correspondencia); San Miguel Izquierdo, Jesús; et al.
    Revista: BLOOD ADVANCES
    ISSN: 2473-9529 Vol.6 N° 4 2022 págs. 1309 - 1318
    Resumen
    Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, showed deep, durable responses in patients with triple-class exposed, relapsed and refractory multiple myeloma (RRMM) in the phase 2 KarMMa (Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma) trial. We assessed health-related quality of life (HRQoL) among KarMMa patients. The European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument, were administered at screening, baseline (<= 72 hours before or same day as lymphodepletion), day of ide-cel treatment, and after ide-cel treatment. Mean changes from baseline that exceeded the predetermined threshold of minimally important difference were deemed clinically meaningful. The proportions of patients experiencing clinically meaningful changes in HRQoL were assessed using within-patient change thresholds. Time to stable improvement (<= consecutive visits with clinically meaningful HRQoL improvements) was analyzed by using the Kaplan-Meier method. A total of 126 (98%) of 128 patients treated with ide-cel were included in the HRQoL analysis. Pretreatment baseline RRMM burden was high and meaningfully worse than that in the age- and sex-weighted general population. Statistically significant and clinically meaningful improvements from baseline were observed by month 1 for pain (-8.9) and disease symptoms (-10.2), and by month 2 for fatigue (-7.2), physical functioning (6.1), cognitive functioning (6.7), and global health status/QoL (8.0). Clinically meaningful improvements in fatigue, pain, and physical functioning were most prominent at months 9, 12, and 18, respectively, and were sustained through 15 to 18 months after ide-cel treatment. For triple-class exposed patients with RRMM with a poor prognosis and few treatment options, a single ide-cel infusion provides early, sustained, statistically significant, and clinically meaningful improvements in HRQoL.
  • Autores: Garcés Latre, Juan José (Autor de correspondencia); San Miguel Izquierdo, Jesús; Paiva, Bruno (Autor de correspondencia)
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 6 2022 págs. 1430
    Resumen
    Simple Summary Bone marrow (BM) aspirates are mandatory for diagnosis and follow-up of patients with multiple myeloma (MM). However, they present two important caveats: Their invasiveness and limited scope to capture the broad tumor heterogeneity. Conversely, circulating tumor cells (CTCs) are detectable in the peripheral blood of patients with precursor and malignant disease states and have strong prognostic value. Moreover, the high genetic and transcriptomic overlap between both plasma cell compartments suggests that CTCs might reflect with notable precision the medullar clone. Furthermore, the study of CTCs could be used as a model to identify mechanisms favoring BM egression and disease spreading. Here, we summarize the state of the art on MM CTCs and provide insights on what they may offer in research and clinical scenarios. Bone marrow (BM) aspirates are the gold standard for patient prognostication and genetic characterization in multiple myeloma (MM). However, they represent an important limitation for periodic disease monitoring because they entail an aggressive procedure. Moreover, recent findings show that a single BM aspirate is unable to reflect the complex MM heterogeneity. Recent advances in flow cytometry, microfluidics, and "omics" technologies have opened Pandora's box of MM: The detection and isolation of circulating tumor cells (CTCs) offer a promising and minimally invasive alternative for tumor assessment and metastasis study. CTCs are detectable in premalignant and active MM states, and their enumeration has strong prognostic value, to the extent that it is challenging current stratification systems. In addition, CTCs reflect with high precision both intra- and extra-medullary disease at the phenotypic, genomic, and transcriptomic levels. Despite this high resemblance between tumor clones in distinct locations, some subtle (not random) differences might shed some light on the metastatic process. Thus, it has been suggested that a hypoxic and pro-inflammatory microenvironment could induce an arrest in proliferation forcing tumor cells to recirculate. Herein, we summarize data on the characterization of MM CTCs as well as their clinical and research potential.
  • Autores: Encinas, C.; Hernández-Rivas, J. A.; Oriol, A.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.12 N° 4 2022 págs. 68
    Resumen
    Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin <= 30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0-2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies.
  • Autores: Nevone, A.; Girelli, M.; Mangiacavalli, S.; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.36 N° 8 2022 págs. 2076 - 2085
    Resumen
    Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal kappa LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic kappa LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.
  • Autores: Böttcher, S. (Autor de correspondencia); Engelmann, R.; Grigore, G.; et al.
    Revista: BLOOD ADVANCES
    ISSN: 2473-9529 Vol.6 N° 3 2022 págs. 976 - 992
    Resumen
    Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing 9 disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis, we subsequently used canonical correlation analysis of 176 training cases to project the multidimensional space of all 26 immunophenotypic parameters into 36 2-dimensional plots for each possible pairwise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%), and mantle cell lymphoma (95.4%). Burkitt and CD101 diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD102 diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms.
  • Autores: Larocca, A.; Leleu, X.; Touzeau, C.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN: 0007-1048 Vol.196 N° 3 2022 págs. 639 - 648
    Resumen
    Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.
  • Autores: Rojas, E. A.; Corchete, L. A.; De Ramon, C.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN: 0361-8609 Vol.97 N° 6 2022 págs. 700 - 710
    Resumen
    Loss and/or mutation of the TP53 gene are associated with short survival in multiple myeloma, but the p53 landscape goes far beyond. At least 12 p53 protein isoforms have been identified as a result of a combination of alternative splicing, alternative promoters and/or alternative transcription site starts, which are grouped as alpha, beta, gamma, from transactivation domain (TA), long, and short isoforms. Nowadays, there are no studies evaluating the expression of p53 isoforms and its clinical relevance in multiple myeloma (MM). We used capillary nanoimmunoassay to quantify the expression of p53 protein isoforms in CD138-purified samples from 156 patients with newly diagnosed MM who were treated as part of the PETHEMA/GEM2012 clinical trial and investigated their prognostic impact. Quantitative real-time polymerase chain reaction was used to corroborate the results at RNA levels. Low and high levels of expression of short and TAp53 beta/gamma isoforms, respectively, were associated with adverse prognosis in MM patients. Multivariate Cox models identified high levels of TAp53 beta/gamma (hazard ratio [HR], 4.49; p < .001) and high-risk cytogenetics (HR, 2.69; p < .001) as independent prognostic factors associated with shorter time to progression. The current cytogenetic-risk classification was notably improved when expression levels of p53 protein isoforms were incorporated, whereby high-risk MM expressing high levels of short isoforms had significantly longer survival than high-risk patients with low levels of these isoforms. This is the first study that demonstrates the prognostic value of p53 isoforms in MM patients, providing new insights on the role of p53 protein dysregulation in MM biology.
  • Autores: Mateos, M. V. (Autor de correspondencia); Weisel, K.; De Stefano, V.; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.36 N° 5 2022 págs. 1371 - 1376
    Resumen
    Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, >= 3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.
  • Autores: Bras, A. E.; Matarraz, S.; Nierkens, S.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 8 2022 págs. 2011
    Resumen
    Simple Summary Flow cytometry allows detailed characterization of large numbers of cells and plays an important role in the diagnosis of acute myeloid leukemia. To facilitate analysis of flowcytometric data, reference databases of normal bone marrow samples and samples from acute myeloid leukemia patients, together with new software tools, are required. We here report on the building of a large database of acute myeloid leukemia patients (n = 1142) and 22 normal samples. We report on the quality assessment procedure used and its validation, discuss potential pitfalls, and provide possible solutions for avoiding such flaws in the construction of other databases. Our data show that obtaining and collecting reproducible flow cytometric data over time and across centers is feasible, but also that strict quality assessment remains crucial, even when standardized protocols for staining and instrument settings are being used in a multicenter setting. Flowcytometric analysis allows for detailed identification and characterization of large numbers of cells in blood, bone marrow, and other body fluids and tissue samples and therefore contributes to the diagnostics of hematological malignancies. Novel data analysis tools allow for multidimensional analysis and comparison of patient samples with reference databases of normal, reactive, and/or leukemia/lymphoma patient samples. Building such reference databases requires strict quality assessment (QA) procedures. Here, we compiled a datase
  • Autores: de Leval, L. (Autor de correspondencia); Alizadeh, A. A.; Bergsagel, P. L.; et al.
    Revista: BLOOD
    ISSN: 1528-0020 Vol.140 N° 21 2022 págs. 2193 - 2227
    Resumen
    With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. While the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses and epigenetic profiling will be discussed, as these will likely become important future tools for implementing precision medicine approaches in clinical decision-making for patients with lymphoid malignancies.
  • Autores: D'Agostino, M. (Autor de correspondencia); Cairns, D. A.; Lahuerta, J. J.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 29 2022 págs. 3406 - 3418
    Resumen
    PURPOSE Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+. PATIENTS AND METHODS The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated. RESULTS In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value. CONCLUSION The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.
  • Autores: Mosquera Orgueira, A.; González Pérez, M. S.; Díaz Arias, J.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.12 N° 4 2022 págs. 76
    Resumen
    The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification.
  • Autores: Guerrero De Blois, Camila; Puig, N.; Cedena, M. T.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.28 N° 12 2022 págs. 2598 - 2609
    Resumen
    Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treat-ment individualization based on the probability of a patient achiev-ing undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma. Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 trans-plant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Espanol de Mieloma (GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial. Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predic -ti ons of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years main-tenance (GEM2014MAIN). High-confidence prediction of unde-tectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years. Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma.
  • Autores: Morales Lozano, María Isabel; Rodríguez Otero, Paula; Sancho Rodriguez, Lidia; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 17 2022 págs. 9895
    Resumen
    Multiple myeloma (MM) is the second most common haematological malignancy and remains incurable despite therapeutic advances. 18F-FDG (FDG) PET/CT is a relevant tool MM for staging and it is the reference imaging technique for treatment evaluation. However, it has limitations, and investigation of other PET tracers is required. Preliminary results with L-methyl-[11C]- methionine (MET), suggest higher sensitivity than 18F-FDG. This study aimed to compare the diagnostic accuracy and prognostic value of 1FDG and MET in MM patients. We prospectively compared FDG and MET PET/CT for assessment of bone disease and extramedullary disease (EMD) in a series of 52 consecutive patients (8 smoldering MM, 18 newly diagnosed MM and 26 relapsed MM patients). Bone marrow (BM) uptake patterns and the detection of focal lesions (FLs) and EMD were compared. Furthermore, FDG PET parameters with known MM prognostic value were explored for both tracers, as well as total lesion MET uptake (TLMU). Median patient age was 61 years (range, 37-83 years), 54% were male, 13% of them were in stage ISS (International Staging System) III, and 31% had high-risk cytogenetics. FDG PET/CT did not detect active disease in 6 patients, while they were shown to be positive by MET PET/CT. Additionally, MET PET/CT identified a higher number of FLs than FDG in more than half of the patients (63%). For prognostication we focussed on the relapsed cohort, due to the low number of progressions in the two other cohorts. Upon using FDG PET/CT in relapsed patients, the presence of more than 3 FLs (HR 4.61, p = 0.056), more than 10 FLs (HR 5.65, p = 0.013), total metabolic tumor volume (TMTV) p50 (HR 4.91, p = 0.049) or TMTV p75 (HR 5.32, p = 0.016) were associated with adverse prognosis. In MET PET/CT analysis, TMTV p50 (HR 4.71, p = 0.056), TMTV p75 (HR 6.27, p = 0.007), TLMU p50 (HR 8.8, p = 0.04) and TLMU p75 (HR 6.3, p = 0.007) adversely affected PFS. This study confirmed the diagnostic and prognostic value of FDG in MM. In addition, it highlights that MET has higher sensitivity than FDG PET/CT for detection of myeloma lesions, including FLs. Moreover, we show, for the first time, the prognostic value of TMTV and TLMU MET PET/CT in the imaging evaluation of MM patients.
  • Autores: Shah, N. (Autor de correspondencia); Delforge, M.; San Miguel Izquierdo, Jesús; et al.
    Revista: LEUKEMIA RESEARCH
    ISSN: 0145-2126 Vol.120 2022 págs. 106921
    Resumen
    Objective: To understand the experience of patients with relapsed and refractory multiple myeloma (RRMM) receiving idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in the pivotal, phase 2 KarMMa trial. Methods: Optional semi-structured interviews before leukapheresis (pre-treatment) captured expectations and after ide-cel infusion (1, 2, and 3 months post-treatment), assessed treatment experience, ide-cel advantages/ disadvantages, and health and well-being. In a mixed-method analysis, treatment experiences were categorized by clinical response status, health and well-being, and self-reported recovery after infusion.Results: Pre-treatment interviews indicated unmet treatment needs. In post-treatment interviews, most patients reported the positives of ide-cel outweighed negatives (69%, n = 27/39). Most common advantages of ide-cel were efficacy (18-64%), favorable side-effect profile (46-68%), and recovery time (13-18%); most common disadvantages were related to side effects (13-20%). When analyzed by clinical response, patients most often had stringent complete or very good partial response and improved health and well-being with mild or severe recovery from the infusion (27/58, 47%). Most patients with minimal clinical response reported mild infusion recovery (5/6, 83%).Conclusions: Patient interviews before ide-cel treatment showed unmet needs in triple-class exposed RRMM. Posttreatment experiences generally favored ide-cel versus previously received treatments.
  • Autores: Buske, C. (Autor de correspondencia); Dreyling, M.; Álvarez-Larrán, A.; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.7 N° 2 2022 págs. 100403
    Resumen
    Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. Results and conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.
  • Autores: Botta, C. (Autor de correspondencia); Da Silva Maia, Catarina Alexandra; Garcés Latre, Juan José; et al.
    Revista: BLOOD ADVANCES
    ISSN: 2473-9529 Vol.6 N° 2 2022 págs. 690 - 703
    Resumen
    Large-scale immune monitoring is becoming routinely used in clinical trials to identify determinants of treatment responsiveness, particularly to immunotherapies. Flow cytometry remains one of the most versatile and high throughput approaches for single cell analysis; however, manual interpretation of multidimensional data poses a challenge when attempting to capture full cellular diversity and provide reproducible results. We present FlowCT, a semi-automated workspace empowered to analyze large data sets. It includes pre-processing, normalization, multiple dimensionality reduction techniques, automated clustering, and predictive modeling tools. As a proof of concept, we used FlowCT to compare the T-cell compartment in bone marrow (BM) with peripheral blood (PB) from patients with smoldering multiple myeloma (SMM), identify minimally invasive immune biomarkers of progression from smoldering to active MM, define prognostic T-cell subsets in the BM of patients with active MM after treatment intensification, and assess the longitudinal effect of maintenance therapy in BM T cells. A total of 354 samples were analyzed and immune signatures predictive of malignant transformation were identified in 150 patients with SMM (hazard ratio [HR], 1.7; P < .001). We also determined progression-free survival (HR, 4.09; P < .0001) and overall survival (HR, 3.12; P 5 .047) in 100 patients with active MM. New data also emerged about stem cell memory T cells, the concordance between immune profiles in BM and PB, and the immunomodulatory effect of maintenance therapy. FlowCT is a new open-source computational approach that can be readily implemented by research laboratories to perform quality control, analyze high-dimensional data, unveil cellular diversity, and objectively identify biomarkers in large immune monitoring studies. These trials were registered at www. clinicaltrials.gov as #NCT01916252 and #NCT02406144.
  • Autores: Campo, E. (Autor de correspondencia); Jaffe, E. S. (Autor de correspondencia); Cook, J. R.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° 11 2022 págs. 1229 - 1253
    Resumen
    Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.
  • Autores: Paiva, Bruno; San Miguel Izquierdo, Jesús; Avet-Loiseau, H. (Autor de correspondencia)
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° 23 2022 págs. 2423 - 2428
    Resumen
    Multiple myeloma embodies the paradigm of the deepest the response the longer the survival. However, there are conflicting results between the achievement of complete remission and MRD negativity, because some patients with persistent M-protein have nonetheless undetectable MRD. We reviewed the frequency of this discordancy and the outcome of these patients. We spotlighted possible explanations and consequences of conflicting response criteria, and suggest that MRD should be assessed in patients achieving very good partial response or better in clinical trials.
  • Autores: Weisel, K. (Autor de correspondencia); Ottosson Wadlund, A.; Gungor, G.; et al.
    Revista: EUROPEAN JOURNAL OF HAEMATOLOGY
    ISSN: 0902-4441 Vol.109 N° 4 2022 págs. 388 - 397
    Resumen
    Objectives This non-interventional observational study described the current standard-of-care for transplant-eligible newly diagnosed multiple myeloma (TE-NDMM) patients in France, Germany, Spain, and Italy, and recorded the evolution in regimen adoption in distinct elements of frontline treatment during 2017-2020/2021. Methods Clinical information on ongoing (I) or previous (II) TE-NDMM patients was extracted from the Cancerology database. Proportions of patients receiving regimens in each element and the evolution in regimen adoption were determined for the entire population and each country. Results Most common induction regimens among I patients were VRd in France (75.3%) and Spain (44.1%), VTd in Italy (65.2%), and regimens other than VRd/VTd/VCd in Germany. Maintenance was ongoing/planned for 78.3%, 62.3%, 65.2%, and 61.4% patients in France, Germany, Spain, and Italy, respectively. Among II patients, VRd induction increased from 27.0% in 2017 to 65.7% in 2019 in France, remained relatively low in Spain and Germany, and not present in Italy. In Italy and Spain, VTd induction declined from 72.4% and 58.3% in 2017 to 52.8% and 17.3% in 2019, respectively. VCd induction in Germany declined from 85.2% in 2017 to 64.1% in 2019. Conclusion The use of bortezomib triplets in induction varied markedly over time and between selected countries.
  • Autores: Davies, F. E. (Autor de correspondencia); Pawlyn, C.; Usmani, S. Z.; et al.
    Revista: BLOOD CANCER DISCOVERY
    ISSN: 2643-3230 Vol.3 N° 4 2022 págs. 273 - 284
    Resumen
    The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continu-ing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.
  • Autores: Moreau, P. (Autor de correspondencia); Garfall, A. L.; van de Donk, N. W. C. J.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.387 N° 6 2022 págs. 495 - 505
    Resumen
    BACKGROUND Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS Among 165 patients who received teclistamab, 77.8% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2.
  • Autores: Botta, C. (Autor de correspondencia); Gigliotta, E.; Paiva, Bruno; et al.
    Revista: HEMATOLOGICAL ONCOLOGY
    ISSN: 0278-0232 Vol.40 N° 5 2022 págs. 987 - 998
    Resumen
    The treatment scenario for newly-diagnosed transplant-ineligible multiple myeloma patients (NEMM) is quickly evolving. Currently, combinations of proteasome inhibitors and/or immunomodulatory drugs +/- the monoclonal antibody Daratumumab are used for first-line treatment, even if head-to-head comparisons are lacking. To compare efficacy and safety of these regimens, we performed a network meta-analysis of 27 phase 2/3 randomized trials including a total of 12,935 patients and 23 different schedules. Four efficacy/outcome and one safety indicators were extracted and integrated to obtain (for each treatment) the surface under the cumulative ranking-curve (SUCRA), a metric used to build a ranking chart. With a mean SUCRA of 83.8 and 80.08 respectively, VMP + Daratumumab (DrVMP) and Rd + Daratumumab (DrRd) reached the top of the chart. However, SUCRA is designed to work for single outcomes. To overcome this limitation, we undertook a dimensionality reduction approach through a principal component analysis, that unbiasedly grouped the 23 regimens into three different subgroups. On the bases of our results, we demonstrated that first line treatment for NEMM should be based on DrRd (most active, but continuous treatment), DrVMP (quite fixed-time treatment), or, alternatively, VRD and that, surprisingly, melphalan as well as Rd doublets still deserve a role in this setting.
  • Autores: Nadeem, O.; Mateos, M. V.; Efebera, Y. A.; et al.
    Revista: DRUGS OF TODAY
    ISSN: 1699-3993 Vol.58 N° 8 2022 págs. 407 - 423
    Resumen
    Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with relapsed/refractory MM (RRMM), especially those with triple-class-refractory disease or poor-prognostic features, have substantially unmet needs for new therapies with novel mechanisms of action. Melphalan flufenamide (melflufen) is the first alkylating peptide-drug conjugate that targets aminopeptidases to show efficacy and manageable safety, in combination with dexamethasone, in patients with RRMM who had received >= 4 prior lines of therapy, including >= 1 immunomodulatory drug, >= 1 proteasome inhibitor and >= 1 anti-CD38 monoclonal antibody, and received accelerated approval by the U.S. Food and Drug Administration (FDA) in early 2021 for use in this patient population. Initial analyses of the phase III OCEAN study data led to melflufen being voluntarily withdrawn from the U.S. market in late 2021, but subsequent analyses have prompted the manufacturer to rescind its voluntary withdrawal to allow further discussions with the U.S. FDA and the regulatory review with the European Medicines Agency (EMA) is also ongoing. Here, we provide a review of the novel mechanism of action and pharmacokinetics of melflufen, as well as key efficacy and safety from clinical studies that supported its initial approval, and discuss the nuances of the OCEAN study data. Melflufen demonstrates the potential of novel peptide-drug conjugates to positively impact the treatment landscape in RRMM.
  • Autores: Richardson, P.; Perrot, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S32
  • Autores: Nooka, A. K.; Moreau, P.; Usmani, S. Z.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Ludwig, H.; Melchardt, T.; Sormann, S.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 10185 - 10188
  • Autores: Eckmann, J.; Fauti, T.; Zabaleta Azpiroz, Aintzane; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 2091 - 2092
  • Autores: Puig, N.; Agullo, C.; Contreras Sanfeliciano, T.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 2098 - 2100
  • Autores: Popat, R.; Usmani, S. Z.; Garfall, A.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN: 0007-1048 Vol.197 N° Supl. 1 2022 págs. 35 - 36
  • Autores: Munshi, N. C.; Paiva, Bruno; Martin, T.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4652 - 4654
  • Autores: Moreau, P.; Usmani, S.; van de Donk, N. W. C. J.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S181 - S182
  • Autores: Mateos, M. V.; Rodríguez Otero, Paula; Koh, Y.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 7317 - 7319
  • Autores: Zamagni, E.; Ottosson, A.; Gungor, G.; et al.
    Revista: VALUE IN HEALTH
    ISSN: 1098-3015 Vol.25 N° 12 (Supplement) 2022 págs. S209 - S209
  • Autores: Paiva, Bruno; Manrique, I.; Dimopoulos, M. A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S63 - S64
  • Autores: Paiva, Bruno; Manrique Sáenz de Tejada, Irene; Rytlewski, J.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S7 - S8
  • Autores: Usmani, S.; Patel, K.; Hari, P.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022
  • Autores: San Miguel Izquierdo, Jesús; Mateos, M. V.; Cohen, Y. C.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S35 - S36
  • Autores: Notarfranchi, L.; Zherniakova, Anastasiia; Lasa Ventura, Marta; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 2095 - 2097
  • Autores: Bahlis, N. J.; Usmani, S. Z.; Rosinol, L.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Martin, T. G.; Moreau, P.; Usmani, S. Z.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Guerrero De Blois, Camila; Puig, N.; Cedena Romero, M. T.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° SUPLLE 1 2022
  • Autores: Ahlis, N. J.; Tomasson, M. H.; Mohty, M.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022
  • Autores: Waesch, R.; Rodríguez Otero, Paula; D'Souza, A.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 248 - 249
  • Autores: Lakhwani, S.; Mateos, M. V.; Martínez-López, J.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 2344 - 2346
  • Autores: Tahri, S.; Su, N. K.; Lampe, L.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S47 - S48
  • Autores: Moreau, P.; Usmani, S. Z.; van de Donk, N. W. C. J.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Chari, A.; Touzeau, C.; Schinke, C.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022
  • Autores: Raab, M. S.; Dimopoulos, M.; Dytfeld, D.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 87 - 87
  • Autores: Gonzalez-Calle,V.; Rodríguez Otero, Paula; Rey-Bua, B.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 7286 - 7288
  • Autores: Lahuerta Palacios, J. J.; Jiménez Ubieto, A.; Rosinol, L.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S24 - S25
  • Autores: Mateos, M. V.; Richardson, P.; Weisel, K.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S179 - S180
  • Autores: Richardson, P. G.; Perrot, A.; San Miguel Izquierdo, Jesús; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022
  • Autores: Puertas, B.; González, V.; Sureda, A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S30 - S31
  • Autores: Mateos, M. V.; Martínez-López, J.; Rodríguez Otero, Paula; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022
  • Autores: Wong, S. W.; Bar, N.; Paris, L.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022
  • Autores: Minnema, M. C.; Krishnan, A. Y.; Berdeja, J. G.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Kater, A. P.; Van de Donk, N. W. C. J.; Rodríguez Otero, Paula; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4608 - 4609
  • Autores: Cohen, A. D.; Mateos, M. V.; Cohen, Y. C.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4646 - 4648
  • Autores: Lesokhin, A. M.; Arnulf, B.; Niesvizky, R.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Corsale, A. M.; Azgomi, M. S.; Plano, F.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 9943 - 9944
  • Autores: Mateos, M. V.; San Miguel Izquierdo, Jesús; Cavo, M.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 10157 - 10159
  • Autores: Lesokhin, A. M.; Richter, J.; Trudel, S.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4415 - 4417
  • Autores: Rodríguez Otero, Paula; Joseph, N. S.; Kumar, S. K.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 2022 págs. 4444 - 4446
  • Autores: Paiva, Bruno; Gaffney, B.; Burnett, K.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 7054 - 7055
  • Autores: Cohen, A.; Mateos, M. V.; Cohen, Y.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S26 - S27
  • Autores: Rodríguez Otero, Paula; D'Souza, A.; Reece, D. E.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Einsele, H.; Shah, N.; Munshi, N.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 248 - 248
  • Autores: Weisel, K.; Dimopoulos, M.; Oriol, A.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 283 - 283
  • Autores: Raab, M. S.; Usmani, S. Z.; Mielnik, M.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 145 - 146
  • Autores: Kortuem, K. M.; Bahlis, N.; Mateos, M. V.; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 144 - 145
  • Autores: Da Silva Maia, Catarina Alexandra; Puig, N.; Cedena, M. T. ; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S84 - S85
  • Autores: Boccadoro, M.; San Miguel Izquierdo, Jesús; Suzuki, K.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4630 - 4632
  • Autores: Tahri, S.; Su, N. K.; Lampe, L. M.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4204 - 4206
  • Autores: Trudel, S.; Bahlis, N. J.; Spencer, A.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 1363 - 1365
  • Autores: Touzeau, C.; Chari, A.; Schinke, C.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4447 - 4449
  • Autores: Da Silva Maia, Catarina Alexandra; Puig, N.; Pérez Ruiz, Cristina; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 4200 - 4203
  • Autores: Weisel, K.; Rodríguez Otero, Paula; San Miguel Izquierdo, Jesús; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN: 2296-5270 Vol.45 N° SUPPL 2 2022 págs. 305 - 305
  • Autores: Morales Lozano, María Isabel; Marcos Jubilar, María; Sancho Rodriguez, Lidia; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supplement 1 2022 págs. 7170 - 7171
  • Autores: Paiva, Bruno; Manrique Sáenz de Tejada, Irene; Rytlewski, J. A.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 2104 - 2105
  • Autores: Lakhwani, S.; Rosinol-Dachs, L.; Puig, N.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.140 N° Supl. 1 2022 págs. 2101 - 2103
  • Autores: Lonial, S.; Berdeja, J. G.; Dimopoulos, M. A.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.22 2022 págs. S177 - S178
  • Autores: Terpos, E. (Autor de correspondencia); Zamagni, E.; Lentzsch, S.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 3 2021 págs. e119 - e130
    Resumen
    In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.
  • Autores: Musto, P. (Autor de correspondencia); Engelhardt, M.; Caers, J.; et al.
    Revista: HAEMATOLOGICA
    ISSN: 0390-6078 Vol.106 N° 11 2021 págs. 2799 - 2812
    Resumen
    According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of monoclonal gammopathy of undetermined significance-like, in which patients never progress during their lifetimes, to early multiple myeloma, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a split personality makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide +/- dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.
  • Autores: Ríos-Tamayo, R. (Autor de correspondencia); Puig, N.; Algarín, M.; et al.
    Revista: DIAGNOSTICS
    ISSN: 2075-4418 Vol.11 N° 11 2021 págs. 2020
    Resumen
    Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.
  • Autores: Moreau, P. (Autor de correspondencia); Kumar, S. K.; San Miguel Izquierdo, Jesús; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 3 2021 págs. e105 - e118
    Resumen
    This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
  • Autores: Ludwig, H. (Autor de correspondencia); Sonneveld, P.; Facon, T.; et al.
    Revista: THE LANCET. HAEMATOLOGY
    ISSN: 2352-3026 Vol.8 N° 12 2021 págs. e934 - e946
    Resumen
    Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 vaccination in patients with multiple myeloma was condensed into this Review.
  • Autores: Ludwig, H. (Autor de correspondencia); Boccadoro, M.; Moreau, P.; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.35 N° 1 2021 págs. 31 - 44
    Resumen
    Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice.
  • Autores: Ruiz-Pablos, M. (Autor de correspondencia); Paiva, Bruno; Montero-Mateo, R.; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.12 2021 págs. 656797
    Resumen
    Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.
  • Autores: Rodríguez Otero, Paula; Paiva, Bruno; San Miguel Izquierdo, Jesús (Autor de correspondencia)
    Revista: CANCER TREATMENT REVIEWS
    ISSN: 0305-7372 Vol.100 2021 págs. 102284
    Resumen
    Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive. We propose in this review a roadmap to achieve the dream of cure for multiple myeloma based on five complementary strategies. First, to increase knowledge about disease pathogenesis with a focus on the biology of circulating tumor cells, responsible for dissemination and extramedullary disease, and minimal residual disease clones who represent the reservoir of clonal evolution and disease recurrence. Second, to consider undetectable measurable residual disease (MRD), defined by high-sensitive techniques, as the new endpoint of therapy. Third, to treat disease causation instead of symptomatology through early detection and intervention. Thereby, by treating high-risk smoldering myeloma patients early, we may not only contribute to delay disease progression into active disease but also to increase the cure rates. Fourth, to use the most active scheme in standard-risk patients if the cure is in the horizon. Fifth, to investigate experimental therapies in newly diagnosed patients with high-risk MM, implementing early rescue intervention strategies with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity.
  • Autores: Moreau, P. (Autor de correspondencia); Ghori, R.; Farooqui, M.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN: 0007-1048 Vol.194 N° 1 2021 págs. E48 - E51
  • Autores: Munshi, N. C. (Autor de correspondencia); Hege, K.; San Miguel Izquierdo, Jesús
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.384 N° 24 2021 págs. 2357 - 2358
  • Autores: Jiménez-Ubieto, A.; Paiva, Bruno; Puig, N.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.138 N° 19 2021 págs. 1901 - 1905
  • Autores: Lahuerta Alsina, Juan José; Paiva, Bruno; de-Ubieto, A. J.; et al.
    Revista: BLOOD ADVANCES
    ISSN: 2473-9529 Vol.5 N° 5 2021 págs. 1340 - 1343
  • Autores: Ludwig, H. (Autor de correspondencia); San Miguel Izquierdo, Jesús; Munshi, N.; et al.
    Revista: AMERICAN JOURNAL OF HEMATOLOGY
    ISSN: 0361-8609 Vol.96 N° 8 2021 págs. 896 - 900
  • Autores: Dimopoulos, M. (Autor de correspondencia); Bringhen, S.; Anttila, P.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.137 N° 9 2021 págs. 1154 - 1165
    Resumen
    This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ¿3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ¿75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252.
  • Autores: Tamariz Amador, Luis Esteban; Battaglia, A. M.; Da Silva Maia, Catarina Alexandra; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.11 N° 12 2021 págs. 202
    Resumen
    There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.
  • Autores: Murray, D. L.; Puig, N.; Kristinsson, S.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.11 N° 2 2021 págs. 24
    Resumen
    Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.
  • Autores: Dimopoulos, M. A. (Autor de correspondencia); Moreau, P.; Terpos, E.; et al.
    Revista: HEMASPHERE
    ISSN: 2572-9241 Vol.5 N° 24 2021 págs. e528
  • Autores: Rossi, M. (Autor de correspondencia); Altomare, E.; Botta, C. ; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.35 N° 3 2021 págs. 823 - 834
    Resumen
    Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.
  • Autores: Vives, S.; Martinez Cuadron, D.; Bergua Burgues, J.; et al.
    Revista: CANCER
    ISSN: 0008-543X Vol.127 N° 12 2021 págs. 2003 - 2014
    Resumen
    BACKGROUND Options to treat elderly patients (>= 65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). METHODS Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was >= 0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. RESULTS The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). CONCLUSIONS FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.
  • Autores: Richardson, P. G. (Autor de correspondencia); Oriol, A.; Larocca, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 7 2021 págs. 757 - 767
    Resumen
    Purpose: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. Patients and methods: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. Results: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ¿ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. Conclusion: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease. Trial registration: ClinicalTrials.gov NCT02963493.
  • Autores: Knop, S. (Autor de correspondencia); Mateos, M. V.; Dimopoulos, M. A.; et al.
    Revista: BMC CANCER
    ISSN: 1471-2407 Vol.21 N° 1 2021 págs. 659
    Resumen
    BackgroundIn the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE.MethodsThe European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3months (year 1) and every 6months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model.ResultsCompliance with PRO assessments was comparable at baseline (>90%) and throughout study (>76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p =0.0240) and VAS (p =0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful.ConclusionsPatients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP.Trial registrationClinicalTrials.gov identifier NCT02195479, registered September 21, 2014
  • Autores: Luo, M. M. (Autor de correspondencia); Usmani, S. Z. ; Mateos, M. V. ; et al.
    Revista: JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN: 0091-2700 Vol.61 N° 5 2021 págs. 614 - 627
    Resumen
    We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (C-trough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the <= 65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients <= 50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.
  • Autores: Munshi, N. C. (Autor de correspondencia); Anderson, L. D. ; Shah, N.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.384 N° 8 2021 págs. 705 - 716
    Resumen
    BACKGROUND Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigendirected chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulating agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 x 10(6) to 450 x 10(6) CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10(-5) nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome.
  • Autores: Laubach, J. P. (Autor de correspondencia); Schjesvold, F.; Mariz, M.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 1 2021 págs. 142 - 154
    Resumen
    Background: Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods: PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990. Findings: Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8-24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8-72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8-75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4-61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3-4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (¿20% patients in any group) grade 3-4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (¿10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation: The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. Funding: Novartis Pharmaceuticals and Secura Bio.
  • Autores: Puig, N. (Autor de correspondencia); Flores-Montero, J.; Burgos Rodríguez, Leire; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 19 2021 págs. 4924
    Resumen
    Although the majority of patients with myeloma who achieve undetectable minimal residual disease show prolonged survival, some of them relapse shortly afterwards. False-negative results due to hemodiluted bone marrow samples could explain this inconsistency, but there is no guidance on how to evaluate them. We analyzed three cell populations normally absent in peripheral blood in 1404 aspirates obtained in numerous disease settings and in 85 healthy adults. Pairwise comparisons according to age and treatment showed significant variability, thus suggesting that hemodilution should be preferably evaluated with references obtained after receiving identical regimens. Leveraging the minimal residual disease results from 118 patients, we showed that a comparison with age-matched healthy adults could also inform on potential hemodilution. Our study supports the routine assessment of bone marrow cellularity to evaluate hemodilution, using as reference values either treatment-specific or from healthy adults if the former are unavailable.
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); Sirvent, M.; González-Rodríguez, A. P.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.21 N° 6 2021 págs. 413 - 420
    Resumen
    Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging. We analyzed the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex) in a real-world RRMM population. Median progression-free and overall survival were 7.6 and 12.6 months, respectively, which compares favorably with other triplets in the same setting. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM. Introduction: Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations. Patients and Methods: A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy. Results: Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease. Conclusion: Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients. (C) 2021 Published by Elsevier Inc.
  • Autores: Palladini, G. (Autor de correspondencia); Paiva, Bruno; Wechalekar, A.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.11 N° 2 2021 págs. 34
    Resumen
    Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.
  • Autores: Nooka, A. K. ; Weisel, K.; van de Donk, N. W. C. J. ; et al.
    Revista: FUTURE ONCOLOGY
    ISSN: 1479-6694 Vol.17 N° 16 2021 págs. 1987 - 2003
    Resumen
    Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ¿4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).
  • Autores: Plesner, T. (Autor de correspondencia); Dimopoulos, M. A.; Oriol, A.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN: 0007-1048 Vol.194 N° 1 2021 págs. 132 - 139
    Resumen
    In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient-reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires. Changes from baseline are presented as least-squares mean changes with 95% confidence intervals (CIs) derived from a mixed-effects model. PRO assessment compliance rates were high and similar in both D-Rd and Rd groups through cycle 40 (week 156). In this on-treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ-C30 global health status, physical functioning, and pain scores in the D-Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health-related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D-Rd treatment. These findings complement the sustained and significant improvement in progression-free survival observed with D-Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009.
  • Autores: Mendonca-de-Pontes, R.; Flores-Montero, J.; Sanoja-Flores, L.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 7 2021 págs. 1704
    Resumen
    Simple Summary B-cell regeneration during therapy has been associated with the outcome of multiple myeloma (MM) patients. However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated. Here, we show that hemodilution is present in a significant fraction of MM BM samples, leading to lower total B-cell, B-cell precursor (BCP), and normal plasma cell (nPC) counts. Among MM BM samples, decreased percentages (vs. healthy donors) of BCP, transitional/naive B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP, but not TBC/NBC, increased after induction therapy. At day+100 post-autolo-gous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19(-) nPC counts vs. non-CR specimens with no clear association between BM B-cell regeneration profiles and patient outcomes. B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (>= 50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naive B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19(-) nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.
  • Autores: Dhanasiri, S. (Autor de correspondencia); Hollier-Hann, G.; Stothard, C.; et al.
    Revista: CLINICAL THERAPEUTICS
    ISSN: 0149-2918 Vol.43 N° 11 2021 págs. 1983 - +
    Resumen
    Purpose: Patients with relapsed and refractory multiple myeloma (RRMM) have a poor prognosis and limited treatment options after exposure to an immunomodulatory drug, proteasome inhibitor (PI), and anti-CD38 antibody (triple-class exposure [TCE]). However, current understanding about the management of these patients and associated health care resource use (HCRU) is limited outside the United States. The objective of the International Treatment pattern and resource use Evaluation for Multiple myeloma In a Study of triple-class Exposed patients (ITEMISE) study was to use a physician-developed survey fielded to hematologists across Europe and Canada to assess the treatment, management, HCRU, and end of-life care for patients with RRMM after TCE. Methods: The ITEMISE study used a 3-phase Delphi-like approach that consisted of in-depth interviews with 7 hematology experts; the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom from August to October 2020; and a final workshop of hematology experts to validate the pooled findings. Hematologists were asked to consider the management of patients in the first 3 treatment lines after TCE, including treatment options, treatment duration and outcomes, and frequency of outpatient visits and hospitalizations. Findings: The survey was completed by 202 hematologists (60% from academic hospitals, 38% from other public hospitals, and 2% from private hospitals). Hematologists estimated that 55% of patients would receive active treatment after TCE, the equivalent of fourth-line treatment onward since diagnosis of multiple myeloma. Immunomodulatory drug, anti-CD38 antibody plus immunomodulatory drug, and PI-based regimens (received by 22.5%, 17.8%, and 15.1% of patients, respectively) were reported for first treatment strategy after TCE. Pomalidomide, daratumumab, lenalidomide, bortezomib, and carfilzomib were the most frequently selected antimyeloma agents. Associated outcomes of median overall survival, progression-free survival, and objective response rate for first treatment after TCE were estimated as 12 months, 4 months, and 40%, respectively. HCRU included outpatient visits and unplanned hospitalizations that were commonly reported during treatment after TCE. Implications: Findings indicate an intent to actively treat patients after TCE with a range of combination regimens frequently consisting of immunomodulatory drugs, PIs, and anti-CD38 antibodies, highlighting the lack of standard of care and suggesting a large clinical unmet need. Estimated clinical outcomes are consistent with data from US studies and indicate the poor prognosis for patients after TCE. Substantial HCRU is associated with management of patients after TCE across Europe and Canada, signifying a high patient and societal impact and a need for better treatment options to reduce this burden. (Clin Ther. 2021;43:1983- 1996.) (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC ND license ( http://creativecommons.org/licenses/bync-nd/4.0/ )
  • Autores: Rodríguez Otero, Paula (Autor de correspondencia); Ayers, D.; Cope, S.; et al.
    Revista: LEUKEMIA AND LYMPHOMA
    ISSN: 1042-8194 Vol.62 N° 10 2021 págs. 2482 - 2491
    Resumen
    Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.
  • Autores: Usmani, S. Z. (Autor de correspondencia); Garfall, A. L.; van-de-Donk, N. W. C. J.; et al.
    Revista: LANCET
    ISSN: 0140-6736 Vol.398 N° 10301 2021 págs. 665 - 674
    Resumen
    Background There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma. Methods This open-label, single-arm, phase 1 study enrolled patients with multiple myeloma who were relapsed, refractory, or intolerant to established therapies. Teclistamab was administered intravenously (range 0.3-19.2 mu g/kg [once every 2 weeks] or 19.2-720 mu g/kg [once per week]) or subcutaneously (range 80-3000 mu g/kg [once per week]) in different cohorts, with step-up dosing for 38.4 mu g/kg or higher doses. The primary objectives were to identify the recommended phase 2 dose (part one) and characterise teclistamab safety and tolerability at the recommended phase 2 dose (part two). Safety was assessed in all patients treated with at least one dose of teclistamab. Efficacy was analysed in response-evaluable patients (ie, patients who received at least one dose of teclistamab and had at least one post-baseline response evaluation). This ongoing trial is registered with ClinicalTrials.gov, NCT03145181. Findings Between June 8, 2017, and March 29, 2021, 219 patients were screened for study inclusion, and 157 patients (median six previous therapy lines) were enrolled and received at least one dose of teclistamab (intravenous n=84; subcutaneous n=73). 40 patients were administered the recommended phase 2 dose, identified as once per week subcutaneous administration of teclistamab at 1500 mu g/kg, after 60 mu g/kg and 300 mu g/kg step-up doses (median follow-up 6.1 months, IQR 3.6-8.2). There were no dose-limiting toxicities at the recommended phase 2 dose in part one. In the 40 patients treated at the recommended phase 2 dose, the most common treatment-emergent adverse events were cytokine release syndrome in 28 (70%; all grade 1 or 2 events) and neutropenia in 26 (65%) patients (grade 3 or 4 in 16 [40%]). The overall response rate in response-evaluable patients treated at the recommended phase 2 dose (n=40) was 65% (95% CI 48-79); 58% achieved a very good partial response or better. At the recommended phase 2 dose, the median duration of response was not reached. 22 (85%) of 26 responders were alive and continuing treatment after 7.1 months' median follow-up (IQR 5.1-9.1). At the recommended phase 2 dose, teclistamab exposure was maintained above target exposure levels, and consistent T-cell activation was reported. Interpretation Teclistamab is a novel treatment approach for relapsed or refractory multiple myeloma. At the recommended phase 2 dose, teclistamab showed promising efficacy, with durable responses that deepened over time, and was well tolerated, supporting further clinical development.
  • Autores: Ocio, E. M. (Autor de correspondencia); Motllo, C.; Rodríguez Otero, Paula; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN: 0007-1048 Vol.192 2021 págs. 522 - 530
    Resumen
    This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) patients. Forty-seven RRMM patients with a median of three prior lines (2-8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1 center dot 25 mg/m(2) of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1-21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% >= MR, resulting in a median progression-free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1-acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0 center dot 04), which also translated into a longer mPFS (9 vs. 2 months; P = 0 center dot 014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy.
  • Autores: Mateos, M. V. (Autor de correspondencia); Dimopoulos, M. A.; Cavo, M.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.21 N° 11 2021 págs. 785 - 798
    Resumen
    In the global phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved outcomes versus VMP in transplant-ineligible patients with newly diagnosed multiple myeloma. In this subgroup analysis of ALCYONE, frailty was assessed retrospectively among all randomized patients (D-VMP, n = 350; VMP, n = 356). Improved efficacy with D-VMP versus VMP was observed across frailty subgroups, with no new safety concerns. Background: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. Patients and Methods: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (>= 2); a nonfrail category combined fit and intermediate patients. Results: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median followup, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P <.0001), frail (32.9 vs. 19.5 months; HR, 0.51; P <.0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10(-5))-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%). Conclusion: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
  • Autores: Puig, N.; Hernández, M. T.; Rosiñol, L.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.11 N° 5 2021 págs. 101
    Resumen
    Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the >= CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.
  • Autores: San Miguel Izquierdo, Jesús (Autor de correspondencia); Usmani, S. Z.; Mateos, M. V.; et al.
    Revista: HAEMATOLOGICA
    ISSN: 0390-6078 Vol.106 N° 6 2021 págs. 1725 - 1732
    Resumen
    Intravenous daratumumab is approved for the treatment of multiple myeloma. In part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and an efficacy similar to that of intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC). Patients who had received two or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, were given daratumumab (1,800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3 to 5 minutes as per the approved intravenous monotherapy dosing schedule. Primary endpoints were daratumumab trough concentration at the end of weekly dosing (just prior to the day 1 dose of cycle 3) and safety. Twenty-five patients were enrolled in PAVO part 2. DARA SC achieved daratumumab trough concentrations similar to or greater than those achieved with intravenous daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with that of intravenous daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, the median duration of response was 15.7 months, and the median progression-free survival was 12.0 months. DARA SC 1,800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with those following intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in the treatment of multiple myeloma and other conditions.
  • Autores: Prieto Azcárate, Elena; García Velloso, María José (Autor de correspondencia); Dámaso-Aquerreta, J.; et al.