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Therapeutic strategies for patients with newly diagnosed multiple myeloma (NDMM) have considerably improved during the last 10 years. The IFM2014-03 trial proposed an all-oral triplet induction/consolidation regimen in transplant-eligible NDMM patients, followed by lenalidomide maintenance. Induction consisted of three 21-day cycles of ixazomib, lenalidomide and dexamethasone (IRd), before high-dose Melphalan with transplant followed by eight 28-day cycles of IRd consolidation before 13 cycles of lenalidomide maintenance. Forty-six patients were enrolled and received at least one dose of therapy, and 39 entered the maintenance phase. The primary end-point was stringent complete response after consolidation, and was achieved in nine patients (20.9%, 90% CI 11.4-33.7; p = 0.998). Ten patients (24.4%) had an undetectable minimal residual disease. The overall response rate was 95.7%. The 3-year progression-free survival was 66.3%. No unexpected toxicities were recorded, and only eight patients suspended from any study drug. Of note, 21 (45.7%) patients reported peripheral neuropathy (PN) (grades 1-2 with no serious adverse events). IRd induction and consolidation with transplant before lenalidomide maintenance shows lower response rates compared to other triplet therapies. It could be an alternative for patients who require an all-oral regimen and/or with pre-existent PN, especially if quadruplet regimens including anti-CD38 antibody are not available., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA., Methods: CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18-65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov, NCT02541383., Findings: Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7-85·6) from first randomisation and 70·6 months (66·4-76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9-not estimable (NE)] vs 45·8 months [41·8-49·6]; HR 0·49 [95% CI 0·40-0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6-NE] vs 72·1 months [52·8-NE]; 0·76 [0·58-1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9-NE] vs 32·7 months [27·2-38·7]; 0·34 [0·26-0·44]; p<0·0001)., Interpretation: The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma., Funding: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development., Competing Interests: Declaration of interests PM served on advisory boards for and received honoraria from Janssen, Bristol Myers Squibb, Amgen, Takeda, AbbVie, Sanofi, and Pfizer. CH received honoraria from Janssen, Bristol Myers Squibb, Amgen, AbbVie, and Pfizer. AP served in a consulting or advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and received research funding from Bristol Myers Squibb, Sanofi, and Takeda. BA received research funding (paid to institution) from Bristol Myers Squibb; received honoraria from Janssen, Bristol Myers Squibb, Sanofi, and GSK; received travel funding from Janssen, Bristol Myers Squibb, and Sanofi; and served on an advisory board for Janssen, Bristol Myers Squibb, and Takeda. KB has a direct financial relationship with Janssen, Bristol Myers Squibb, Amgen, Sanofi, and Pfizer. SZ received research support from Janssen and Takeda; and served on advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen, and Takeda. MD received honoraria from and served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Janssen, Sanofi, and Stemline; and received research funding from Janssen. CS received consulting fees or honoraria from Takeda, Bristol Myers Squibb, Janssen, Amgen, Sanofi, and Pfizer. MMo received honoraria from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, Janssen, Takeda, Novartis, and Sanofi; and received research funding from Celgene, Janssen, and Sanofi. LK received honoraria from, served on advisory boards for, or received travel funding from AbbVie, Amgen, Janssen, Celgene/Bristol Myers Squibb, Pfizer, Sanofi, and Takeda. MMa received honoraria from and served in a consulting or advisory role for Janssen, Bristol Myers Squibb/Celgene, Sanofi, and Takeda; received research funding from Janssen and Takeda; and received travel, accommodations, or expenses from Janssen and Sanofi. FO-P served on boards for Janssen, Sanofi, and Pfizer. MR served on an advisory board for Janssen and Pfizer; received research funding from Bristol Myers Squibb, Janssen, and Sanofi; gave lectures for Amgen, Bristol Myers Squibb, Janssen, and Takeda; and had travel, accommodations, or other expenses paid or reimbursed by Amgen, Bristol Myers Squibb, GSK, Janssen, Pfizer, Sanofi, and Takeda. JMSdC served on an advisory board and received honoraria from Janssen, Sanofi, GSK, and AbbVie; and received accommodations from Pfizer and Amgen. NWCJvdD received research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen, Amgen, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Merck, Pfizer, AbbVie, and Servier (all paid to institution). AB served on advisory boards for Janssen, Sanofi, Amgen, and Bristol Myers Squibb. CT served on an advisory board for and received honoraria from Janssen. NM served on an advisory board for Janssen. M-CV received travel support from Janssen and Sanofi. M-DL received travel expenses from Janssen. WH is an employee of Cytel and is a contractor for Johnson & Johnson. JW, CdB, MR, VV, RC, and JV are employees of Janssen and hold stock in Johnson & Johnson. AT is an employee of Janssen. JC served on advisory boards for Sanofi and Bristol Myers Squibb; served as a consultant for Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; received research support from Sanofi and Bristol Myers Squibb; and received travel support from Janssen, Sanofi, Bristol Myers Squibb, and Pfizer. PS served on an advisory board for Amgen, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, and Pfizer; and received research funding from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Karyopharm. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10 -5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10 -5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10 -5 and 10 -6 , and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10 -5 , the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 ., (© 2024. The Author(s).)

Abstract: High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival., Methods: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0-2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1-2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172., Findings: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7-59·9), median progression-free survival was not reached (95% CI 54·8-not reached) in the daratumumab group versus 34·4 months (29·6-39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43-0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached-not reached; control group, 95% CI 55·7-not reached; HR 0·68 [95% CI 0·53-0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group., Interpretation: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation., Funding: Janssen Research & Development., Competing Interests: Declaration of interests TF received payment or honoraria for speakers bureaus for Bristol Myers Squibb, Janssen, and Takeda; and participated on advisory boards for AbbVie, Amgen, Bristol Myers Squibb, Janssen, Karyopharm, Oncopeptides, Roche, and Takeda. SKK received research funding from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, CARsgen, Janssen, Molecular Templates, Novartis, Roche-Genentech, Takeda, and TeneoBio; and consulted for or participated on an advisory board for AbbVie, Amgen, Antengene, AstraZeneca, BeiGene, bluebird bio, Bristol Myers Squibb, Epizyme, Janssen, Oncopeptides, Roche-Genentech, Secure Biotherapeutics, and Takeda. TP received consulting fees from Celgene and Janssen; received payment or honoraria for educational events from Janssen; received payment for expert testimony from CSL Behring, Oncopeptides, and Takeda; and holds stock or stock options in Novo Nordisk. RZO received support for the present manuscript from Janssen; received laboratory research funding from Asylia Therapeutics, BioTheryX, and Heidelberg Pharma; received clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, and Takeda; received royalties or licenses for, has patents planned, issued or pending for, and holds stock or stock options in Asylia Therapeutics; received consulting fees from EcoR1 Capital; and participated on an advisory board for Amgen, BioTheryX, Bristol Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis, Janssen Biotech, Juno Therapeutics, Karyopharm, Kite, Neoleukin, Oncopeptides, Regeneron, Sanofi-Aventis, Servier, and Takeda. PM received honoraria from AbbVie, Amgen, Celgene, Janssen, Oncopeptides, and Sanofi. NB received research funding from Celgene, Janssen, and Pfizer; participated on an independent review committee for Janssen, Karyopharm, and Legend Biotech; received honoraria for educational events from Bristol Myers Squibb, Celgene, and Janssen; and participated on an advisory board for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Janssen, Karyopharm, Pfizer, Sanofi, and Takeda. HQ received grants or contracts from Amgen, Celgene, GlaxoSmithKline, Karyopharm, and Sanofi; and had a leadership or fiduciary role in advisory boards for Amgen, Celgene, CSL Behring, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda. HG received grants or contracts from Amgen, Bristol Myers Squibb, Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, and Sanofi; received consulting fees from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, and Takeda; received payment or honoraria for lectures and presentations from Amgen, Art Tempi, Bristol Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Novartis, and Sanofi; received support for attending meetings or travel, or both, from Adaptive Biotechnologies, Amgen, Art Tempi, Bristol Myers Squibb, Celgene, Chugai, Janssen, Sanofi, and Takeda; and received research support from Amgen, Bristol Myers Squibb, Celgene, Chugai, Incyte, Janssen, Merck Sharp & Dohme, Molecular Partners, MundiPharma, Novartis, Sanofi, and Takeda. MOD received consulting fees from Janssen; has several patents planned, issued, or pending relating to the use of natural killer cells and sialyltransferase inhibition in the treatment of cancer; participated on an advisory board for Amgen, Celgene, and Janssen; serves as a director of ONK Therapeutics; and holds stock or stock options in ONK Therapeutics and Carrick Therapeutics. AP received grants or contracts from Sanofi and Takeda; received payment or honoraria for presentations and educational events from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Sanofi, and Takeda; received payment or honoraria for a speakers bureau from Janssen and Sanofi; received support for attending meetings or travel, or both, from Amgen and Janssen; and participated on a data safety monitoring board or advisory board for Janssen and Sanofi. CPV received honoraria from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Takeda. KW received honoraria from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda; and received grants from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, and Sanofi. NR served in an advisory role for Amgen, bluebird bio, Caribou, GlaxoSmithKline, and Immuneel. MM received research funding from Janssen and Takeda; received honoraria from GlaxoSmithKline, Janssen, Sanofi, and Takeda; and received travel accommodations from Janssen and Takeda. LF received support for attending meetings or travel, or both, from Amgen and Janssen; and received payment or honoraria for educational events from Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, and Takeda. TA is an employee of and holds equity in Genmab. JW and RVR are employees of Janssen. CMU, BT, MD, and JV are employees of Janssen; and hold equity in Johnson & Johnson. SZU received grants from Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; and received personal fees from AbbVie, Amgen, Celgene, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, MundiPharma, Oncopeptides, Sanofi, Seattle Genetics, SkylineDX, and Takeda. SB, HN, CH, JRM, MT, and XL declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only., Methods: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants., Findings: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment., Interpretation: Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy., Funding: Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology., Competing Interests: Declaration of interests PM reports personal fees from Celgene, Amgen, Takeda, Janssen, and AbbVie, outside the submitted work. CH reports personal fees from Janssen, AbbVie, Amgen, and Celgene, outside the submitted work. AP reports personal fees from Celgene, Amgen, Janssen, Sanofi, and Takeda, outside the submitted work. BA reports grants from Amgen, Celgene, Sanofi, and Janssen, during the conduct of the study; personal fees from Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline, Takeda, and Janssen, outside the submitted work; and advisory board participation from Amgen, Celgene/Bristol Myers Squibb, Sanofi, GlaxoSmithKline, and Janssen, outside the submitted work. KB reports grants from Celgene outside the submitted work; personal fees from Celgene, Janssen, Takeda, and Amgen, outside the submitted work; and non-financial support from Celgene, AbbVie, and Takeda, outside the submitted work. SZ reports grants from Celgene, Janssen, and Takeda, during the conduct of the study. MD reports grants from Celgene and Janssen during the conduct of the study; participation on an advisory board for Celgene, Takeda, Janssen, Sanofi, and Oncopeptides, outside the submitted work. TD reports grants from Celgene and Janssen, during the conduct of the study; and personal fees and advisory board participation from Celgene, Takeda, Janssen, and Amgen, outside of the submitted work. CD reports personal fees from Janssen, outside the submitted work. TF reports personal fees from Janssen, Bristol Myers Squibb, Takeda, Amgen, Roche, Karyopharm, Sanofi, and Oncopeptides, outside the submitted work. CS reports personal fees from Celgene, outside the submitted work. MMo reports grants from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene; non-financial support from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene; and personal fees from Stemline, BMS, Amgen, Jazz Pharmaceuticals, Novartis, Takeda, Janssen, GSK, Sanofi, and Celgene, outside the submitted work. LK reports personal fees from Amgen, Janssen, Celgene, Takeda, and AbbVie, outside the submitted work. XL reports personal fees from Janssen, outside the submitted work. MMa reports personal fees from and advisory board participation for Amgen, Celgene, Janssen, and Takeda, outside the submitted work. A-MS reports personal fees from Celgene outside the submitted work. NWCJvdD reports grants from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Novartis, during the conduct of the study; and personal fees from Amgen, Bristol Myers Squibb, Celgene, Janssen, Novartis, Bayer, Roche, Servier, and Takeda, outside the submitted work. AB reports personal fees from Amgen, Celgene, Janssen, and Bristol Myers Squibb, outside the submitted work. CT reports personal fees from Janssen, outside the submitter work. MR reports grants from Janssen, during the conduct of the study; personal fees and travel support from Celgene, Amgen, Sanofi, Takeda, and Janssen, outside the submitted work. M-DL reports grants from AbbVie, Amgen, Janssen, Roche, and Takeda, during the conduct of the study; and personal fees and advisory board participation from AbbVie, Janssen, Roche, and Takeda, outside the submitted work. TA reports employment and equity ownership from Genmab. MK reports employment with Janssen. KZ reports employment with Janssen. CdB reports employment and equity ownership from Janssen. SV reports employment with Janssen. TK reports employment with Janssen. VV reports employment with Janssen. JV reports employment with Janssen. HA-L reports grants from Celgene and Janssen, during the conduct of the study; and personal fees from Celgene, Amgen, Bristol-Myers Squibb, Sanofi, and Janssen, outside the submitted work. PS reports personal fees from Celgene and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study., Patients and Methods: PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs., Results: A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score., Conclusion: D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.

Background: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population., Methods: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival., Results: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10 5 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%)., Conclusions: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.)., (Copyright © 2019 Massachusetts Medical Society.)

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has proved effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome. MM remains an incurable disease with unavoidable relapses, and the outcome after pomalidomide is still dismal. However, some patients demonstrate prolonged survival even beyond pomalidomide therapy.We sought to analyze the treatment of RRMM patients following Pom-Dex therapy and the response and survival after this next treatment line.We studied 134 patients treated with Pom-Dex until progression across two IFM studies. Seventy percent of these patients received further therapy after Pom-Dex. Among the treated patients, one third responded and one third maintained stable disease. The median OS for treated patients was 12 months (6.5;17), with 22 and 12.5% of patients surviving beyond 2 and 3 years, respectively. The factors associated with a better outcome were exposure to a triplet-based regimen containing a novel agent, response to therapy, absence of adverse cytogenetic, and a longer time from diagnosis to post pomalidomide therapy.This study suggests that patients relapsing after Pom-Dex therapy can still benefit from a further line of treatment. A subset of these treated patients even displayed a prolonged OS, while the prognosis remained very poor without treatment. An active approach could therefore be recommended even in this adverse situation, however guided by the patients' prognosis factors.

Background: High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation., Methods: We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival., Results: Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy., Conclusions: Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).

The phase 3 FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial demonstrated that lenalidomide plus low-dose dexamethasone (Rd) until disease progression (Rd continuous) is an effective treatment option for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Given genetic differences between Asian and Western populations, this subanalysis of the FIRST trial examined the safety and efficacy of Rd (given continuously or for 18 cycles [Rd18]) and MPT (melphalan, prednisone, thalidomide) in 114 Asian patients from Mainland China, South Korea and Taiwan. Efficacy and safety with Rd continuous in Asian patients were consistent with those in the overall study population. The overall response rates were 77·8% for Rd continuous, 57·5% for MPT and 65·8% for Rd18. The risk of progression or death was reduced by 39% with Rd continuous versus MPT and by 35% with Rd continuous versus Rd18. Rd continuous improved the 3-year survival rate compared with MPT (70·2% vs. 56·4%) and Rd18 (58·1%). Common grade 3/4 adverse events in the Rd continuous and MPT arms were neutropenia (25·0% vs. 43·6%), infection (19·4% vs. 28·2%) and anaemia (19·4% vs. 15·4%), respectively. Thromboembolic event rates were low, and no second primary malignancies were observed. Rd continuous is safe and effective in transplant-ineligible Asian patients with NDMM., (© 2017 The Authors. British Journal of Haematology Published by John Wiley & Sons Ltd.)

Objective: To conduct a cost-effectiveness assessment of lenalidomide plus dexamethasone (Rd) vs bortezomib plus melphalan and prednisone (VMP) as initial treatment for transplant-ineligible patients with newly-diagnosed multiple myeloma (MM), from a U.S. payer perspective., Methods: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually., Results: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes., Conclusions: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.

Background: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches., Methods: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT., Results: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers., Conclusions: As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).

Background: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma., Design and Methods: We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression., Results: In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide., Conclusions: Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. (, Clinical Trial Registration Number: NCT00452569).

The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT.

This retrospective analysis investigated the prognostic value of del(13) and t(4;14) abnormalities and the impact of prior treatment on outcomes in 207 heavily pretreated patients with relapsed or refractory multiple myeloma (MM) treated with lenalidomide plus dexamethasone. Patients with relapsed or refractory MM who had either earlier received thalidomide or bortezomib, or for whom continuation of these agents was contraindicated, and who had fluorescence in situ hybridization data available were included in the analysis. Patients with relapsed or refractory MM who received treatment with lenalidomide plus dexamethasone in the presence of del(13) and t(4;14) chromosomal abnormalities had lower overall response rates (ORRs) and shorter median progression-free survival (PFS) and overall survival (OS) compared with those who did not have these abnormalities. The results also showed that prior treatment with bortezomib was associated with shorter median PFS and OS. Progression during thalidomide therapy was the only significant independent predictor for OS and that the presence of del(13) and hemoglobin levels <10 g per 100 ml were prognostic factors for ORR and PFS, but not OS, in these heavily pretreated relapsed or refractory MM patients treated with lenalidomide plus dexamethasone.

Background and Objectives: Induction regimens prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma patients usually result in complete remission (CR) rates of <10%. The use of novel agents may increase the CR rate before ASCT, which may improve post-transplantation response and survival., Design and Methods: This was a phase II, open-label trial of bortezomib (1.3 mg/m(2), days 1,4,8,11) and dexamethasone (40 mg,days 1-4 and 9-12 for cycles 1-2,days 1-4 for cycles 3-4) administered for four 21-day cycles as induction therapy in chemotherapy-naïve myeloma patients., Results: Of 52 recruited patients, 48 were eligible for the study. The overall response rate was 66% including 21% CR and 10% very good partial remission (>90% reduction of the M-component). Four patients had a minimal response, six had stable disease and five had progression. One patient died after salvage therapy with VAD. The most common side effects were gastrointestinal symptoms, peripheral neuropathy, and fatigue. These were usually mild. Peripheral neuropathy was observed in 15 cases but was grade 2-3 in only seven cases (14%). There was no deep vein thrombosis and no hematologic toxicity greater than grade 2. Grade 3 infections were recorded in five patients including three who had herpes zoster infections. Stem cell collection was programmed in 44 cases and all patients had sufficient CD34+ cells to perform one ASCT (> 2 x 10(6)/kg)., Interpretation and Conclusion: This regimen of bortezomib plus dexamethasone appears effective and well tolerated in newly diagnosed myeloma patients.

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.

Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients with relapsed and/or refractory multiple myeloma (RRMM). The REMIX study is one of the largest prospective, real-world analysis of the effectiveness of IXA-Rd in the setting of RRMM. Conducted in France between August 2017 and October 2019, the REMIX study, a non-interventional prospective study, included 376 patients receiving IXA-Rd in second line or later and followed for at least 24 months. Primary endpoint was the median progression-free survival (mPFS). Median age was 71 years (Q1-Q3 65.0 – 77.5) with 18.4% of participants older than 80 years. IXA-Rd was initiated in L2, L3 and L4 + for 60.4%, 18.1% and 21.5%, respectively. mPFS was 19.1 months (95% CI [15.9, 21.5]) and overall response rate (ORR) was 73.1%. mPFS was 21.5, 21.9 and 5.8 months in patients receiving IXA-Rd as L2, L3, L4 + respectively. Among patients receiving IXA-Rd in L2 and L3, mPFS was similar for patients previously exposed to lenalidomide (19.5 months) than for those lenalidomide naive (not exposed, 22.6 months, p = 0.29). mPFS was 19.1 months in patients younger than 80 years and 17.4 months in those 80 years or older (p = 0.06) with similar ORR (72.4% and 76.8%) in both subgroups. Adverse events (AEs) were reported in 78.2% of patients including 40.7% of treatment-related AE. IXA discontinuation was due to toxicity in 21% of patients. To conclude, the results of the REMIX study are consistent with the results of Tourmaline-MM1 and confirm the benefit of IXA-Rd combination in real life. It shows the interest of IXA-Rd in an older and frailer population, with an acceptable effectiveness and tolerance. [ABSTRACT FROM AUTHOR]

Background: The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression- free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. Design: We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (=1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. Results: The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the =1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. Conclusion: Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study. [ABSTRACT FROM AUTHOR]