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Objectives: Gain or amplification of 1q21 (1q21+, ≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma (MM), has a negative impact on prognosis due to its potential involvement in resistance to MM therapy and disease progression. In this subgroup analysis of IKEMA, we evaluated efficacy of isatuximab-carfilzomib-dexamethasone (Isa-Kd) in patients (pts) with 1q21+ status (with or without high-risk chromosomal abnormalities [HRCA]) and related subgroups – isolated 1q21+ (≥ 3 copies without HRCA), gain(1q21), amp(1q21) – at long-term follow-up (44.2 months). Methods: Pts with 1–3 prior lines of therapy were randomized to Isa-Kd (n = 179) or Kd (n = 123). Assessment was prespecified (at 30% cutoff by FISH) for 1q21+ status as ≥3 copies, gain(1q21) as 3 copies, and amp(1q21) as ≥4 copies. Results: In the Isa-Kd and Kd arms, 41.9% and 42.3% of pts had 1q21+ status, 26.3% and 25.2% isolated 1q21+, 24.0% and 30.1% gain(1q21), 17.9% and 12.2% amp(1q21) respectively. Greater progression-free survival (PFS) benefit was achieved with Isa-Kd vs Kd in pts with 1q21+ status (hazard ratio [HR] 0.58, 95% CI 0.37–0.92) and in pts with isolated 1q21+, gain(1q21), or amp(1q21). Responses deepened by adding Isa to Kd, with increased rates of very good partial response or better (≥VGPR), complete response or better (≥CR), minimal residual disease negativity (MRD-), and MRD- ≥CR. Discussion: In the prespecified, long-term analysis of the Phase 3 IKEMA trial in relapsed MM pts, treatment with Isa-Kd showed continued, significant improvement in PFS compared to Kd (HR 0.58; 95.4% CI 0.42–0.79). There was a meaningful increase in the depth of response (≥CR 44.1% vs 28.5%; MRD- 33.5% vs 15.4%, MRD- ≥CR 26.3% vs 12.2%), and a manageable safety profile. The present study demonstrated that Isa-Kd led to deeper responses, with higher ≥VGPR rates, MRD-, and MRD- ≥CR rates in 1q21+ patients (with or without HRCA), isolated 1q21+, gain(1q21), or amp(1q21) compared to Kd. These long-term findings support Isa-Kd as an effective treatment option for patients with relapsed MM, including 1q21+ abnormalities and a higher risk of progression. Conclusions: 1q21 abnormalities may affect PFS in MM pts. Our results at long-term follow-up of pts with 1q21+ status (with or without HRCA) in the IKEMA study continue to show greater PFS benefit and deeper responses with Isa-Kd than Kd, consistent with the overall population and earlier 1q21+ subgroup interim analyses. Thus, they support Isa-Kd as an effective treatment option also for difficult-to-treat, 1q21+ pts with relapsed MM.

In the MAIA study (median follow-up, 56.2 months), daratumumab plus lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival (PFS) and overall survival versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). In this post hoc analysis of clinically important subgroups in MAIA (median follow-up, 64.5 months), transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint was PFS; secondary endpoints included overall response rate (ORR) and measurable residual disease (MRD)-negativity rate (10 -5 ). PFS favored D-Rd versus Rd in most subgroups, including patients aged ≥75 years (HR, 0.59; 95% CI, 0.44-0.79), frail patients (HR, 0.64; 95% CI, 0.48-0.85), patients with high-risk cytogenetics (HR, 0.59; 95% CI, 0.44-0.80), and patients with isolated gain(1q21) (HR, 0.36; 95% CI, 0.19-0.67). ORRs, MRD-negativity rates, and sustained (≥12 months) MRD-negativity rates were higher with D-Rd versus Rd across subgroups. In patients aged ≥75 years, rates of grade 3/4 and serious treatment-emergent adverse events (TEAEs) were similar for D-Rd and Rd, but discontinuation due to TEAEs was lower for D-Rd. Results support use of D-Rd for high-risk patients, supporting D-Rd as a standard of care for transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as NCT02252172., Competing Interests: Competing interests: PM served on an advisory board for and received honoraria from Janssen, Celgene, Amgen, AbbVie, Sanofi, and Oncopeptides. TF has nothing to disclose. SZU received research funding from Amgen, Array BioPharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx, and Takeda; served in a consulting role for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Edo Pharma, Genentech, Gilead, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, SkylineDx, Takeda, and TeneoBio; and served on a speakers bureau for Amgen, Bristol Myers Squibb, Janssen, and Sanofi. NB served in a consulting or advisory role for and received honoraria from AbbVie, Bristol Myers Squibb/Celgene, FORUS, Genentech, Janssen, Karyopharm, Pfizer, Sanofi, and Takeda; and received research funding from Pfizer and Celgene. NR served as a consultant for Bristol Myers Squibb, Janssen, Takeda, Amgen, and GlaxoSmithKline; and received research funding from bluebird bio. TP served as an advisor for Janssen, Celgene, Takeda, Oncopeptides, Genentech, CSL Behring, and AbbVie; and received research support from Janssen, Genmab, Celgene, Takeda, Oncopeptides, Genentech, AbbVie, and Roche. RZO received research funding from Asylia Therapeutics, Biotheryx, Heidelberg Pharma, CARsgen, Celgene/Bristol Myers Squibb, Exelixis, Janssen, Sanofi-Aventis, and Takeda; received honoraria from and served as a member on a board of directors or advisory committee for AbbVie, Biotheryx, Bristol Myers Squibb, Janssen, Karyopharm, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin, Oncopeptides, Regeneron, Sanofi-Aventis, and Takeda; and holds stock in Asylia Therapeutics. SB served as a consultant and on a speakers bureau for Sanofi, Pfizer, and Bristol Myers Squibb. HN is an employee of Genmab. CH received honoraria from Janssen, Bristol Myers Squibb, Amgen, Takeda, and AbbVie. HQ served as a consultant for and received research funding from AbbVie, Bristol Myers Squibb, Karyopharm, Amgen, GlaxoSmithKline, and Antengene. HG received grants and/or provisions of Investigational Medicinal Product from Amgen, Array BioPharma/Pfizer, Bristol Myers Squibb/Celgene, Chugai, Dietmar Hopp Foundation, Janssen, Johns Hopkins University, Mundipharma, and Sanofi; received research support from Amgen, Bristol Myers Squibb, Celgene, GlycoMimetics, GlaxoSmithKline, Heidelberg Pharma, Roche, Karyopharm, Janssen, Incyte, Millennium Pharmaceuticals, Molecular Partners, Merck Sharp & Dohme, MorphoSys AG, Pfizer, Sanofi, Takeda, and Novartis; served on an advisory board for Amgen, Bristol Myers Squibb, Janssen, Sanofi, and Adaptive Biotechnologies; received honoraria from Amgen, Bristol Myers Squibb, Chugai, GlaxoSmithKline, Janssen, Novartis, Sanofi, and Pfizer; and received support for attending meetings and/or travel from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Novartis, Sanofi, and Pfizer. MO served as a consultant for Janssen. AP received honoraria from AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and Takeda; served as a member on a board or advisory committee for Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, and Takeda; and received research funding from Takeda. CPV received honoraria from Janssen, Bristol Myers Squibb, Sanofi, FORUS, Pfizer, AbbVie, GlaxoSmithKline, and Amgen. KW received research funding from Amgen, Adaptive Biotechnologies, AstraZeneca, Bristol Myers Squibb/Celgene, BeiGene, Janssen, GlaxoSmithKline, Sanofi, Stemline, and Takeda; received honoraria from AbbVie, Amgen, Adaptive Biotechnologies, AstraZeneca, Bristol Myers Squibb/Celgene, BeiGene, Janssen, GlaxoSmithKline, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; and received travel support from Janssen, GlaxoSmithKline, and Sanofi. MT has nothing to disclose. MM served on an advisory board for Celgene/Bristol Myers Squibb, Janssen, Takeda, Amgen, GlaxoSmithKline, and Sanofi; received research funding from Janssen and Takeda; and received accommodations from Janssen, Celgene/Bristol Myers Squibb, Takeda, Amgen, and Sanofi. LF received honoraria from Janssen, Sanofi, Amgen, and Takeda; and received funding from Janssen and Amgen. XL received honoraria, research support, and consulting fees from Amgen, Merck, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Oncopeptides, Takeda, Roche, Novartis, AbbVie, Sanofi, Gilead, Pfizer, Harpoon Therapeutics, Regeneron, and iTeos. GW, HP, and FB are employees of Janssen and hold stock in Johnson & Johnson. MK and RC are employees of Janssen. SKK received research funding from AbbVie, Amgen, Allogene, AstraZeneca, Bristol Myers Squibb, CARsgen, GlaxoSmithKline, Janssen, Novartis, Roche-Genentech, Takeda, Regeneron, and Molecular Templates; participated in consulting or an advisory board (with no personal payments) for AbbVie, Amgen, Bristol Myers Squibb, Janssen, Roche-Genentech, Takeda, AstraZeneca, bluebird bio, Epizyme, Secura Bio, Monte Rosa Therapeutics, Trillium, Loxo Oncology, K36, Sanofi, and Arcellx; and participated in consulting or an advisory board (with personal payments) for Oncopeptides, BeiGene, Antengene, and GLH Pharma., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: Quadruplet regimens (anti-CD38 monoclonal antibodies [mAbs] with proteasome inhibitor [PI] and immunomodulatory drugs [IMiDs]) are increasingly being investigated in newly diagnosed multiple myeloma (NDMM). The objective of our study was to conduct a systematic review and meta-analysis to measure the efficacy and toxicity of quadruplet regimens used in NDMM. Embase, MEDLINE, Web of Science, Cochrane Library, clinical trial registries, and meeting libraries from inception to 24 January 2024, in addition to American Society of Clinical Oncology conference abstracts 2024, were searched using terms reflecting multiple myeloma and components of the quadruplet regimen. Included studies were randomized controlled trials (RCTs) that compared backbone regimens consisting of a PI and IMiD vs the same regimen plus an anti-CD38 mAb in NDMM. We identified 7 RCTs including 3716 patients. Compared with triplets, quadruplets increase the overall response rate (ORR; relative risk [RR], 1.03; 95% confidence interval [CI], 1.01-1.05) and progression-free survival (PFS; hazard ratio [HR], 0.55; 95% CI, 0.46-0.66). Quadruplets increase the rates of minimal residual disease (MRD) negativity at 10-5 (RR, 1.39; 95% CI, 1.23-1.58) and 10-6 (RR, 1.62; 95% CI, 1.36-1.94). Quadruplets improve overall survival (OS; HR, 0.65; 95% CI, 0.53-0.79). There was a slight increase in the rates of grade 3 to 4 infections (RR, 1.22; 95% CI, 1.07-1.39) noted with quadruplets compared with triplets. Overall, in this meta-analysis, quadruplets were associated with improved efficacy including ORR, MRD negativity, PFS, and OS, with a slight increase in infection rates. Quadruplet regimens represent a new standard of care, particularly in transplant-eligible NDMM., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Not available.

Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear., Methods: In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response., Results: A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups., Conclusions: Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Isatuximab is an anti-CD38 monoclonal antibody approved for the treatment of relapsed or refractory multiple myeloma. Previous analyses of the IKEMA trial showed prolonged progression-free survival in patients with this disease who received isatuximab in combination with carfilzomib-dexamethasone as compared with those who received carfilzomib-dexamethasone alone. Herein, we report the analysis of overall survival from the IKEMA trial., Methods: This prospective, randomised, open-label, active-controlled, phase 3 study included patients with relapsed or refractory multiple myeloma aged 18 years or older, who had received one to three previous lines of treatment from 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were randomly allocated (3:2) to treatment with either isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). In the isatuximab group, patients received intravenous isatuximab (10 mg/kg on days 1, 8, 15, and 22 of the first 28-day cycle, and days 1 and 15 of subsequent 28-day cycles). In both treatment groups, intravenous carfilzomib (20 mg/m 2 on days 1 and 2 of the first cycle; and 56 mg/m 2 on days 8, 9, 15, and 16 of the first cycle, and days 1, 2, 8, 9, 15, and 16 of subsequent cycles) and intravenous or oral dexamethasone (20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23) were administered. The primary endpoint of the trial was progression-free survival, which was reported previously. Treatment continued until progression, unacceptable toxicity, or patient request to discontine. The overall survival analysis reported here was planned to be conducted 3 years after the primary progression-free survival analysis in the intention-to-treat population. Additional analyses were conducted on the secondary endpoints of time to next treatment and second-progression-free survival. Reported p values are non-inferential due to hierarchical testing. This trial is registered with ClinicalTrials.gov (NCT03275285)., Findings: Between Nov 15, 2017, and March 21, 2019, 302 patients were enrolled and randomly allocated: 179 (59%) to the isatuximab group and 123 (41%) to the control group. 169 (56%) patients were male, 133 (44%) were female, 214 (71%) were White, 50 (17%) were Asian, nine (3%) were Black or African American, and three (1%) were multiracial. At data cutoff for this overall survival analysis (Feb 7, 2023), 79 (44%) overall survival events in the isatuximab group and 59 (48%) in the control group had occurred (median follow-up 56·61 months [IQR 54·90-58·02]). Median overall survival (in months) was not reached (NR; 95% CI 52·17-NR) in the isatuximab group and was 50·60 months (38·93-NR) in the control group (hazard ratio [HR] 0·855 [95% CI 0·608-1·202], nominal one-sided p=0·18). Survival probability at 48 months was 59·7% (95% CI 52·0-66·7) in the isatuximab group and 52·2% (95% CI 42·7-60·8) in the control group (based on Kaplan-Meier analysis). Improvements in time to next treatment (HR 0·583 [95% CI 0·429-0·792], nominal one-sided p=0·0002) and second-progression-free survival (0·663 [0·491-0·895], nominal one-sided p=0·0035) were observed in the isatuximab group. The most common treatment-emergent adverse events were infusion reactions (82 [46%] patients in the isatuximab group and four [3%] in the control group) and upper respiratory tract infections (71 [40%] and 34 [28%], respectively). Discontinuations due to treatment-emergent adverse events were similar between treatment groups (24 [14%] in the isatuximab group and 22 [18%] in the control group), despite an additional 30 weeks of exposure in the isatuximab group. 12 (7%) patients in the isatuximab group and six (5%) patients in the control group had a treatment-related adverse event with a fatal outcome during study treatment., Interpretation: At the time of the current analysis, a difference in overall survival could not be detected between the treatment groups, and no new safety signals were observed. Collectively, the evidence suggests that isatuximab plus carfilzomib-dexamethasone is a key treatment for patients with relapsed or refractory multiple myeloma., Funding: Sanofi., Competing Interests: Declaration of interests KY declares research support from BMS, Janssen, and Sanofi; honoraria from Amgen, Sanofi, and Takeda; and advisory roles for Janssen and Sanofi. TM declares research support from Sanofi. M-AD declares honoraria from Amgen, BeiGene, BMS, Janssen, Sanofi, and Takeda. JM declares consulting for Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda. MC declares honoraria from BMS, Janssen, and Sanofi; and advisory roles for Janssen and Sanofi. RH declares research support from Amgen, BMS, Celgene, Janssen, Novartis, and Takeda; consulting for AbbVie, Amgen, BMS, Celgene, Janssen, Novartis, PharmaMar, and Takeda; honoraria from Amgen, BMS, Celgene, Janssen, PharmaMar, Takeda; and advisory roles for Amgen, BMS, GSK, Janssen, Oncopeptides, Sanofi, Takeda. IS declares research support from and consulting for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, PharmMar, Sanofi, and Takeda. RB declares research support from AbbVie, Acerta Pharma, Alexion, Amgen, Bayer, BeiGene, BMS, Boehringer Ingelheim, Celgene, CSL Behring, Daiichi Sankyo, Janssen-Cilag, MorphoSys, Pfizer, Pharmaxis, Portola, Rigel Pharmaceuticals, Roche, Sanofi, Takeda, and Technoclone; honoraria from Bayer, BMS, Cardinal Health, Janssen-Cilag, and Roche; and advisory roles for Janssen-Cilag, Pharmaxis, and Roche. KK declares consulting for LG Chemistry; and advisory roles for Amgen, GSK, and Janssen. AO declares honoraria from Amgen, BMS/Celgene, GSK, and Sanofi. YK declares honoraria from Amgen, GSK, and Janssen. KS declares honoraria from AbbVie, Amgen, BMS, Janssen, Novartis, ONO, Sanofi, and Takeda; consulting for Amgen, BMS, and Takeda; and research funding from BMS. FC, SM, and M-LR are employees of Sanofi and may hold stock or stock options. PM declares advisory roles for AbbVie, Amgen, Celgene, GSK, Janssen, and Sanofi. 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.)

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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.)

Multiple myeloma (MM) is a chronic hematologic malignancy that remains incurable, because most patients eventually relapse or become refractory to current treatments. MM is a major health problem, with a globally increasing incidence. While, increase in the choice of MM treatment, including new immunotherapies (bispecific monoclonal antibodies and chimeric antigen receptor (CAR)-T cell therapy), may allow to further improve MM patients' outcomes, some non-therapy-related key issues may represent a pre-requisite towards improving MM outcomes in the next few years. This includes, the necessity of real-world evidence data, of a better definition of frailty, of a dynamic disease risk assessment, of a better definition of high-risk disease, broader accessibility to novel drugs, and to ensure diversity and representation of underrepresented groups. These key issues will be discussed in the current perspective review., (© 2024. The Author(s).)

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).)

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.)

Introduction: Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73 years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63 years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777., Methods: Harmonized inclusion/exclusion criteria (including age ≥ 65 years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd., Results: PFS HRs were 0.52 (95% confidence interval [CI] 0.41-0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95% CI 0.63-1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95% CI 0.39-0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results., Conclusion: This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population., (© 2024. The Author(s).)

Introduction: A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment., Methods: Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed., Results: Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without., Conclusion: Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM., (© 2024 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.

Abstract: Multiple myeloma (MM) is primarily a disease of older patients. Until recently, geriatric aspects in the context of MM have been poorly investigated. Treatment outcomes for geriatric patients with MM are often compromised by comorbidities and an enhanced susceptibility to adverse events from therapy. Assessment of patient frailty has become more frequent and will be useful in the context of significant and continuous advances in therapy. The recent emergence of immunotherapy with CD38 monoclonal antibodies and upcoming immunooncology drugs, such as bispecific antibodies, will lead to additional therapeutic progress. The applicability of these new molecules to older and frail patients is a key clinical question. Here, we present 2 patient cases derived from clinical practice. We review current frailty scores and standards of care for older, newly diagnosed patients with MM, including frail subgroups, and discuss ways to tailor treatment, as well as treatment perspectives in this population., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

To improve the outcomes of patients with the otherwise incurable hematologic malignancy of multiple myeloma (MM), a key paradigm includes initial treatment to establish disease control rapidly followed by maintenance therapy to ensure durability of response with manageable toxicity. However, patients' prognosis worsens after relapse, and the disease burden and drug toxicities are generally more challenging with subsequent lines of therapy. It is therefore particularly important that patients with newly diagnosed multiple myeloma (NDMM) receive optimal frontline therapy. The combination of lenalidomide, bortezomib, and dexamethasone (RVd) has consistently demonstrated a tolerable safety profile with significant and clinically relevant benefit, including deep and durable responses with improved survival in patients with NDMM regardless of their transplant eligibility. Furthermore, comparative studies evaluating this triplet regimen against both doublet and other triplet regimens have established RVd as a standard of care in this setting based upon its remarkable and concordant efficacy. Given the breadth of clinical data, physician familiarity, inclusion in treatment guidelines, and the emerging potential of RVd-containing quadruplet regimens, RVd will likely continue as a key cornerstone of the treatment of NDMM, and its role will therefore likely continue to grow as a therapeutic backbone in the initial treatment of MM.

Background: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options., Patients and Methods: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs., Results: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications., Conclusion: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients., Competing Interests: Acknowledgments Karyopharm funded the study and provided selinexor supply. Sharon Furman-Assaf, supported by funding from Karyopharm, provided drafts and editorial assistance to the authors during the preparation of this manuscript. This work was supported by Karyopharm Therapeutics Inc. Karyopharm Therapeutics was the sponsor of this study and was responsible for study design, the collection of data, analysis of data, interpretation of data, writing of the report, and the decision to submit the paper for publication. The corresponding author had full access to all data and had the final responsibility for the decision to submit for publication with the agreement of all other authors., (Copyright © 2023. Published by Elsevier Inc.)

Introduction/background: Multiple myeloma (MM) is considered an incurable cancer. Patients with newly diagnosed MM (NDMM) are at risk for relapse within 1 year of frontline therapy. The immunomodulatory agent lenalidomide combined with dexamethasone (Rd) may be used as treatment for NDMM or relapsed MM, including in patients ineligible for autologous stem cell transplant., Patients: This subanalysis of the phase III FIRST trial characterized patients with transplant-ineligible NDMM who experienced relapse while receiving Rd therapy by relapse timing (early [<12 months] versus late [≥12 months]) and type (CRAB vs. non-CRAB)., Methods: The Kaplan-Meier product limit method was used to estimate time-to-event endpoints, including progression-free survival (PFS) and overall survival (OS). Factors associated with the odds of late relapse were identified by logistic regression with univariate and multivariate analyses using a binary outcome (relapse at <12 vs. ≥12 months) in patient-, disease-, and treatment-specific baseline variables., Results: Patients with early refractory relapse had functionally high-risk disease and inferior outcomes. In patients with early relapse versus those with late relapse, median OS (95% CI) was 26.8 months (21.9-32.8) versus 63.9 months (57.0-78.0), median OS from disease progression to death was 19.9 months (16.0-25.5) versus 36.4 months (27.9-47.0), and median PFS from randomization to second progression was 19.1 months (17.3-22.5) versus 42.1 months (37.4-44.9). Lactate dehydrogenase, baseline β2 microglobulin, and myeloma subtype were shown to predict time to relapse., Conclusions: Clinicians could use these factors to consider more aggressive treatment regimens for those at highest risk of early relapse., Competing Interests: Disclosure SM serves on data safety monitoring boards/advisory boards for AbbVie, Adaptive Biotechnology, Amgen, Celgene/Bristol Myers Squibb, GSK, Janssen, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda. MeD has received honoraria for participation in advisory boards for Amgen, Bristol Myers Squibb, BeiGene, Takeda, and Janssen. CH has received honoraria from Celgene/Bristol Myers Squibb, Janssen, Amgen, AbbVie, and Takeda. XL has received honoraria from Janssen, Bristol Myers Squibb, Takeda, Sanofi, Pfizer, Amgen, Roche, and Gilead. MiD has received research funding from Bristol Myers Squibb and Janssen; consulting fees from Amgen, Bristol Myers Squibb, Janssen, Takeda, and Sanofi; honoraria from Amgen, Bristol Myers Squibb, Janssen, Takeda, and Sanofi; and support for meeting attendance/travel expenses from Amgen, Bristol Myers Squibb, Janssen, Takeda, and Sanofi. KW has received research funding from Amgen, Adaptive Biotech, AstraZeneca, Celgene/Bristol Myers Squibb, BeiGene, Janssen, GSK, Sanofi, Stemline, and Takeda; honoraria from AbbVie, Amgen, Adaptive Biotech, AstraZeneca, Celgene/Bristol Myers Squibb, BeiGene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; and support for travel expenses from Janssen, GSK, and Sanofi. JM, BC, and MS are employees of Bristol Myers Squibb and have received meeting attendance/travel expenses and stock or stock options from Bristol Myers Squibb. TF declares no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Deeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression-free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0-4 months; n  = 424) versus late responders (best confirmed response >4 months; n  = 281). Newly diagnosed patients enrolled in TOURMALINE-MM2 receiving ixazomib-lenalidomide-dexamethasone (IRd) ( n  = 351) or placebo-Rd ( n  = 354) were evaluated post hoc . Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS ( n  = 511) or DOR ( n  = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo-Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo-Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor-immunomodulatory drug-steroid combination is not a negative predictor of outcome., Competing Interests: Paul G. Richardson: Consultancy: BMS/Celgene, Takeda, GSK, Sanofi, Oncopeptides, Secura Bio, Karyopharm, AstraZeneca, Novartis; Research funding: Oncopeptides, BMS/Celgene, Takeda, Karyopharm. Nizar J. Bahlis: Honoraria and advisory board member: Karyopharm, Genentech, Janssen, BMS, Amgen, Takeda, AbbVie, GSK, Sanofi, Pfizer; Research funding: Pfizer. Darrell White: Honoraria: Amgen, Antengene, BMS/Celgene, FORUS Therapeutics, Sanofi, GSK, Janssen, Takeda, Karyopharm. Lionel Karlin: Honoraria: Janssen, AbbVie, Amgen, GSK, Sanofi, BMS/Celgene, Takeda; Advisory board member: Janssen, Amgen, GSK, BMS/Celgene, Takeda, Sanofi. Sung‐Soo Yoon: Member of advisory board: AbbVie, Amgen, Janssen, Novartis, Regeneron; Research funding: Roche‐Genentech, Kyowa‐Kirin, Yuhan Pharma. Christopher P. Venner: Honoraria: Takeda, BMS, Janssen, Pfizer, Sanofi, GSK, AbbVie, FORUS Therapeutics. Kenshi Suzuki: Consultancy: Amgen, Takeda, BMS; Research funding: BMS; Honoraria: BMS, Amgen, Takeda, ONO, Novartis, Sanofi, AbbVie, Janssen. Hirohiko Shibayama: Research funding: Celgene, Ono, AbbVie, Eisai, Novartis, Janssen, Chugai, Essential Pharma Japan, Sanofi, AstraZeneca, HUYABIO International; Honoraria: Ono, Takeda, AbbVie, Eisai, Novartis, Janssen, Chugai, AstraZeneca, Sanofi, Celgene, SymBio, Kyowa Kirin. Xiaoquan Zhang, Miguel Villarreal, Philip Twumasi‐Ankrah: Employee: Takeda. Richard Labotka: Employee and equity holder: Takeda. Robert M. Rifkin: Member of board of directors/advisory committee: Amgen, BMS/Celgene, Coherus, Fresenius‐Kabi, Sanofi, Takeda, Karyopharm; Current employment and equity holder: McKesson. Sagar Lonial: Consultancy: Janssen, BMS/Celgene, Amgen, GSK, AbbVie, Takeda, Genentech, Pfizer, Regeneron; Research funding: Janssen, BMS/Celgene, GSK, Takeda; Honoraria: Janssen, BMS/Celgene, Amgen, GSK, Takeda, AbbVie, Merck; Member of board of directors/advisory committee: TG Therapeutics; Ownership of stock/shares: TG Therapeutics. Shaji K. Kumar: Research funding: Celgene, Adaptive, Sanofi, AbbVie, Takeda, Janssen, KITE, Merck, MedImmune/AstraZeneca, Novartis, Roche; Advisory board member: AbbVie, Celgene, Janssen, Takeda, Adaptive, KITE, MedImmune/AstraZeneca; Member of independent review committee: Oncopeptides. Philippe Moreau: Consultancy and member of advisory board: Janssen, Celgene, Takeda, Amgen, Sanofi, AbbVie, GSK. Thierry Facon, Fritz Offner, Lotfi Benboubker, Eric Voog, and S. Vincent Rajkumar have no conflict of interest to declare., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

This round table discussion organized by the International Academy for Clinical Hematology (IACH) was dedicated to the 19th annual meeting of the International Myeloma Society (IMS), which was held in Los Angeles between the 25th and 27th August 2022. After some key meetings of the discipline of the field of clinical hematology, the IACH organizes regular round table discussion in order to summarize the flow of information and get the opinion of a panel of experts and the key take-home messages. As part of this discussion, the panellists debated 6 key topics: disease monitoring, management of high-risk multiple myeloma (MM), induction for newly-diagnosed MM, management of relapsed MM, immune reconstitution, and vaccination and cellular therapy in MM., (© 2023. The Author(s).)

Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 [95% CI: 25.8-44.0] vs 19.2 [95% CI: 15.8-25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285., (© 2023. The Author(s).)

Background: Because patients with newly diagnosed multiple myeloma (NDMM) do not always receive any treatment beyond first-line (1L) therapy, it is imperative that patients receive the best treatment in the 1L setting. However, the optimal initial treatment remains to be identified. We performed a clinical simulation to assess potential outcomes with different treatment sequences., Patients and Methods: We used a partitioned survival model to compare overall survival (OS) with (1) daratumumab, lenalidomide, and dexamethasone (D-Rd) in 1L followed by a pomalidomide- or carfilzomib-based regimen in second line (2L) versus (2) bortezomib, lenalidomide, and dexamethasone (VRd) in 1L followed by a daratumumab-based regimen in 2L versus (3) lenalidomide and dexamethasone (Rd) in 1L followed by a daratumumab-based regimen in 2L. Probabilities of transition between health states (1L, 2L+, and death) were based on published clinical data and real-world data from the Flatiron Health database. The proportion of patients discontinuing treatment after 1L (attrition rates) in the base case was estimated with a binomial logistic model using data from the MAIA trial., Results: Using D-Rd in 1L conferred a longer median OS compared with delaying daratumumab-based regimens until 2L after VRd or Rd, respectively (8.9 [95% CrI 7.58-10.42] vs. 6.92 [5.92-8.33] or 5.75 [4.50-7.25] years). Results of scenario analyses were consistent with the base case., Conclusion: Our simulation, which incorporates clinically representative treatments and attrition rates, supports the use of D-Rd as initial therapy, rather than delaying the use of daratumumab until later lines of therapy, in patients with transplant-ineligible NDMM., (© The Author(s) 2023. Published by Oxford University Press.)

In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately identified. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to pick out high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of International Staging System (ISS) stage, chromosomal abnormalities and lactate dehydrogenase level in this subgroup. Data were collected from 1,343 patients up to 65 years old with newly diagnosed myeloma, enrolled in three clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible for intensive treatment. Patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I (adjusted hazard ratio=1.6; 95% confidence interval: 1.1-2.2; P=0.01) and patients in R-ISS stage II but with ISS stage III had a better overall survival than patients in R-ISS stage III (adjusted hazard ratio=0.7; 95% confidence interval: 0.4-0.9, P=0.02). However, among patients classified in R-ISS II, ISS stage and chromosomal abnormalities (del[17p] and t[4;14]) were still relevant prognostic factors for death. Dividing R-ISS stage II into three subgroups: ISS I with standard-risk chromosomal abnormalities, ISS II or III with standard-risk chromosomal abnormalities and patients with high-risk chromosomal abnormalities, median overall survival times were, respectively, not reached, 112 months and 71 months (P<0.001). In conclusion, stratification of patients in the R-ISS stage II group can be improved by taking into account chromosomal abnormalities and ISS. However, this does not improve predictive performance of survival models.

Introduction: Despite the implementation of new therapeutic agents, management of relapsed multiple myeloma (MM) remains a challenge. Salvage autologous hematopoietic cell transplant (AHCT) remains a valid therapeutic option for eligible patients who achieve prolonged response after a first AHCT. However, a second graft is not always available, and these patients may need a second mobilization., Patients and Methods: This prospective, non-interventional, multicenter study aimed to collect data on the feasibility of salvage AHCT using a plerixafor-based hematopoietic cell mobilization in relapsed MM, according to the plerixafor label in France. Adult patients with relapsed MM eligible for a second AHCT and mobilized using granulocyte- colony stimulating factor (G-CSF) and plerixafor were included., Results: Of the 23 patients, 17 achieved a successful hematopoietic cell mobilization and 13 were able to proceed to a second AHCT. Median age was 62.9 years (min-max 51-71). Ten patients (77%) were male. Eleven (85%) received AHCT as a third-line treatment or more. Median time between first and second AHCT was 5.4 years (range, 2.6-16.3). Among 18 evaluable patients, mobilization was successful for 17 (94%) of them [95% CI 84-100], with no reported side effects. Among the 13 patients who underwent salvage AHCT, the median time to engraftment was 14 days (min-max 11-29). One-year progression-free and overall survival were 88.9% [95% CI 43.3-98.4] and 100%, respectively., Conclusion: This study demonstrated that plerixafor allows safe and efficient mobilization in relapsed MM patients who are candidates for a salvage AHCT., Trial Registration: NCT02439476 Registered 8 May 2015, https://clinicaltrials.gov/ct2/show/NCT02439476 ., (© 2023. The Author(s).)

Multiple myeloma (MM) is an incurable blood cancer that primarily affects older adults. Several frailty tools have been developed to address the heterogeneity of aging in this population. Uptake of these measures has been variable, leading to a gap in knowledge regarding the proportion of enrolled trial participants considered frail and uncertainty in the treatment-related effects and outcomes among this high-risk population. We performed a systematic review of therapeutic interventional MM clinical trials reporting on frailty. We included 43 clinical trials (24 randomized controlled trials and 19 non-randomized trials) which met eligibility criteria. Frailty was increasingly incorporated in studies in more recent years with 41.9% of included studies being reported in the last two years. Commonly used frailty tools included the International Myeloma Working Group (IMWG) frailty index (41.8%), and the simplified frailty score (39.5%). Frailty status was categorized with 3 levels as (frail, intermediate fit, or fit) in 51.2% of the studies and dichotomized (frail, non-frail) in 18.6% of studies. Frailty prevalence greatly varied across trials ranging from 17.2% to 73.6% of the cohort. Of the included studies, 72.0% conducted subgroup analysis (planned or post-hoc) based on frailty status. Most studies demonstrated a consistent benefit of MM interventions among the frail and non-frail populations, however in general, frail patients had worse outcomes compared to the fit. Although frailty is increasingly being incorporated in MM clinical trials, due to the variation in both the definition and categorization of frailty, there remains heterogeneity in the prevalence of frailty and its potential associated impact on outcomes., (© 2022. The Author(s).)

In this subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285), we evaluated efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with carfilzomib-dexamethasone (Isa-Kd) versus Kd in older (≥70 years of age, n = 86) and younger (<70 years, n = 216) patients with relapsed multiple myeloma (MM). Patients received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks in the Isa-Kd arm, and approved schedule of carfilzomib (twice weekly) and dexamethasone in both study arms. Primary endpoint was progression-free survival (PFS); key secondary efficacy endpoints included rates of overall response (ORR), very good partial response or better (≥VGPR), minimal residual disease negativity (MRD-), and complete response (CR). Addition of Isa to Kd resulted in improved PFS in elderly patients (hazard ratio, 0.36 [95% CI, 0.18-0.75]) consistent with the significant PFS improvement observed in the overall IKEMA population. Treatment with Isa-Kd improved depth of response versus Kd, with higher rates of ≥VGPR (73.1% vs. 55.9%), MRD- (23.1% vs. 11.8%), and CR (38.5% vs. 23.5%). Although the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was higher in Isa-Kd, the incidence of serious TEAEs was similar between arms. Fewer elderly patients definitively discontinued treatment due to TEAEs in Isa-Kd than Kd: 11.8% versus 23.5%. In conclusion, Isa-Kd provides a consistent benefit versus Kd in elderly patients, with a manageable safety profile, and represents a new treatment option for patients with relapsed MM, independent of age., (© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Background: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma., Methods: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3-1·6 mg on days 1-21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030., Findings: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4-8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5-8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0-13·7) in the dose-escalation cohort and 7·7 months (5·3-11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23-43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18-36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events., Interpretation: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests SL reports consulting fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Takeda; institution grants or contracts from Bristol Myers Squibb, Janssen, and Takeda; membership on an entity's Board of Directors or advisory committees for TG Therapeutics; and stock ownership in TG Therapeutics. RP reports honoraria and travel grants from Bristol Myers Squibb. CH reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Cilag, Janssen Pharmaceuticals, Sanofi, and Takeda. SJ reports consulting fees from Bristol Myers Squibb, Elsevier, Janssen Pharmaceuticals, Karyopharm Therapeutics, Legend Biotech, Sanofi, and Takeda. AO reports honoraria and consulting fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi. PGR reports institution grants or contracts from Bristol Myers Squibb, Karyopharm Therapeutics, Oncopeptides, and Takeda; consulting fees from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. KW reports institution grants or contracts from Amgen, Bristol Myers Squibb, Celgene, Janssen Pharmaceuticals, GlaxoSmithKline, and Sanofi; honoraria and consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, and Takeda; and membership of an advisory board for German Society for Hematology and Medical Oncology and Stiftung Immunonkologie. MCM reports honoraria from Alnylam Pharmaceuticals, Bristol Myers Squibb, Cilag, Gilead Sciences, Janssen Pharmaceuticals, and Medscape; travel grants from Celgene, a Bristol Myers Squibb Company; and membership on an entity's Board of Directors or advisory committees for Bristol Myers Squibb. AZB reports research support from GlaxoSmithKline. SK reports honoraria, research support, and consulting fees from Bristol Myers Squibb. EAS reports institution grants or contracts from AbbVie and Bristol Myers Squibb; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, and GlaxoSmithKline; and membership on an entity's Board of Directors or advisory committees for Amgen. YC, TVN, AA, and TP are employees of Bristol Myers Squibb and have stock ownership in Bristol Myers Squibb. MA is an employee of Bristol Myers Squibb, has stock ownership in Bristol Myers Squibb, and has received travel grants from Bristol Myers Squibb. MC is an employee of Bristol Myers Squibb. NWCJvdD reports institution grants or contracts from Amgen, Cellectis, and Janssen Pharmaceuticals; and membership on an entity's Board of Directors or advisory committees for Adaptive Biotechnologies, Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Roche Sanofi, and Takeda. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics., Methods: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff., Results: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266-0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361-1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar., Conclusions: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a potentially transformative new approach to treating hematological malignancies. Ide-cel, an autologous B cell maturation antigen (BCMA) targeting CAR-T cells, has recently been approved to treat multiple myeloma (MM). Here, we review the main clinical trials of CAR-T cells in MM with the most advanced autologous BCMA-directed ide-cel and cilta-cel, the human CARs orva-cel and CT053, the alternative manufacturing process with P-BCMA-101 and bb21217, the dual CAR GC012F and the allogenic BCMA-directed CAR-T cells ALLO-715. In light of those clinical data, we provide an overview of CAR-T cells' main potential resistance mechanisms, including antigen loss, antigen spreading, anti-CAR antibodies, CAR-T cell exhaustion, and the emergence of a non-permissive microenvironment. Finally, we describe the principal area of research to build the next generation of CAR-T cells, with armored-, gated- or commuting-CARs, CARs associated with knock out of specific genes, and CAR-T cells made from γδT cells or NK cells., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221., (© 2022 by The American Society of Hematology.)

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., (© 2022. The Author(s).)

In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P < 0.0001) and frail (NR vs 30.4 months; HR, 0.62; P = 0.003). Improved rates of complete response or better and minimal residual disease (10 -5 ) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status., (© 2021. The Author(s).)

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. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172., (© 2022 by The American Society of Hematology.)

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, patients 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. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE)., (© 2022 by The American Society of Hematology.)