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Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

Background: Combination therapy regimens containing a proteasome inhibitor, an immunomodulatory drug, and a steroid are an established standard of care for patients with newly diagnosed multiple myeloma (NDMM) regardless of transplant eligibility. Triplet regimens that include lenalidomide/dexamethasone combined with daratumumab or carfilzomib are highly active in multiple myeloma, including NDMM. The aim of this open-label, phase 1b study was to evaluate daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) in patients with NDMM., Patients and Methods: Patients (n = 22), regardless of transplant eligibility, received treatment with D-KRd for up to thirteen 28-day cycles or until autologous stem cell transplant. The first daratumumab dose was administered as a split infusion (8 mg/kg on days 1 and 2 of cycle 1). The primary end point was safety and tolerability., Results: A total of 10 patients discontinued treatment, most frequently because of elective autologous stem cell transplant (n = 8). The most common treatment-emergent adverse events (any grade; grade 3/4) were diarrhea (68%; 18%), lymphopenia (64%; 59%), cough (59%; 5%), and upper respiratory tract infection (55%; 0%). Stem cell collection was successful in most patients (91%). Daratumumab infusion-related reactions occurred in 9 (41%) patients, primarily during the first infusion, and were mild in severity (no grade 3/4 events). The best overall response rate was 95%, including 86% with a very good partial response or better and 67% with a complete response or better., Conclusion: D-KRd was well tolerated, and encouraging efficacy results support further investigation of daratumumab-based quadruplet therapies for NDMM., Competing Interests: Conflict of Interest A.J. served on an advisory board and consulted for AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Juno, Karyopharm, Sanofi, and Takeda. S.Z.U. served in a consulting or advisory role for Amgen, AbbVie, Celgene, MundiPharma, Sanofi, Seattle Genetics, Janssen, Takeda, and SkylineDx and received grants from Bristol Myers Squibb and Pharmacyclics. A.K. served as a consultant for Janssen and Celgene; was a member of a speaker's bureau for Janssen, Sutro, Onyx Pharmaceuticals, Takeda, and Celgene; and holds equity in Celgene. S.L. received honoraria from Celgene, Janssen, Takeda, Novartis, Bristol Myers Squibb, GlaxoSmithKline, and Amgen. R.L.C. received research funding from Takeda, Janssen, and Karyopharm and is a scientific advisor for Takeda, Prothena, Caelum, and Janssen. B.M.W. reports research funding from Janssen during the course of the study, current employment with Janssen Research & Development LLC, and equity ownership in Johnson & Johnson. J.W. is an employee of Janssen. C.d.B., W.D., and J.M.S. are employees of Janssen and have equity ownership in Johnson & Johnson. A.C. received research funding from, served on an advisory board for, and consulted for Janssen, Celgene, Novartis, and Amgen; received research funding from and served on an advisory board for Seattle Genetics; received research funding from and consulted for Millennium/Takeda; received research funding from Pharmacyclics; served on an advisory board for Karyopharm, Sanofi, and Oncopeptides; and consulted for Bristol Myers Squibb and Antegene., (Copyright © 2021. Published by Elsevier Inc.)

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma., Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736., Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group., Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting., Funding: European Myeloma Network and Janssen Research and Development., Competing Interests: Declaration of interests MAD received honoraria for participation in advisory boards from Amgen, Takeda, Bristol Myers Squibb, Janssen, and BeiGene. ET received honoraria from Janssen, Genesis, Celgene, and Bristol Myers Squibb; research funding from Janssen and Genesis; and non-financial support from Genesis. MBo received honoraria and research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, and Bristol Myers Squibb; received honoraria from AbbVie; received research funding from Mundipharma; and served on an entity's board of directors or advisory committees for Janssen and GlaxoSmithKline. MBe served as a member on an entity's board of directors or advisory committees, and on a speakers' bureau for Janssen, Sanofi, Amgen, Bristol Myers Squibb, Oncopeptides, and Takeda. EK received honoraria, research funding, personal fees, and non-financial support from Janssen-Cilag. PM served as a consultant for and received honoraria from Celgene/Bristol Myers Squibb, Janssen, Amgen, AbbVie, and Sanofi. AS served on advisory committees and received research funding from Bristol Myers Squibb; served on advisory committees and speakers' bureaus for, and received research funding from, AbbVie, Amgen, Celgene/Genesis, and Sanofi/Genzyme; and received research funding from Astellas. AO served on advisory committees for Celgene/Bristol Myers Squibb, Sanofi, Amgen, and GlaxoSmithKline. M-VM served as a consultant for, received honoraria from, and served on an entity's board of directors or on advisory committees for Janssen, Bristol Myers Squibb/Celgene, Amgen, Takeda, Oncopeptides, GlaxoSmithKline, Sanofi, Pfizer, Regeneron, AbbVie/Genentech, Seattle Genetics, and Adaptive Biotechnologies. HE served as a consultant for, received honoraria and research funding from, and served on a speakers' bureau for Janssen, Celgene, Amgen, GlaxoSmithKline, and Sanofi; and served as a consultant for, received honoraria from, and served on a speakers' bureau for Takeda. TA is an employee of Genmab and is current equity holder in a publicly traded company. JU was an employee of Janssen and equity holder in a publicly traded company at the time of the study, and is currently an employee of Genmab and equity holder in a publicly traded company. TK, JMS, YQ, and RC are employees of Janssen. HA and JV are employees of Janssen and are current equity holders in a publicly traded company. PS received research funding from Amgen, Celgene, Janssen, and Takeda, and received honoraria and served on advisory committees for Janssen, Celgene, Amgen, Takeda, Bristol Myers Squibb, and Skyline Dx. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed., Patients and Methods: Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression., Results: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10 -5 ) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed., Conclusion: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates., (Copyright © 2019 Janssen Global Services, LLC. Published by Elsevier Inc. All rights reserved.)