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The treatment landscape for multiple myeloma (MM) has rapidly evolved over the last 2 decades. The development of triplet and quadruplet regimens including proteasome inhibitors (PI), immunomodulatory agents (IMiDs), and anti-CD38 monoclonal antibodies has dramatically extended overall survival. In addition to effective multidrug regimens, autologous stem cell transplant (ASCT) is a cornerstone of management in newly diagnosed multiple myeloma (NDMM). However, despite these combined treatment modalities, curative therapy for MM remains elusive. Recent, novel immunotherapies including chimeric antigen T-cell (CAR-T) therapy have demonstrated deep and durable responses in relapsed and refractory multiple myeloma (RRMM). Currently 2 CAR-T products, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), are approved by the FDA for the treatment of RRMM. The success of CAR-T therapy revolutionized the management of RRMM prompting clinical trials studying CAR-T therapy in the first line setting. The ongoing KarMMa-4, CARTITUDE-5, and CARTITUDE-6 clinical trials may establish CAR-T therapy as a first line option potentially supplanting ASCT in the initial treatment of NDMM. In this review, we discuss the current standard of care management of NDMM, trace the evolution of CAR-T clinical trials in RRMM, and survey ongoing clinical trials studying CAR-T therapy in NDMM., Competing Interests: Disclosure EC reports no confilcts. SZU reports grants and personal fees from AbbVie, Amgen, BMS, Celgene, GSK, Gilead, Genentech, Janssen, Merck, Oncopeptides, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, Takeda and Teneobio., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) report significantly lower HRQoL compared with patients with newly diagnosed MM and experience further deterioration in HRQoL with each relapse and subsequent treatment. Therefore, consideration of the impact of treatment on HRQoL in addition to clinical outcomes is vital., Patients and Methods: In the phase I/II MajesTEC-1 (NCT03145181, NCT04557098) study, patients with RRMM who received teclistamab, an off-the-shelf, T-cell redirecting BCMA × CD3 bispecific antibody, had deep and durable responses with manageable safety. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30-item and the EuroQol 5 Dimension 5 Level descriptive questionnaire. Changes over time from baseline were measured with a repeated measures mixed-effects model. Proportions of patients with clinically meaningful improvement after starting treatment and time to clinically meaningful worsening were assessed., Results: Compliance was maintained throughout the study. Compared with baseline, positive changes were observed for pain, global health status, and emotional functioning with treatment; other assessments were largely unchanged from baseline. Post hoc analysis showed patients with deeper clinical response generally reported improved HRQoL outcomes. Following an initial decline in HRQoL in some scales, the proportion of patients reporting clinically meaningful improvements increased, while the proportion reporting clinically meaningful worsening decreased over time. Clinically meaningful improvements in pain were reported in ≥40% of patients at most assessment time points., Conclusions: These results complement previously reported clinical benefits and support teclistamab as a promising therapeutic option for patients with RRMM., (Copyright © 2023. Published by Elsevier Inc.)

Background: Daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are preferred regimens for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). Both DRd and VRd demonstrated superior efficacy versus Rd in the MAIA and SWOG S0777 trials, respectively, but there is no head-to-head (H2H) clinical trial comparing their efficacy. Differing populations in the MAIA and S0777 trials make an unadjusted comparison of outcomes challenging and biased. The current TAURUS study is the first real-world H2H study comparing progression-free survival (PFS) among TIE NDMM patients treated with DRd or VRd as first-line (1L) in similar clinical settings., Materials and Methods: A multicenter chart review study was conducted at nine sites across the United States. All TIE patients treated with DRd and a randomly selected population of VRd patients were included. TIE NDMM patients aged ≥65 were included if they initiated 1L DRd/VRd between January 2019 and September 2021. PFS was defined as the time from DRd/VRd initiation until disease progression or death. A doubly-robust multivariable Cox regression model combined with inverse probability of treatment weighting (IPTW) methodology was used to compare PFS between cohorts., Results: Weighted cohorts comprised 91 DRd and 87 VRd patients. Thirteen DRd and 24 VRd patients experienced progression/death. Patients treated with DRd had a lower risk of progression/death versus VRd (adjusted hazard ratio: 0.35, 95% confidence interval: [0.17; 0.73])., Conclusion: DRd is associated with a significantly lower risk of disease progression or death compared to VRd as 1L treatment for TIE NDMM patients., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with prior allogeneic stem cell transplant (alloSCT) are typically excluded from trials of chimeric antigen receptor (CAR) T cell therapies, because their engineered cells may include allogeneic T cells. Ciltacabtagene autoleucel (cilta-cel) demonstrated early, deep, durable responses and manageable safety in heavily pretreated relapsed/refractory multiple myeloma patients. We retrospectively analyzed patients who received alloSCT prior to cilta-cel in CARTITUDE-1., Patients and Methods: Patients eligible for CARTITUDE-1 were ≥18 years, had ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Patients with active graft-versus-host disease (GVHD) or had alloSCT within 6 months before apheresis were excluded. Patients received cilta-cel 5 to 7 days after lymphodepletion., Results: Patients (N = 7) received median 9 prior LOTs (range, 6-14); median time since alloSCT was 5.1 years (range, 2.7-6.2). At median follow-up 27.7 months after cilta-cel infusion, overall response rate was 85.7% (n = 6). The safety profile was generally consistent with patients without alloSCT as prior therapy (cytokine release syndrome, 85.7% vs. 95.6%, respectively; immune effector cell-associated neurotoxicity syndrome, 14.3% vs. 16.7%). One patient with prior alloSCT had grade 3 movement and neurocognitive treatment-emergent adverse events/parkinsonism. No GVHD cases were reported. Two patients died due to adverse events (treatment-related lung abscess; unrelated liver failure)., Conclusion: Cilta-cel efficacy and safety were comparable between CARTITUDE-1 patients with and without prior alloSCT. Additional studies are needed to fully elucidate the suitability of CAR-T cell therapy in the post-alloSCT setting., Competing Interests: Disclosure M. Htut consulted and served on advisory committees for and received travel funding from Millennium; and received research funding from Judy and Bernard Briskin Center for Multiple Myeloma Research (Inst) and BMS (Inst). B. Dhakal consulted and served on advisory committees for Amgen, Takeda, Janssen, GlaxoSmithKline, Natera, and Sanofi; received honoraria from Celgene, Karyopharm Therapeutics, Sanofi, and GlaxoSmithKline; and received research funding from Amgen, Janssen, and GlaxoSmithKline. A.D. Cohen consulted and served on advisory committees for Celgene, Janssen Oncology, Oncopeptides, Takeda, Seattle Genetics, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, AstraZeneca, and Roche/Genentech; received research funding from Novartis (Inst) and GlaxoSmithKline (Inst); has patents related to CAR-T cells and biomarkers of cytokine release syndrome; has given expert testimony for Janssen Oncology; and received travel funding from GlaxoSmithKline, Takeda, Celgene, and Janssen Oncology. T. Martin consulted and served on advisory committees for GlaxoSmithKline and Legend Biotech USA Inc. and received research funding from Sanofi (Inst), Amgen (Inst), and Janssen Oncology (Inst). J.G. Berdeja consulted and served on advisory committees for Takeda (Inst), Bristol-Myers Squibb (Inst), CRISPR Therapeutics (Inst), Celgene (Inst), Kite, a Gilead company (Inst), Janssen (Inst), Legend Biotech (Inst), Secura Bio (Inst), and Bluebird Bio (Inst); and received research funding from Celgene (Inst), Takeda (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Janssen (Inst), Novartis (Inst), AbbVie (Inst), Bluebird Bio (Inst), Teva (Inst), Genentech/Roche (Inst), Poseida Therapeutics (Inst), Sanofi (Inst), Acetylon Pharmaceuticals (Inst), Lilly (Inst), Celularity (Inst), CRISPR Therapeutics (Inst), EMD Serono (Inst), Ichnos Sciences (Inst), GlaxoSmithKline (Inst), and Incyte (Inst). S.Z. Usmani consulted and served on advisory committees for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GlaxoSmithKline, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol-Myers Squibb/Celgene; served on speakers’ bureaus for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol-Myers Squibb/Celgene; and received research funding from Celgene, Array BioPharma, Janssen Oncology, Pharmacyclics, Sanofi, Bristol-Myers Squibb, Amgen, Seattle Genetics, Merck, SkylineDx, and GlaxoSmithKline. M. Agha owns stock in GenCART, Inc. D. Madduri is employed by Janssen Oncology; owns stock in Roivant; and consulted and served on advisory committees for Takeda, Janssen Oncology, Celgene, Legend Biotech USA Inc., GlaxoSmithKline, and Foundation Medicine. C.C. Jackson is employed by Janssen and owns stock in Janssen; and served as a consultant physician for Memorial Sloan Kettering Cancer Center. W. Deraedt, T.-m. Yeh, and X. Xu are employed by and own stock in Janssen. E. Zudaire is employed by, owns stock in, received travel funding from, and has patents pending with Janssen. L. Pacaud is employed by and owns stock in Legend Biotech USA Inc. M. Akram is employed by Legend Biotech USA, Inc. S. Jagannath consulted and served on advisory committees for Bristol-Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech USA Inc., Takeda, and Sanofi; and received travel funding from Bristol-Myers Squibb and Janssen., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Multiple myeloma is a hematologic malignancy that is typically associated with recurrent relapses. There are numerous frontline treatment regimens that are highly effective for individual patients. The introduction of anti-CD38 monoclonal antibody therapy has shifted treatment decision-making in this setting, with many centers now considering the use of daratumumab as part of initial therapy regardless of patient eligibility for autologous stem cell transplantation (ASCT). Daratumumab has demonstrated clinical efficacy and acceptable toxicity in the first and later lines of therapy, increasing complexity in treatment selection and sequencing. Although daratumumab-containing regimens may not be appropriate for every patient, it is increasingly recognized that the most effective regimens should be used upfront, as high rates of attrition mean that many patients in real-world practice may see a limited number of lines of therapy., Methods: A panel of experts in multiple myeloma was convened to consider current evidence and treatment practices to inform a series of consensus statements on the optimal management of newly diagnosed multiple myeloma, including not only treatment selection, but the need for infection prophylaxis, route of administration, and mitigation of potential infusion-related reactions, among other clinical challenges., Results/conclusions: The goal of the present review article is to encapsulate these consensus statements and the rationale for their development, which altogether may help inform treatment selection and clinical decision-making in the front line., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Treatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy., Methods: Enrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression. The primary endpoint was VGPR or better (≥VGPR) postinduction. Secondary endpoints were MRD by flow cytometry, OS, PFS, and safety. Correlatives included characterization of the impact of Elo-KRd on NK and T cell subsets via flow cytometry. Target accrual of 40 patients was not met due to COVID-19 pandemic., Results: Of 15 patients enrolled, 10 (67%) had high-risk features (del17p, t[4;14], t[14;16], 1q gain/amplification, plasma cell leukemia, extramedullary MM, or functional high risk), 12 (80%) were lenalidomide-refractory, and 5 (33.3%) bortezomib-refractory. Postinduction ≥VGPR was 7/15 (46.7%) and MRD-negative (10 -5 ) rate 20%. Overall response during study was 80%, including ≥VGPR as best response of 53.3%. At median follow-up of 28.2 (range, 3.8 to 44.2) months, the median PFS was 11.5 months (95% CI 1.9, 18), and median OS not reached (95% CI 10.1, NA). No new safety concerns were reported. Elo-KRd treatment did not augment NK cell distribution or activity in blood or bone marrow. Effector CD4+ and CD8+ T cells significantly decreased postinduction, with concomitant acquisition of T central memory phenotype, particularly at a high rate in ≥VGPR group., Conclusion: A short course of Elo-KRd induction followed by Elo-lenalidomide maintenance demonstrated activity in predominantly lenalidomide-refractory and / or high-risk MM. The results with this well-tolerated combination are comparable to other contemporary approved triplet combinations., Competing Interests: Disclosure Bhutani: Research Funding: Janssen R&D, MedImmune, Legend Biotech, Amgen, Celularity, Adaptive Biotechnologies, Bristol Myers Squibb / Celgene, Bluebird bio, Millenium, Cerecor, Takeda; Consultancy: Sanofi, Janssen, Atrash: Honoraria and Research Funding: GSK; Honoraria and Speakers Bureau: Celgene, Sanofi, Janssen; Honoraria: Takeda; Membership on an entity's Board of Directors or advisory committees: Janssen; Research Funding: Amgen. Paul: Membership on an entity's Board of Directors or advisory committees: Abbvie, Janssen, Regeneron; Speakers Bureau: Amgen, Symanowski: Consultancy: Camarus, Eli Lilly and Co, CARsgen, Immatics, Voorhees: Consultancy and Honoraria: Abbvie, Amgen, BMS, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Sanofi, SecuraBio, Usmani: Research Funding: AbbVie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen Pharmaceuticals, Oncopeptides, Sanofi, Seagen Inc, formerly Seattle Genetics, Inc, Secura Bio, Inc, SkylineDX, Takeda, TeneoBio, Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen; Consultancy: Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen Pharmaceuticals, Merck, Pharmacyclics, Sanofi, Seagen Inc, formerly Seattle Genetics, Inc, SkylineDX, Takeda; Speakers Bureau: Amgen, BMS, Janssen Pharmaceuticals, Sanofi. *Other authors declare no COI., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The efficacy and safety of teclistamab in patients with RRMM who received ≥3 prior lines of therapy and were triple-class exposed (TCE) are being evaluated in the single-arm, multicohort, phase I/II MajesTEC-1 trial (NCT04557098). We evaluated the comparative effectiveness of teclistamab versus physician's choice (PC) of therapy in TCE RRMM patients., Methods: Individual patient-level data from MajesTEC-1 patients who received teclistamab (1.5 mg/kg weekly; clinical cutoff March 16, 2022) were included. An external control arm was created from patients in long-term follow-up of 4 clinical trials of daratumumab who were treated with PC therapy after discontinuation of trial treatments. In the primary analysis, inverse probability of treatment weighting was used to adjust for imbalances in 9 baseline covariates. A fully adjusted model included 5 additional prognostic factors. Outcomes included overall response rate (ORR), very good partial response or better (≥VGPR) rate, overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT)., Results: After adjustment, baseline characteristics were balanced between cohorts. In the primary analysis, outcomes were significantly improved with teclistamab versus PC: ORR (OR [95% CI] 4.81 [3.04-7.72]; P < .0001); ≥VGPR rate (OR, 12.07 [6.91-22.11]; P < .0001); OS (HR, 0.54 [0.40-0.73]; P < .0001); PFS (HR, 0.59 [0.46-0.78]; P = .0001); and TTNT (HR, 0.32 [0.24-0.42]; P < .0001). Results of the fully adjusted model were consistent with the primary analysis., Conclusion: Teclistamab showed significantly improved effectiveness versus PC on all outcomes, highlighting its clinical benefit in patients with TCE RRMM and limited treatment options., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Infections are a common reason for hospitalization and death in multiple myeloma (MM). Although pneumococcal vaccination (PV) and influenza vaccination (FV) are recommended for MM patients, data on vaccination status and outcomes are limited in MM., Materials and Methods: We utilized data from the global, prospective, observational INSIGHT MM study to analyze FV and PV rates and associated outcomes of patients with MM enrolled 2016-2019., Results: Of the 4307 patients enrolled, 2543 and 2500 had study-entry data on FV and PV status. Overall vaccination rates were low (FV 39.6%, PV 30.2%) and varied by region. On separate multivariable analyses of overall survival (OS) by Cox model, FV in the prior 2 years and PV in the prior 5 years impacted OS (vs. no vaccination; FV: HR, 0.73; 95% CI, 0.60-0.90; P = .003; PV: HR, 0.51; 95% CI, 0.42-0.63; P < .0001) when adjusted for age, region, performance status, disease stage, cytogenetics at diagnosis, MM symptoms, disease status, time since diagnosis, and prior transplant. Proportions of deaths due to infections were lower among vaccinated versus non-vaccinated patients (FV: 9.8% vs. 15.3%, P = .142; PV: 9.9% vs. 18.0%, P = .032). Patients with FV had generally lower health resource utilization (HRU) versus patients without FV; patients with PV had higher or similar HRU versus patients without PV., Conclusion: Vaccination is important in MM and should be encouraged. Vaccination status should be recorded in prospective clinical trials as it may affect survival. This trial was registered at www., Clinicaltrials: gov as #NCT02761187., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Minimal residual disease (MRD) status is an established prognostic biomarker for patients with multiple myeloma. Commonly used MRD testing techniques such as next generation sequencing or next generation flow cytometry can detect as little as one or two multiple myeloma plasma cells in 10 6 normal bone marrow cells. Early pull of bone marrow aspirates (BMA), necessary to achieve such level of sensitivity, can be difficult to secure in routine clinical practice due to the competing need for early pull samples for clinical response assessment, therefore introducing the risk of analytical interference during MRD testing., Methods: To overcome this challenge, we standardized our workflow for collecting specimens by using a technical first pull after needle repositioning for MRD testing. To capture a comprehensive picture of MRD assay performance and specimen adequacy, we tested for MRD on 556 technical first pull bone marrow aspirates by next generation flow cytometry. Among the specimens, several key multiple myeloma treatment milestones were represented: end of induction therapy, two to three months post-autologous stem cell transplant, early and late stages of maintenance therapy., Results: By using the technical first pull bone marrow aspirate, we achieved an analytical assay input of 10 million nucleated cells for 97.5% of specimens. Our analytical sensitivity reached 10 -6; (i.e., 10 multiple myeloma plasma cells in 10 × 10 6 bone marrow cells). Twenty-four percent of specimens were significantly hemodiluted. Low assay input or hemodilution quantifiably lowered the assay sensitivity., Conclusion: Specimen adequacy is, therefore, an important metric to incorporate into MRD status reporting., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation., Methods: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study., Results: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments., Conclusion: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody., Patients and Methods: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival., Results: After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant., Conclusion: Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed)., Patients and Methods: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients., Results: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods., Conclusion: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.)

Introduction: Daratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab., Methods: A retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort)., Results: The study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003)., Conclusion: Subcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications., (Copyright © 2021. Published by Elsevier Inc.)

Background: We evaluated time to thromboembolism (TE) and risk factors in multiple myeloma (MM) patients after first exposure to immunomodulatory therapy, stratified by thromboprophylaxis., Patients and Methods: We retrospectively analyzed adult MM patients who received immunomodulatory therapy with or without dexamethasone between February 2012 and October 2017. Thromboprophylaxis included aspirin, anticoagulants (low-molecular-weight heparin, direct oral anticoagulants, or warfarin), or none. Primary endpoint was time to on-treatment TE by thromboprophylaxis type. Time to TE using death as a competing risk censored at 12 months was used in univariate and multivariable analyses to identify risk factors., Results: Of 485 evaluable patients, 57% were white and 36% African American; median age was 66. Most received lenalidomide (97.5%) and dexamethasone (90%). Half presented with ≥ 1 comorbidities. Sixty-nine had no documented receipt of prophylaxis, 357 aspirin, and 59 anticoagulation. More patients receiving anticoagulants had ≥ 1 comorbidities compared to aspirin or no-prophylaxis groups (P < .001). There was no difference in 12-month estimated cumulative incidence of TE (7.3%; 95% confidence interval, 5.2-9.9) between thromboprophylaxis groups (none 4.4%, aspirin 8.5%, anticoagulant 3.4%) (P = .24). In multivariable analyses, male sex (hazard ratio, 2.50; 95% confidence interval, 1.21-5.17; P = .014) and presence of any comorbidity (hazard ratio, 2.35; 95% confidence interval, 1.17-4.73; P = .016) were associated with TE incidence; thromboprophylaxis type was not (P = .12)., Conclusion: Male sex and presence of any comorbidity were associated with time to TE. There were no differences in TE incidence between thromboprophylaxis groups despite a higher proportion of those in the anticoagulant group having ≥ 1 comorbidities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Relapsed/refractory multiple myeloma (MM) remains a significant clinical challenge, despite a wide array of approved therapeutic agents. Immunotherapy offers an advantage in this setting. Chimeric antigen receptor (CAR) modified T-cells have transformed care for patients with hematologic malignancies. CAR-T cells targeting CD-19 B-cell lymphoma cells have shown prominent activity in lymphoma and acute lymphoblastic leukemia. Recently, the CAR-T cell platform for MM demonstrated therapeutic benefit. Hence, it is rapidly progressing. The most commonly tested target for MM is the B-cell maturation antigen. Complexities involved in the generation and use of CAR-T cells for MM include the identification of appropriate target antigens that are specific, and tumor type restricted, in addition to the optimization of CAR constructs to mitigate toxicities including cytokine release syndrome. CAR-T cells hold immense promise as a therapeutic modality for the treatment of MM. In this article, we provide an updated review of clinical trials of MM-specific CAR-T cells., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs., Patients and Methods: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion., Results: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations., Conclusion: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol., Patients and Methods: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity., Results: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively., Conclusion: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Considerable advances have been made in the treatment of relapsed and relapsed/refractory multiple myeloma, with numerous novel agents and combination strategies receiving regulatory approval worldwide during the past several years. An increasing body of phase III data has clearly demonstrated increased overall response rates, improved depths of response, and more durable responses when a third novel agent is incorporated into lenalidomide-dexamethasone and bortezomib-dexamethasone platforms, in most cases with acceptable toxicity. The carfilzomib-dexamethasone doublet has also demonstrated promising activity. With this rapid progress has come many new questions. We review the data supporting the use of these novel treatment paradigms for relapsed/refractory multiple myeloma, discuss the place of autologous and allogeneic hematopoietic stem cell transplantation in this rapidly evolving treatment space, and propose strategies to best use these regimens, considering the disease, host, and previous treatment factors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The outcomes and management of multiple myeloma (MM) in the United States have changed dramatically over the past 15 years with the approval by the US Food and Drug Administration (FDA) of 6 new drugs (thalidomide, lenalidomide, bortezomib, pegylated liposomal doxorubicin [Doxil], carfilzomib, and pomalidomide). Despite these advances, a majority of patients with MM relapse, requiring subsequent lines of therapy to manage their disease as a chronic condition. Even though oncologists recognize the heterogeneity in the biology and clinical presentation of patients with newly diagnosed MM, clinical investigations still approach MM in a one-size-fits-all manner. The clinical management becomes even more challenging for relapsed/refractory MM, in which the clinician is balancing disease biology, disease burden, host factors, and financial limitations. There are several new drug targets and antibodies making their way through clinical development, but clinical trials remain an important avenue for patients with relapsed/refractory MM. The present review highlights some of the novel agent combinations in clinical trials that include the 2 most recently approved anti-MM agents, carfilzomib and pomalidomide, and looks ahead toward new drugs and targets in myeloma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Invasion of CNS in MM is an extremely rare occurrence that is associated with advanced disease with poor prognosis., Patients and Methods: Our MM database identified 35 CNS MM cases presenting between January 1996 and March 2012. Descriptive analyses were performed on available data on patient characteristics, disease course, and outcomes., Results: The mean age at diagnosis was 55.4 years; 23.5% (n = 8) patients had elevated levels of beta-2-microglobulin > 5.5 mg/L; 68.6% (n = 24) of patients had elevated lactate dehydrogenase (LDH) levels (≥ 2 times upper limit of normal); and 14% (n = 5) of patients had secondary plasma cell leukemia. Magnetic resonance imaging (MRI), which was performed in 34 patients, showed diffuse or localized leptomeningeal disease in 20 patients (58.8%). Monoclonal malignant plasma cells were found by CSF analysis in all 35 patients. In total, 31 patients received chemotherapy, including intrathecal chemotherapy as a part of their treatment, with a median survival of 4 months after CNS MM diagnosis., Discussion: In our experience, CNS MM is an aggressive terminal disease feature associated with high beta-2-microglobulin level, high LDH level, and secondary plasma cell leukemia. This study highlights an unmet need in this subset of patients with high-risk, relapsed or refractory MM., Conclusion: Achieving adequate CSF penetration while limiting the off-target effects needs to be considered in MM-specific novel drug development., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The heat shock protein 90 (HSP90) family of proteins are ubiquitous molecular chaperones that are intricately involved in folding, activation, maturation, and assembly of many proteins that include essential mediators of signal transduction and cell cycle progression. They are abundant in eukaryotic cells and localized to the cytoplasm and mitochondria as well as the endoplasmic reticulum under normal conditions, making up 1% to 2% of all cellular proteins. HSP90 proteins have increased expression in a number of malignancies, including multiple myeloma. HSP90 inhibition can influence multiple oncogenic pathways and proteins involved in myeloma, therefore making it an attractive target for drug development in this disease. This article serves as an overview of the pre-clinical data and clinical trial data on HSP90 inhibitors in multiple myeloma., (Copyright © 2011. Published by Elsevier Inc.)