Patients with multiple myeloma (MM) that is relapsed or refractory to all three classes of drugs — including immunomodulatory agents (IMiD), proteasome inhibitors (PI), and anti-CD38 monoclonal antibodies — have a poor prognosis, with a median progression-free survival (PFS) of 3 to 4 months and overall survival (OS) ranging from 5.6 to 13 months.1,2 The U.S. Food and Drug Administration (FDA) approved the B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel) in March 2021 for patients treated with four or more prior lines of therapy including an IMiD, PI, and anti-CD38 monoclonal antibody.3 Given the remarkable efficacy and acceptable safety in patients with heavily pretreated relapsed and refractory MM (RRMM), as seen in the pivotal phase II KarMMa trial, ide-cel is being explored in earlier lines of therapy.4
KarMMA-3 is a randomized, open-label, phase III trial comparing ide-cel versus standard regimens for patients with RRMM after two to four previous therapies, including daratumumab, an IMiD, and a PI.5 Patients were randomized 2:1 to receive either of the following:
ide-cel (target dose range, 150×106 to 450×106 CAR-positive T cells)
one of five standard regimens chosen before randomization on the basis of the patient’s most recent treatment regimen and investigator discretion (daratumumab, pomalidomide, and dexamethasone; daratumumab, bortezomib, and dexamethasone; ixazomib, lenalidomide, and dexamethasone; carfilzomib and dexamethasone; or elotuzumab, pomalidomide, and dexamethasone)
The primary endpoint was PFS, and the primary efficacy analysis was conducted in the intention-to-treat population, which included all patients who had undergone randomization. Baseline patient characteristics were well-balanced in the two groups, except for race: Fewer black patients received ide-cel therapy (7%) than the standard regimen (14%). Nearly 25% of the patients had extramedullary disease, 40% had high-risk cytogenetic abnormalities, two-thirds had triple-class-refractory MM, and 95% had daratumumab-refractory MM. The median number of previous regimens in each group was three (range, 2-4).
Over a median follow-up of 18.6 months, PFS was significantly longer in the ide-cel group (13.3 months) than in the standard regimen group (4.4 months), with a consistent benefit of ide-cel observed across all prespecified subgroups. Similarly, ide-cel led to superior overall response rates (71% versus 42%) and complete response rates (39% vs. 5%) than the standard regimens. Common CAR T-cell–related toxicities included cytokine release syndrome (all grades, 88%; grade ≥3, 5%) and neurotoxicity (all grades, 15%; grade ≥3, 3%), at rates comparable to those in previous reports. Treatment-related cytopenias were more common with ide-cel than with the standard regimen, including neutropenia (78% vs. 44%), anemia (66% vs. 36%), and thrombocytopenia (54% vs. 29%). There were no significant differences in risk of infections (54-58%). Treatment-related mortality was seen in 6% of patients in each group; the most common cause of death in either group was disease progression (17%).
In Brief
Results from the KarMMa-3 trial reinforce that, regardless of the number of lines of therapy in triple-class–exposed MM, outcomes are poor when patients are refractory to an anti-CD38 monoclonal antibody, as shown by the inferior PFS in the standard regimen group. This trial had a high proportion of patients with high-risk features, including extramedullary disease, high-risk cytogenetic abnormalities, daratumumab refractoriness, a median time from diagnosis of four years, and a median time to progression on last line of therapy of seven months. The efficacy outcomes were similar with ide-cel across all these subgroups. It is important to highlight that, despite most patients having daratumumab-refractory disease, the most commonly used chemotherapy combinations in the standard regimen group were daratumumab-based. This reveals an area of unmet need for this patient population during the time of accrual on this clinical trial. The safety profile of ide-cel was similar to that described in previous reports, with no new safety signals associated with CAR T-cell therapy. The trial’s followup period is short, so it will be important to see whether there is a difference in OS in the two groups, especially for patients who receive CAR T-cell therapy upon progression on standard regimens. The key questions around optimal sequencing of this option in earlier lines of therapy will be dependent on the approved indication by the regulatory authorities.
Competing Interests
Dr. Hashmi reported advisory board activity for Janssen. Dr. Usmani received research funding from Amgen, BMS/Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, amd Takeda, and reported consulting/advisory board activity for Abbvie, Amgen, BMS, Celgene, Genentech, Gilead, GSK, Janssen, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
