In patients with lenalidomide-refractory multiple myeloma (MM) who had received one to three previous therapies, a single infusion of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapy, resulted in a lower risk of disease progression or death than standard care, according to an interim study analysis published in the New England Journal of Medicine.
“Since lenalidomide is extensively used as frontline therapy in patients with myeloma, lenalidomide refractoriness early in the patient disease course is becoming increasingly common, which rules out the use of lenalidomide-based regimens in subsequent lines,” said study author Binod Dhakal, MD, of the Medical College of Wisconsin in Milwaukee. “Our results show a strong progression-free survival (PFS) benefit and rapid and deep response with cilta-cel. This highlights the potential for cilta-cel to become a key therapeutic option for patients with MM after first relapse.”
The phase III, randomized, open-label CARTITUDE-4 trial is investigating the use of cilta-cel as an earlier line therapy compared with the currently approved use of cilta-cel in the U.S., where patients must have received four or more prior lines of therapy, and in Europe, where patients must have received three or more prior lines of therapy. To be eligible for the study, patients had to have received one to three prior therapies and have MM that was no longer responding to lenalidomide.
From July 10, 2020, to November 17, 2021, a total of 419 patients were randomized to either receive a single dose of cilta-cel or standard care, which was physician’s choice of pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone. Of the 208 patients who were assigned to receive cilta-cel (median age = 61.5; 55.8% male), 176 received the treatment. Of the 211 patients who were assigned to received standard care (median age = 61.0; 58.8% male), 208 received it. The primary outcome was PFS.
At a median follow-up of 15.9 months, the median PFS was not reached in the cilta-cel group and was 11.8 months in the standard care group (hazard ratio [HR] = 0.26; 95% CI 0.18-0.38; p<0.0001). The PFS at 12 months was 75.9% and 48.6%, respectively, in the cilta-cel and standard care groups. Cilta-cel also led to higher rates of overall response than standard care (84.6% vs. 67.3%), complete response or better (73.1% vs. 21.8%), and measurable residual disease negativity (60.6% vs. 15.6%).
“These findings are important because they show the superiority of cilta-cel compared with highly effective standard-of-care therapies in patients with lenalidomide-refractory MM as early as after first relapse,” Dr. Dhakal said.
Death from any cause was reported in 39 patients in the cilta-cel group and 46 patients in the standard care group (HR=0.78; 95% CI 0.5-1.2). Most patients reported grade 3 or 4 adverse events (AEs) during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 76.1% had cytokine release syndrome (CRS), 4.5% had immune effector cell–associated neurotoxicity syndrome (ICANS), one patient had movement and neurocognitive symptoms, 9.1% had cranial nerve palsy, and 2.8% had CAR-T-related peripheral neuropathy.
“We observed lower incidences of CRS, ICANS, and movement and neurocognitive treatment-emergent AEs in CARTITUDE-4 versus CARTITUDE-1 (patients with three or more prior lines of therapy), suggesting improved tolerability of cilta-cel when used in earlier lines of treatment,” said study author Jesús San-Miguel, MD, PhD, of the University of Navarra in Spain.
“We will continue to follow patients in this study to better understand the longer-term efficacy and safety profile of cilta-cel. We are currently performing deeper analysis of the data from CARTITUDE-4, including looking at health-related quality of life as well as biomarker analysis,” said Dr. San-Miguel.
A limitation to the study was that two highly efficacious triplet regimens – daratumumab, carfilzomib, and dexamethasone; and isatuximab, carfilzomib, and dexamethasone – were not approved at the time of trial initiation and could not be included as standard care options.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma [published online ahead of print, 2023 Jun 5]. N Engl J Med. doi: 10.1056/NEJMoa2303379.
Perspectives
BCMA-directed CAR T-cell therapies idecabtagene vicleucel (ide-cel) and cilta-cel are approved for patients with relapsed or refractory (R/R) myeloma with at least four prior lines of therapy. However, effective fourth-line (or bridging) therapies that can successfully transition patients to commercial product are lacking. Furthermore, many patients have received years of immunosuppressive therapy, raising concern about T-cell fitness. Thus, the randomized CARTITUDE-4 and KarMMa-3 trials that demonstrated superior PFS with CAR-T compared to standard-of-care (SOC) combinations in earlier lines are of significant interest.1,2 But, do these studies mean that all patients with R/R disease should receive CAR-T as early as possible? To answer this key question, we need to determine whether CAR-T in earlier lines is substantially more efficacious than in late lines, whether there are any late-occurring toxicities, and whether we can ensure equitable access.
With respect to the first point, the 12-month PFS rate for cilta-cel was 76% in CARTITUDE-4, very similar to the 77% from CARTITUDE-1.3 The median PFS in KarMMa-1 was 8.8 months versus 13.3 months in KarMMa-3.2,4 CARTITUDE-4 and KarMMa-3 enrolled different patient populations: one to three prior lines with only 25% receiving prior anti-CD38 monoclonal antibodies (mAbs; CARTITUDE-4) versus two to four prior lines with 95% refractory to anti-CD38 mAbs (KarMMa-3). The two studies used different SOC combinations in the control arms (primarily daratumumab, pomalidomide, and dexamethasone in CARTITUDE-4), and neither study included the highly effective combination of anti-CD38 mAbs, carfilzomib, and dexamethasone.
CARTITUDE-4 reported the expected acute ICANS events but also noted movement disorders, cranial nerve palsies, and peripheral neuropathy. Whether other late-occurring toxicities will be recognized remains to be determined.
The implementation of commercial CAR-T has been confounded by insufficient manufacturing capacities, leading to waiting lists and delays. The lack of equitable access to myeloma CAR-T trials has been established.5 In CARTITUDE-4, only 3% of the enrolled participants identified as Black, thus raising questions regarding safety and efficacy in this population.
The results of CARTITUDE-4 are impressive and represent an important step toward use of cilta-cel in earlier lines, although uncertainty remains about optimal sequencing. Concerted efforts are required to ensure that all underserved populations (racial/ethnic, geographic, socioeconomic) have equitable access to CAR-T therapy.
Sarah A. Holstein, MD, PhD
University of Nebraska Medical Center
Omaha, Nebraska
Conflict of Interest Statement: Dr. Holstein has served as a consultant for Abbvie, Celgene, Genentech, Janssen, Oncopeptides, Sorrento, and Takeda and has received research funding from BMS and Oncopeptides.
References
- San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. [published online ahead of print, 2023 Jun 5]. N Engl J Med. doi: 10.1056/NEJMoa2303379.
- Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014.
- Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label. Lancet. 2021;398(10297):314-324.
- Munshi NC, Anderson Jr LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716.
- Alqazaqi R, Schinke C, Thanendrarajan S, et al. Geographic and racial disparities in access to chimeric antigen receptor-T cells and bispecific antibodies trials for multiple myeloma. JAMA Netw Open. 2022;5(8):e2228877.
