Oncologists Favor CAR T-Cell Therapy for Early Relapsed Myeloma

Marc Braunstein, MD, PhD

Combination antimyeloma regimens with or without high-dose chemotherapy, autologous stem cell transplantation, and maintenance therapy have demonstrated the ability to achieve responses in most patients with newly diagnosed multiple myeloma (MM).^1-3 However, most patients will relapse, and effective treatment of relapsed/refractory MM (R/R MM) requires interventions that eliminate heterogenous clonal plasma cell populations that have evolved to increasingly resist treatment. One approach that has shown impressive outcomes in R/R MM is the use of chimeric antigen receptor (CAR) T cells that target B-cell maturation antigen (BCMA), a receptor involved in plasma cell differentiation and highly expressed in MM.⁴

Here we highlight data supporting the recent 2024 FDA approvals for use of 2 CAR T-cell products in MM, namely cilta-cel (ciltacabtagene autoleucel; Carvykti) and ide-cel (idecabtagene vicleucel; Abecma), in the early relapse setting. In addition, we include results summarizing the opinions of a series of 31 expert-led independent Case-Based Roundtables conducted in 2024 by Targeted Oncology, in which a total of 271 practicing oncologists across the United States discussed their views on operationalizing CAR T-cell therapy for early R/R MM.

Use of Anti-BCMA CAR T-Cells in R/R MM

Following the initial approvals of ide-cel in 2021 and cilta-cel in 2022 for R/R MM after 4 or more prior lines of treatment based on phase 2 data showing overall response rates (ORRs) of 73% and 97%, respectively, randomized data emerged in 2023 for patients with earlier relapses.^5,6 Ide-cel and cilta-cel showed superior progression-free survival (PFS) compared with standard 2- and 3-drug combination regimens [TABLE].^5,6

Data from KarMMA-3 (NCT03651128) and CARTITUDE-4 (NCT04181827) showed superiority in terms of all surrogate measures, including PFS, ORR, and minimal residual disease (MRD) negativity, while overall survival analyses are ongoing.^5,6 In addition, subgroup analyses of patients in CARTITUDE-4 with functionally high-risk MM who relapsed less than 18 months from frontline therapy showed superiority compared with standard-of-care regimens.⁷

CAR T cells require anywhere from 4 to 8 weeks from apheresis to manufacturing, and 86% of patients in KarMMA-3 received bridging therapy after apheresis. Fourteen percent of patients in CARTITUDE-4 did not immediately receive cilta-cel due to progressive disease. In addition to myelosuppression, in part related to the conditioning chemotherapy given immediately before CAR T-cell reinfusion, cytokine release syndrome occurred in most patients. However, this toxicity was mostly low grade in nature.

Neurotoxicity occurred in 15% and 21% of patients with ide-cel and cilta-cel, respectively, with 3% at grade 3 or higher in both studies. The risk of infections is increased due to immunosuppression for months after CAR T-cell infusion, and grade 3 or higher infections occurred in 24% vs 18% of patients in KarMMa-3 and 27% vs 25% in CARTITUDE-4. Despite the potential for serious adverse events, patient-reported outcomes were superior with CAR T cells.⁸ Emerging data comparing outcomes for cilta-cel and ide-cel suggest superior outcomes with cilta-cel.^9,10

Survey results from Case-Based Roundtables

When participants in the Case-Based Roundtable events were asked whether they currently refer patients with R/R MM for early-line use of CAR T cells, the overwhelming majority responded affirmatively [POLL 1].

In reviewing the case of a patient with lenalidomide-refractory MM, when asked about the next treatment after 1 prior line of therapy, 58% preferred CAR T cells [POLL 2]. In general, reasons for choosing “off- the-shelf” standard-of-care regimens may include availability, cost, poor fitness and perceived toxicity, lack of caregiver support, prohibitive distance from the treatment center, or patient preference.

Nevertheless, after reviewing the randomized data for using CAR T cells in the early relapse setting for MM, most respondents remained likely or very likely to refer [POLL 3].

Ongoing Analyses

Given the success of both ide-cel and cilta-cel in R/R MM, ongoing studies are exploring CAR T cells’ role in newly diagnosed MM. CARTITUDE-6 (NCT05257083) is examining PFS and MRD outcomes for patients with MM who initially receive quadruplet regimens and are randomly assigned to autologous stem cell transplant or cilta-cel. KarMMa-4 (NCT04196491) is a single-arm study exploring the safety of ide-cel in high-risk patients with newly diagnosed MM. In addition, the role of maintenance after CAR T-cell therapy remains uncertain. Studies are beginning to explore maintenance therapy, for example, with immunomodulatory drugs such as lenalidomide (NCT03070327) or cereblon E3 ligase modulators such as mezigdomide (NCT06048250).

Although survey results from the Case-Based Roundtables indicate a high preference for CAR T-cell therapy, issues including cost and access remain.¹¹ As CAR T cells become a mainstay of treatment paradigms across cancer types, the hope is that these issues will be surmountable and that more patients will be afforded CAR T-cell therapy.

_References:

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_{2. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. Published online February 5, 2025. doi:10.1038/s41591-024-03485-7}

_{3. Facon T, Dimopoulos MA, Leleu XP, et al; IMROZ Study Group. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712}

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_{5. 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. doi:10.1056/NEJMoa2213614}

_{6. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379}

_{7. Weisel K, Costa LJ, van de Donk NWCJ, et al. Ciltacabtagene autoleucel vs standard of care in patients with functional high-risk multiple myeloma: CARTITUDE-4 subgroup analysis. European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P959.}

_{8. Mina R, Mylin AK, Yokoyama H, et al. Patient-reported outcomes following ciltacabtagene autoleucel or standard of care in patients with lenalidomide-refractory multiple myeloma (CARTITUDE-4): results from a randomised, open-label, phase 3 trial. Lancet Haematol. 2025;12(1):e45-e56. doi:10.1016/S2352-3026(24)00320-X}

_{9. Merz M, Albici AM, von Tresckow B, et al. Idecabtagene vicleucel or ciltacabtagene autoleucel for relapsed or refractory multiple myeloma: an international multicenter study. Hemasphere. 2025;9(1):e70070. doi:10.1002/hem3.70070}

_{10. Bar N, Diels J, van Sanden S, et al. Comparative efficacy of ciltacabtagene autoleucel versus idecabtagene vicleucel in the treatment of patients with relapsed or refractory multiple myeloma previously treated with 2-4 prior lines of therapy: a matching-adjusted indirect comparison. Curr Med Res Opin. 2024;40(9):1597-1603. doi:10.1080/03007995.2024.2391112}

_{11. Ahmed N, Shahzad M, Shippey E, et al. Socioeconomic and racial disparity in chimeric antigen receptor T cell therapy access. Transplant Cell Ther. 2022;28(7):358-364. doi:10.1016/j.jtct.2022.04.008}