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The Impact of Car-t in Multiple Myeloma

Year: 2025
Type: article
Abstract: T-cell redirecting therapies (TCR) marked a step forward in the treatment of relapsed/refractory multiple myeloma (RRMM). These agents, represented by chimeric antigen receptor (CAR) T-cells and bispecific antibodies (BsAbs), proved to ameliorate the prognosis of RRMM in pivotal clinical trials, leading to their introduction into clinical practice and are currently under investigation in newly diagnosed patients (NDMM). The main targets explored with available CART constructs include the B-cell maturation antigen (BCMA) and the G protein-coupled receptor class C group 5 member D (GPRC5D). Other products designed to recognize further antigens that can be targeted either alone or in combination with B-cell maturation antigen (BCMA) are under development. Idecabtagene vicleucel (Ide-cel) was first explored in patients exposed to at least 3 previous lines of therapy (LOT) in the phase II KarMMa trial; Overall response rate (ORR) was 73%; 52% of patients obtained a very good partial response (VGPR), or better. Median progression-free survival (mPFS) was 8.8 months (mos) and mOS was 19.4 mos.1 Subsequently, the phase III KarMMa-3 trial enrolled patients exposed to two-four previous LOT, who were randomized to receive either ide-cel or standard of care (SOC) therapy. ORR was 71% for ide-cel vs 42% for SOC; CR rate was 44% vs 6%, respectively. Ide-cel demonstrated a PFS benefit with a mPFS of 13.8 mos vs 4.4 mos. Partially due to the possibility of crossover, no OS benefit was demonstrated, with a mOS of 41.4 mos and 37.9 mos respectively. When adjusting for crossover, the ide-cel arm portended a trend toward superior OS when compared to the SOC arm (mOS 41.4 mos vs 23.4 mos, respectively).2,3 Ide-cel is currently approved by FDA and EMA for RRMM who received at least two prior LOT, including an IMiD, a PI and an anti-CD38 antibody and have demonstrated disease progression on the last therapy. Ciltacabtagene autoleucel (cilta-cel) is a CAR-T agent expressing two BCMA-targeting single-domain antibodies designed to confer high avidity4 CARTITUDE-1 was a phase Ib/II study that explored cilta-cel for patients previously exposed to at least 3 LOT or double refractory to a PI and an IMiD. ORR was 97.9%, with a stringent complete response (sCR) rate of 82.5%. At 27 mos, PFS was 54.9% and OS 70.4%. At a subsequent update, mPFS for the cilta-cel arm was 34.9 mos and 30% of the patients did not relapse after 5 years, offering a potential cure fraction.5 The phase III CARTITUDE-4 trial was designed to compare cilta-cel vs SOC therapies in patients exposed to 1-3 prior LOT and who were refractory to lenalidomide. Efficacy results at 3 years follow-up showed an ORR of 84.6% in the cilta-cel arm vs 67.3% in the SOC arm, with ≥VGPR being 81.2% vs 45.5% and ≥CR 76.9% vs 24.2%, respectively. PFS was significantly better in the cilta-cel arm (mPFS not reached [NR] vs 11.8 mos; PFS at 30 mos 59.4% vs 25.7%). An OS advantage at 30 mos was also showed (76.4% vs 63.8 respectively). Consistently, minimal residual disease (MRD) negativity rates with a minimal sensitivity of 10-5 were superior in the cilta-cel arm (62% vs 18.5% respectively), in an intention-to-treat analysis.6 Currently, cilta-cel is approved by FDA and EMA for the treatment of adult RRMM patients who have received at least one prior therapy, including IMiD and a PI, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide. In the absence of a randomized head-to-head comparison among ide-cel and cilta-cel, a retrospective, multicenter, analysis of 586 pts treated with either cilta-cel or ide-cel showed the superiority of Cilta-cel vs ide-cel in terms of response rates, PFS and OS, though associated with a more burdensome toxicity profile in terms of high-grade CRS, delayed neurotoxicity, and infections.7 Anitocabtagene autoleucel (anito-cel, previously known as CART-ddBCMA) is an anti-BCMA CAR T-cell construct modeled to express a D-domain binder between the CD8 hinge-region and the transmembrane domain. The D-domain is of synthetic and non-antibody origin, facilitating the transduction of activation signals, while reducing tonic signaling. In the iMMagine-1 phase I/II trial patients exposed to at least three previous LOT and to at least a PI, an IMiD, and an anti-CD38 antibody, received anito-cel, with a dose-finding approach. Collectively, ORR was 100%, CR rate 76%, while 24-mos-PFS was 56%. MRD negativity with a minimum sensitivity of 10-5 was reached in 89% of all evaluable patients.8 Furthermore, a phase III, randomized, registrational trial (iMMagine-3, NCT06413498) is ongoing to confront anito-cel vs SOC therapies in patients with RRMM previously exposed to 1-3 LOT and at least to an anti-CD38 and an IMiD. MCARH109 is a CAR T-cell construct with a GPRC5D single-chain variable fragment. MCARH109 safety and efficacy were explored in a phase I trial that enrolled triple-class exposed patients with RRMM with 3 or more previous LOT. Interestingly, 59% of patients were exposed to a prior anti-BCMA therapy and 47% to a prior CAR T-cell therapy. ORR was 71% in the whole population, 70% in BCMA-exposed patients, and 75% in BCMA CAR T-cells treated patients.9 Arlocabtagene autoleucel (arlo-cel) is another GPRC5D-targeting autologous CAR T-cell agent. Preliminary data from a phase I trial enrolling triple-class exposed patients with three or more previous LOT (49% of whom had received a prior BCMA-targeted therapy, including a BCMA-directed CAR T-cells therapy in 38% of them) showed efficacy and a favorable safety profile. At almost 15 mos median follow-up, ORR was 87% (38% CR) in the whole population and 79% in patients previously treated with anti BCMA therapy, while mPFS was 14.5 mos. Also, long-term safety data revealed a manageable profile, supporting BMS-986393 as a potential treatment for RRMM and further research (e.g., the ongoing phase II QUINTESSENTIAL study.10 Interestingly, preliminary data from patients with 1-3 prior lines of therapy including a PI and an IMiD are also encouraging, with high rates of response that deepened over time and no new safety concerns, though the follow-up is still limited.10 Moreover, a phase III, randomized, registrational clinical trial (QUINTESSENTIAL-2, NCT06615479) is ongoing to confront arlo-cel vs SOC therapies in patients with lenalidomide-refractory RRMM exposed to 1-3 LOT including an anti-CD38, a PI and an IMiD. The efficacy results of the most relevant CAR T-cells trials are summarized in Table 1. Table 1. Pivotal CAR T-cells trials - Efficacy. References 1. Munshi NC, Anderson LD, Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb 25;384(8):705–16. 2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002–14. 3. Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. 2024 Dec 5;144(23):2389–401. 4. Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, 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 study. The Lancet. 2021 Jul 24;398(10297):314–24. 5. Jagannath s, Martin TG, Lin Y, Cohen AD, Raje N, Htut M et al, Long-Term (5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma. J Clin Oncol. 2025 Jun 3: pub ahead of print. 6. San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023 Jul 26;389(4):335–47. 7. Hansen DK, Peres LC, Dima D, Richards A, Shune L, Afrough A, et al. US Multiple Myeloma Immunotherapy Consortium. Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma. J Clin Oncol. 2025 Feb 18:JCO2401730. 8. Bishop MR, Rosenblatt J, Dhakal B, Raje N, Cook D, Gaballa MR, et al. Phase 1 Study of Anitocabtagene Autoleucel for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM): Efficacy and Safety with 34-Month Median Follow-up. Blood. 2024 Nov 5;144(Supplement 1):4825. 9. Jurgens EM, Firestone RS, Chaudhari J, Hosszu K, Devlin SM, Shah UA, et al. Phase I Trial of MCARH109, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma: An Updated Analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2024 Dec 4;JCO2401785. 10. Bal S, Anderson LD Jr, Nadeem O, Berdeja JG, Rossi A, Gregory T, et al. Efficacy and Safety with Extended Follow-up in a Phase 1 Study of BMS-986393, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted CAR T Cell Therapy, in Patients (pts) with Heavily Pretreated Relapsed/Refractory (RR) Multiple Myeloma (MM). Blood. 2024 Nov 5;144(Supplement 1):922.
Authors: E. Zamagni, P. Tacchetti, K. Mancuso
Language: English
Subfield: Hematology
Field: Medicine
Open Access status: green
OpenAlex ID: W7094977019
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