CAR-T Moves to the Front Line: Rethinking the Multiple Myeloma Sequence

For nearly 2 decades, the treatment paradigm in multiple myeloma has followed a familiar trajectory: induction therapy, autologous stem-cell transplantation (ASCT) when feasible, maintenance, and sequential therapy at relapse. Each wave of therapeutic innovation—proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and most recently cellular therapies—has been layered upon this framework. Yet the emergence of chimeric antigen receptor T-cell (CAR-T) therapy has begun to challenge the fundamental sequencing of myeloma treatment.

In this issue, Yan and colleagues report results from the CAREMM-001 study (NCT05860036), a phase 2, open-label, single-arm trial evaluating B-cell maturation antigen (BCMA)–directed CAR-T therapy as a frontline consolidation strategy for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or not proceeding to autologous transplantation. Thirty-six patients enrolled between April 2023 and December 2024 received three to four cycles of protocol-allowed induction, followed by BCMA CAR-T infusion, consolidation, and lenalidomide (Revlimid) maintenance. The results are striking: 100% MRD negativity at 10⁻⁵ sensitivity, a complete response rate of 94.4%, and no disease progression or death at a median follow-up of 15.8 months post-infusion.¹

Although small and single-arm, the magnitude and uniformity of these responses raise an important question for the field: should CAR-T therapy move earlier in the treatment course of multiple myeloma?

The Evolution of Myeloma Therapy—and Its Limitations

The frontline treatment landscape for multiple myeloma has advanced dramatically over the past decade. The phase 3 SWOG S0777 trial (NCT00644228) established VRd as a standard backbone, demonstrating significantly improved progression-free survival (43 vs 30 months) and overall survival (75 vs 64 months) compared with lenalidomide-dexamethasone alone.²

More recently, anti-CD38 quadruplets have further deepened responses. In the phase 3 IMROZ trial (NCT03319667), isatuximab (Sarclisa) plus VRd (Isa-VRd) produced an estimated 60-month PFS of 63.2% vs. 45.2% with VRd alone in transplant-ineligible NDMM.³ Similarly, in the phase 3 CEPHEUS trial (NCT03652064), adding subcutaneous daratumumab (Darzalex) to VRd improved MRD negativity to 60.4% vs. 39.3% at 10⁻⁵ and reduced the risk of progression or death by 43% compared with VRd alone.⁴

Despite these advances, a substantial proportion of patients—particularly those who are older, frail, or burdened by comorbidities—are not candidates for ASCT. These patients frequently experience attrition across lines of therapy, with many never reaching later treatments because of disease progression, treatment toxicity, or declining functional status.⁵ Consequently, achieving maximal disease control early in the disease course has become an increasingly important goal.

Why Earlier CAR-T May Be Better CAR-T

CAR-T therapies targeting BCMA have transformed the relapsed or refractory setting. The pivotal KarMMa trial (NCT03361748) demonstrated that idecabtagene vicleucel (ide-cel; Abecma) induced an overall response rate of 73%, a complete response rate of 33%, and a median overall survival of 24.8 months in triple-class–exposed patients.⁶ Ciltacabtagene autoleucel (cilta-cel; Carvykti), assessed in CARTITUDE-1 (NCT03548207), produced a 98% overall response rate with 83% achieving stringent complete response at extended follow-up.⁷

Randomized trials have since confirmed the superiority of these approaches over standard regimens in relapsed disease. In KarMMa-3 (NCT03651128), ide-cel significantly improved progression-free survival compared with standard regimens.⁸ Similarly, CARTITUDE-4 (NCT04181827) demonstrated improved progression-free survival with cilta-cel versus standard-of-care therapy in lenalidomide-refractory myeloma.⁹

Yet CAR-T therapy is currently deployed after multiple prior lines—often when patients have accumulated substantial immune dysfunction and T-cell exhaustion. Administering CAR-T earlier offers theoretical advantages: lower tumor burden, less immunologic exhaustion, and more robust T-cell fitness, all of which may enhance CAR-T expansion and persistence.¹

The precedent for moving cellular therapy earlier has already been established in lymphoma. The randomized phase 3 ZUMA-7 trial (NCT03391466) demonstrated that axicabtagene ciloleucel (Yescarta) produced superior event-free survival compared with salvage chemotherapy in second-line large B-cell lymphoma.¹⁰ Similarly, lisocabtagene maraleucel (Breyanzi) demonstrated superior outcomes compared with standard-of-care transplant in the TRANSFORM trial (NCT03575351).¹¹

The Significance of Universal MRD Negativity

Perhaps the most compelling signal in CAREMM-001 is the uniform achievement of MRD negativity.

MRD has emerged as one of the most powerful prognostic markers in multiple myeloma, consistently correlating with improved progression-free and overall survival across therapeutic platforms.¹²

Contemporary frontline quadruplet regimens achieve MRD negativity rates of approximately 53% to 61%. In IMROZ, Isa-VRd achieved MRD negativity in roughly 53% of patients at 10⁻⁵ sensitivity,³ while Dara-VRd achieved 60.4% MRD negativity in the CEPHEUS study.⁴

Against this backdrop, the 100% MRD negativity observed in CAREMM-001 suggests that cellular therapy may deliver a qualitatively deeper level of disease eradication. However, this observation must be interpreted cautiously given the small sample size, single-arm design, and relatively short follow-up.¹

Interestingly, the investigators observed that MRD negativity often preceded clearance of serum monoclonal protein—a discordance that likely reflects the rapid cytotoxic activity of CAR-T cells compared with the slower physiologic clearance of circulating immunoglobulin.¹

Importantly, while MRD negativity is a validated prognostic surrogate, it is not a direct readout of overall survival. The current follow-up remains too short to determine whether these responses translate into durable remission or cure.

Safety in a Frail Population

The feasibility of CAR-T therapy in transplant-ineligible patients is another key observation from CAREMM-001. Cytokine release syndrome occurred in approximately half of patients but was limited to grade 1–2 events, neurotoxicity was rare, and no treatment-related deaths occurred.¹

These toxicity rates appear lower than those reported in pivotal late-line CAR-T trials, including KarMMa and CARTITUDE-1^6,7. This observation is consistent with the hypothesis that lower tumor burden and reduced systemic inflammation at the time of frontline infusion yield a more favorable therapeutic index.

Notably, the median age of patients in the study was 68 years, demonstrating that cellular therapy can be delivered safely even in populations historically considered unsuitable for intensive treatment.¹

Remaining Challenges

Despite the enthusiasm generated by these findings, several important questions remain unanswered.

First, this trial is small, non-randomized, and single-arm, with follow-up too limited to assess the durability most relevant to myeloma practice.¹

Second—and critically—the post-relapse landscape following frontline BCMA-directed CAR-T remains largely uncharted. BCMA antigen loss or downregulation is a recognized resistance mechanism that may limit subsequent use of BCMA-targeting therapies. Emerging data suggest that BCMA- and GPRC5D-directed bispecific antibodies retain activity after prior CAR-T therapy, though response rates may be modestly reduced compared with CAR-T–naive populations.⁸

Third, CAR-T therapy introduces substantial logistical and economic barriers, including manufacturing lead times, access to certified treatment centers, and high acquisition costs.

Finally, several randomized phase 3 trials are now underway to clarify the role of frontline CAR-T therapy. CARTITUDE-5 (NCT04923893) is evaluating cilta-cel after VRd induction in transplant-ineligible NDMM, whereas CARTITUDE-6 (NCT05257083) is comparing cilta-cel against autologous transplantation in transplant-eligible patients.

A Paradigm Shift on the Horizon

The CAREMM-001 study offers a glimpse into a potential future in which the therapeutic sequence of multiple myeloma is fundamentally reimagined—one in which frontline immune-mediated disease eradication replaces the stepwise attrition model of sequential salvage therapy.¹

If validated in randomized trials, this approach could transform the treatment landscape, bringing the possibility of deep, durable remission to patients who have historically faced limited therapeutic options.

Yet that validation remains the critical next step. For now, CAREMM-001 represents what it is: a landmark, hypothesis-generating signal trial that justifies urgent prioritization of the phase 3 studies now underway.

References

1. Yan W, Du C, Lv R, et al. Phase II study of BCMA chimeric antigen receptor T-cell therapy in patients with newly diagnosed multiple myeloma ineligible for or not proceeding to autologous stem-cell transplantation (CAREMM-001). J Clin Oncol. 2026;44. doi:10.1200/JCO-25-01969.
2. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519-527. doi:10.1016/S0140-6736(16)31594-X
3. Facon T, Dimopoulos MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391:1597-1609. doi:10.1056/NEJMoa2400712
4. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma (CEPHEUS). Nat Med. 2025. doi:10.1038/s41591-024-03485-7.
5. Fonseca R, Usmani SZ, Mehra M, et al. Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. BMC Cancer. 2020;20:1087. doi:10.1186/s12885-020-07503-y
6. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384:705-716. doi:10.1056/NEJMoa2024850
7. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed CAR T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398:314-324. doi:10.1016/S0140-6736(21)00933-8
8. 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;388:1002-1014. doi:10.1056/NEJMoa2213614
9. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389:335-347. doi:10.1056/NEJMoa2303379
10. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi:10.1056/NEJMoa2116133
11. Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem-cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM). Lancet. 2022;399:2294-2308. doi:10.1016/S0140-6736(22)00662-6
12. Paiva B, van Dongen JJM, Orfao A. New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood. 2016;127:2905-2912. doi:10.1182/blood-2014-11-568907
13. Merz M, Dima D, Hashmi H, et al. Bispecific antibodies targeting BCMA or GPRC5D in relapsed multiple myeloma after CAR T-cell therapy. Blood Cancer J. 2024;14:214. doi:10.1038/s41408-024-01197-2