CAR T Achieves 100% MRD Negativity in Newly Diagnosed Multiple Myeloma

A B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy, administered after short-course induction in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or unable to proceed to autologous stem-cell transplantation (ASCT), produced deep and durable remissions with a manageable toxicity profile, according to results published in the Journal of Clinical Oncology.¹

The findings from the single-arm phase 2 CAREMM-001 trial (NCT05860036) represent the first prospective data evaluating BCMA-directed CAR T in this historically underserved frontline population. Among all 36 patients who received CAR T-cell infusion, the rate of minimal residual disease (MRD) negativity at a sensitivity threshold of 10^-5 by next-generation flow (NGF) cytometry at the primary end point of month 3 postinfusion was 100% (95% CI, 90.3%-100.0%). With a median postinfusion follow-up of 15.8 months, no MRD recurrence, disease progression, or treatment-related death was recorded by the data cutoff of September 1, 2025.

Trial Design and Patient Population

CAREMM-001 enrolled patients between April 4, 2023, and December 26, 2024, at the Institute of Hematology and Blood Diseases Hospital in Tianjin, China. Eligibility required a confirmed diagnosis of symptomatic, measurable NDMM per International Myeloma Working Group (IMWG) criteria, with transplant ineligibility established by protocol-defined parameters: age ≥65 years, ECOG performance status of 3 to 4, significant comorbidities, repeated stem-cell mobilization failure, or patient preference to defer ASCT.

Patients had received 3 to 4 cycles of protocol-allowed induction therapy which consisted of VRd (bortezomib [Velcade], lenalidomide [Revlimid), and dexamethasone) or a protocol-allowed alternative daratumumab (Darzalex)-based regimen.

Of 43 patients screened, 40 were enrolled and underwent leukapheresis, comprising the intention-to-treat (ITT) population. Four patients subsequently withdrew before infusion due to serious adverse events (SAEs)—specifically, severe infection (n = 2) and renal dysfunction (n = 2) rather than disease progression. The remaining 36 patients received lymphodepleting chemotherapy (fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² daily on days −5 through −3) followed by a single intravenous infusion of the investigational BCMA CAR T product YK-hBCMA BB-002 at a target dose of 3.0 × 10⁶ cells/kg.

The infused cohort had a median age of 68 years (range, 46-75), with 85% of patients aged 65 years or older. Twenty-eight percent were classified as frail by the IMWG Frailty Index. High-risk features were prevalent: 25.6% had R-ISS stage III disease, 50% were identified as consensus genomic staging high-risk, and 38.5% met protocol-defined ultra-high-risk criteria, including 9 patients with double-hit cytogenetics, 4 with extramedullary disease, and 3 with at least 2% circulating plasma cells. All participants were Asian.

Following CAR T-cell infusion, patients received consolidation therapy consistent with induction, excluding glucocorticoids, beginning after month 3, followed by lenalidomide maintenance planned for at least 2 years or until disease progression or unacceptable toxicity.

Efficacy Outcomes

The primary end point of NGF-MRD negativity at month 3 postinfusion was met in all 36 infused patients. The median time to MRD negativity was 28 days (range, 28-33). Sustained clearance was observed in 26 of 36 patients for at least 12 months and 31 of 36 for at least 6 months; the remaining 5 patients maintained MRD-negative status throughout available follow-up. No NGF-MRD recurrences were detected during the observation period.

The complete response (CR) rate deepened progressively across time points: from 33.3% (95% CI, 18.6%-51.0%) at the time of infusion to 69.4% (95% CI, 51.9%-83.7%) at month 3, and 94.4% (95% CI, 81.3%-99.3%) at last follow-up. All 36 patients achieved at least a very good partial response (VGPR). The 2 patients whose best response was VGPR were both NGF-MRD–negative; 1 had only 4 months of follow-up at the time of data cutoff.

In the ITT population of all 40 enrolled patients, the month 3 MRD-negativity rate was 90.0% (95% CI, 76.3%-97.2%) and the CR rate was 62.5% (95% CI, 45.8%-77.3%). Among 26 patients evaluable for next-generation sequencing (NGS)–MRD at a 10⁻⁶ threshold, the MRD negativity rate increased from 26.9% at baseline to 92.3% at month 3. Soluble BCMA levels declined by a mean of 96.4% from baseline to month 3 postinfusion. At the data cutoff, median duration of response, progression-free survival, and overall survival were not estimable; no progression or death events had been recorded.

Safety Profile

Among the 36 infused patients, hematologic toxicities largely attributable to lymphodepleting chemotherapy rather than the CAR T product itself were the most common adverse events. Grade 3 or higher cytopenias included lymphopenia in 100%, neutropenia in 88.9%, leukopenia in 80.6%, thrombocytopenia in 19.4%, and anemia in 8.3%. These were transient in most patients; median durations ranged from 4 days for anemia to 10 days for leukopenia and lymphopenia.

The Immune Effector Cell–Associated Hematotoxicity (ICAHT) framework was applied to characterize delayed hematologic events. Early ICAHT (days 0 to 30) occurred in 52.8% of patients, and late ICAHT (after day 30) in 36.1%. One patient experienced a grade 3 late ICAHT event persisting for 105 days, which precluded consolidation and led directly to maintenance; this patient remained in the study.

Cytokine release syndrome (CRS) occurred in 19 patients (52.8%); all events were grade 1 to 2, with a median onset of 2 days and a median duration of 3 days. Management included tocilizumab (Actemra) in 36.8% and glucocorticoids in 78.9% of CRS cases. Immune effector cell–associated neurotoxicity syndrome occurred in 2 patients (5.6%), both grade 1, resolving within 1 to 2 days with glucocorticoid treatment. No cases of tumor lysis syndrome, hemophagocytic lymphohistiocytosis, or second primary malignancy were observed.

Infections occurred in 11 patients (30.6%), with grade 3 or higher infections in 7 (19.4%). Pneumonia was the most common infection (25.0%). Eight patients (22.2%) experienced treatment-related SAEs. Hypogammaglobulinemia occurred in 44.4% of patients; 75% of these recovered with intravenous immunoglobulin (IVIG) support. All patients developed peripheral B-cell aplasia postinfusion (median duration, 82.5 days; range, 14–464 days).

CAR T Construct and Mechanism

The CAR-T product evaluated in CAREMM-001, YK-hBCMA BB-002, developed by Shanghai YaKe Biotechnology Ltd, is a second-generation, lentiviral-transduced autologous CAR T construct comprising a fully human single-chain variable fragment (scFv) targeting BCMA, a CD8α hinge and transmembrane domain, a 4-1BB costimulatory domain, and a CD3ζ activation domain. The fully human scFv design was chosen to reduce immunogenicity relative to murine-derived constructs.

All 36 infused patients showed detectable CAR T expansion with peak expansion at a median of 11 days. Transgene persistence was detectable in 50% of patients beyond 3 months and 32.3% beyond 6 months. Patients who were MRD positive at infusion had higher values compared with those who were MRD negative, consistent with antigen-driven expansion.

Clinical Context

Early-line investigation of FDA-approved CAR T-cell therapies is now being pursued in randomized phase 3 trials. In the transplant-ineligible setting, CARTITUDE-5 (NCT04923893) is comparing ciltacabtagene autoleucel (cilta-cel; Carvykti) after VRd with VRd followed by lenalidomide maintenance.² In the transplant-eligible setting, CARTITUDE-6 (NCT05257083) is comparing daratumumab plus VRd followed by cilta-cel with daratumumab/VRd followed by ASCT with lenalidomide maintenance in both arms.³ Prospective data on frontline post-induction CAR T-cell therapy in transplant-ineligible NDMM were not available prior to CAREMM-001.¹

The observed 100% MRD-negativity rate at month 3 and 94.4% CR rate at last follow-up compare favorably with outcomes from quadruplet regimens now considered standard in transplant-ineligible NDMM. If replicated in randomized trials, these results could represent a meaningful shift in the treatment paradigm for this population.

In the journal’s Context section, associate editor Suzanne Lentzsch, MD, PhD, stated “The high rates of complete response and MRD negativity are encouraging; however, longer follow-up and comparative studies are needed to determine the durability of benefit and to establish whether this approach offers a significant advantage over current standard-of-care quadruplet regimens in this population.”

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. Published online February 27, 2026. doi:10.1200/JCO-25-01969

2. A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Cilta-cel, a CAR-T Therapy Directed Against BCMA Versus VRd Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom ASCT is Not Planned as Initial Therapy (CARTITUDE-5). ClinicalTrials.gov. Updated March 13, 2026. Accessed March 17, 2026.. https://clinicaltrials.gov/study/NCT04923893

3. A Study of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Ciltacabtagene Autoleucel Versus Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Autologous Stem Cell Transplant (ASCT) in Participants With Newly Diagnosed Multiple Myeloma (CARTITUDE-6). ClinicalTrials.gov. Updated March 17, 2026. Accesed March 17, 2026.https://clinicaltrials.gov/study/NCT05257083