Early and Sustained Undetectable Measurable Residual Disease (MRD) after Idecabtagene Vicleucel (ide-cel) Defines a Subset of Multiple Myeloma (MM) Patients in Karmma Achieving Prolonged Survival

Background: MRD is a key prognostic factor in MM but there is limited information about its clinical meaning in patients treated with CAR T cells. Furthermore, as serological responses are often delayed compared to MRD negativity, there is uncertainty regarding the optimal time points to assess the efficacy of CAR T therapy in MM using each response criterion. Aim: Analyze the prognostic value of the depth of serological and MRD responses after CAR T cell therapy. Methods: MRD was analyzed at months 1, 3, 6 and 12 after ide-cel infusion regardless of clinical response in the KarMMa phase 2 clinical trial. Of 128 patients receiving ide-cel, 125 had at least one MRD assessment. A total of 336 and 257 MRD assessments using next generation flow cytometry (NGF, EuroFlow) and next generation sequencing (NGS, clonoSEQ®) respectively, were performed in bone marrow (BM). Any detectable level of MRD >1x10-6 was considered positive. Median follow-up was 24.8 months. Results: The percentage of concordant MRD status between NGF and NGS was 67%, 75%, 81.5% and 73% at months 1, 3, 6 and 12 after ide-cel, respectively. Most discordances were due to BM samples classified as hemodiluted by NGF and as MRD negative by NGS, which peaked immediately after ide-cel infusion and persisted until one year after (27.5%, 14%, 12.5% and 13% at months 1, 3, 6 and 12, respectively). That notwithstanding, NGF and NGS showed similar prognostic value at all time points. Therefore, subsequent analyses were done on the NGF dataset because a more complete dataset was available and monitoring of hemodilution was intrinsic to the method. The rates of stringent plus conventional complete remission (CR) on the treated patient population at months 1, 3, 6 and 12 after ide-cel, were 11%, 23%, 26% and 23%, respectively. The rates of undetectable MRD in the treated patient population at months 1, 3, 6 and 12 after ide-cel, were 41%, 45%, 35% and 18% at 10-6, and 42%, 47%, 38% and 19.5% at 10-5. Of note, persistent MRD in the 10-6 logarithmic range was detected in nine samples from eight patients, all of whom progressing shortly thereafter (median 5.5 months, range 2 - 9). At month 1 after ide-cel, there were no significant differences in progression-free survival (PFS) between patients in less than CR (n = 103) vs those in CR (n = 14) (median of 8 vs 11 months, p = .09). By contrast, presence of MRD at month 1 (n = 24) predicted dismal PFS when compared to cases with undetectable MRD (n = 53) (median of 2 vs 11.5 months, p < .001). At months 3, 6 and 12 after ide-cel, patients in CR and undetectable MRD showed significantly longer median PFS vs those in less than CR and undetectable MRD (p ≤ .007). At month 12, the landmark median PFS of patients in CR/MRDneg (n = 19) vs