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 <CR/MRDneg (n = 4) vs CR/MRDpos (n = 4) vs <CR/MRDpos (n = 9) was 18 vs 6 vs 2 vs 0.3 months, respectively. Patients with early and sustained undetectable MRD for 12 months (n = 14), did not reach median PFS. Biomarker analysis for screening features that characterized patients that may achieve early and sustained undetectable MRD for 12 months, will be presented at the meeting.

Due to the high interpatient variability in terms of CAR T cell persistence, we hypothesized that the reappearance of normal plasma cells (PC), which are formally analyzed during MRD assessment using NGF, could be used as a surrogate for loss of CAR T cell persistence and/or functionality. In such cases, this information could help identify patients with undetectable MRD at higher risk of progression. Interestingly, reappearance of normal PC was observed at all time points and was systematically associated with inferior PFS. None of the three cases showing absence of normal PC and undetectable MRD at month 12 progressed thus far.

Conclusion: Our results show that patients achieving early and sustained undetectable MRD after ide-cel have prolonged PFS. Furthermore, we unveiled the prognostic implication of different serological and MRD response dynamics: only MRD (and not CR) status at month 1 after ide-cel predicted early relapse because of delayed clearance of the M-component, whereas both CR and undetectable MRD at month 12 were required to identify patients with longer PFS. This study also uncovers a high frequency of hemodilution in BM aspirates after CAR T therapy, confirms the poor prognosis of persistent MRD in the 10^-6 logarithmic range, and suggests potential value of studying the reappearance of normal PC as a surrogate of loss of CAR T cell functionality and inferior PFS.

Paiva:Adaptive: Honoraria; Takeda: Honoraria, Research Funding; GSK: Honoraria, Research Funding; EngMab: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche Glycart AG: Honoraria, Research Funding; Amgen: Honoraria; Gliead: Honoraria; Oncopeptides: Honoraria. Rytlewski:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Kazanecki:Bristol-Myers Squibb: Current Employment. Martin:Bristol-Myers Squibb: Current Employment. Kaiser:Bristol-Myers Squibb: Current Employment. Anderson:Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja:Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Fate Therapeutics: Research Funding; Acetylon: Research Funding; SecuraBio: Consultancy; Genentech: Research Funding; Legend Biotech: Consultancy; Cartesian Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; Incyte: Research Funding; Karyopharm: Research Funding; Lilly: Research Funding; Novartis: Research Funding; C4 Therapeutics: Research Funding; EMD Sorono: Research Funding; Teva: Research Funding; Celularity: Research Funding; Poseida: Research Funding; Zentalis: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Research Funding; CARsgen: Research Funding; AbbVie: Research Funding; 2Seventy bio: Research Funding; Celgene: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Lonial:Novartis, BMS, GSK, Amgen, Merck, Janssen: Honoraria; Celgene, Janssen, Takeda: Research Funding; AbbVie, Bluebird, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis Pharma, and Takeda.: Consultancy. Raje:Bristol Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Honoraria; Research to Practice: Honoraria; Two Seventy Bio: Research Funding; Massachusetts General Hospita: Current Employment; Celgene: Honoraria; Janssen: Consultancy, Honoraria. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Vineti: Consultancy; Legend: Consultancy; Sorrento: Consultancy; Merck: Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Juno: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria. San-Miguel:Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Takeda, Regeneron, Roche, Sanofi, and SecuraBio: Consultancy, Other: Advisory Board. Munshi:Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda Oncology: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; GSK: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Legend: Consultancy.