Prognostic Value of Month 1 Bone Marrow and PET MRD Status in CAR-T Therapy for Myeloma

Background: Minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). MRD is usually assessed in the bone marrow (BM) by flow cytometry or NGS. Guideline is also available for MRD assessment by positron emission tomography with computed tomography (PET/CT) to provide a global representation of the tumor burden beyond osteolytic lesions and evaluate for response to extra-medullary disease (EMD). We examined MRD status in MM patients using a combination of BM and PET/CT MRD during the first-year post CAR-T infusion.

Methods: We conducted a retrospective chart review of MM patients infused with different CAR-T products between Apr 2018 and Jun 2022 at Mayo Clinic. All PET/CT scans were assessed as per IMWG criteria. BM MRD was assessed by flow cytometry with a sensitivity of 10^-5 (minimum 2x10⁶ events acquired). Patient best response was defined as per IMWG criteria. The Kruskal-Wallis rank sum test was used to determine associations between continuous variable and categories, and Pearson's chi-square test were used to evaluate associations for categorical variables. PFS was analyzed using Kaplan-Meier analysis and statistical significance was assessed using the two-tailed log-rank test.

Results: In our cohort of 94 CAR-T recipients, including 40 patients who received FDA-approved CAR-T in standard of care practice, median age was 63 years, 50% (47/94) were males, 40% (38/94) had high risk cytogenetics with median of 5 prior lines of therapy, 16% (15/94) had bone independent EMD and 29% (27/94) had bone associated EMD. Incidence of CRS was 81%, 5% grade ≥ 3 CRS. Incidence of ICANS was 21%, 4% grade ≥ 3 ICANS. CR/sCR rate was 32%. At median follow-up of 12.8 months, median PFS was 10.8 (95% CI: 7.8, 26.4) mo.

Eighty-three patients (88%) had evaluable BM at month (mo) 1, 80% (67/83) were BM MRDneg at mo 1. Baseline demographics were comparable between the two groups except age (BM MRDneg;63 years vs BM MRDpos;58 years, p<0.05). Among the MRDneg patients, IMWG response at month 1 was CR/sCR in 42% (27/67), VGPR in 39% (25/67), PR in 15% (10/67), SD in 3% (2/67) and 1% (1/67) patients were not evaluable. 16/26 (62%) had sustained BM MRDneg at month 6 and 9/20 (45%) at month 12. At median follow-up of 14.7 months, median PFS among patients with BM MRDneg at 1 mo was 17.5 (95% CI: 10.8, NA) mo vs 2.9 (95%CI: 1.5, NA) for BM MRDpos (p<0.0001).

At month 1, 58 pts had both BM and PET/CT assessments available, 26/58 (45%) were both BM MRDneg/PET MRDneg, 22/58 (38%) were MRDneg for either BM or PET and 10/58 (17%) were positive for both BM and PET (BM MRDpos/PET MRDpos). Baseline demographics except age were comparable between the 2 groups (Table 1). Rate of sustained BM MRDneg/PET MRDneg was 33% (6/18) at 6 mo and 44% (7/16) at 12 mo post CAR-T. Two patients who were BM MRDneg/PET MRDpos at mo 1 had eventual radiologic conversion to PET MRDneg at mo 3 and 12 (2/58, 3.4%). The median PFS for BM MRDneg/ PET MRDneg was significantly longer as compared to others (p<0.001, Figure 1).

Conclusion: MRD status at month 1 is prognostic for prolonged PFS. The rate of dual BM/PET MRDneg rate is lower than BM MRD alone. The PFS is longer for patients with dual MRDneg for BM and PET. These results highlight the need for additional interventions among patients with evidence of residual disease early after CART infusion.

Dingli:Bristol Myers Squibb: Consultancy; GlaxoSmithKline: Consultancy; Sanofi S.A.: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy. Kapoor:Sanofi: Honoraria, Research Funding; X4 Pharmaceuticals: Honoraria; Regeneron: Research Funding; Amgen: Research Funding; Ichnos: Research Funding; Loxo: Research Funding; Karyopharma: Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Research Funding; Casma: Honoraria; Pharmacyclics: Honoraria; Imedex: Honoraria; GSK: Honoraria; Cellectar: Honoraria; Oncopeptides: Honoraria. Kourelis:Novartis: Research Funding. Fonseca:H3 Therapeutics: Consultancy; AbbVie: Consultancy; BMS/Celgene: Consultancy; Pharmacyclics: Consultancy; Merck: Consultancy; Janssen: Consultancy; Juno: Consultancy; Karyopharm: Consultancy; Kite: Consultancy; Oncopeptides: Consultancy; Takeda: Consultancy; GSK: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Sanofi: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; OncoMyx: Membership on an entity's Board of Directors or advisory committees. Bergsagel:Janssen: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Research Funding; MedImmune/Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis,: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee. Lin:Janssen: Consultancy, Research Funding; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy; Novartis: Consultancy.