Outcomes of MRD-Adapted Treatment Modulation in Patients with Newly Diagnosed Multiple Myeloma Receiving Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) and Autologous Transplantation: Extended Follow up of the Master Trial

Background: Quadruplet induction and consolidation therapy in the setting of autologous hematopoietic cell transplantation (AHCT) leads to high rates of minimal/measurable residual disease (MRD) negativity in patients (pts) with newly diagnosed MM (NDMM), enabling MRD response-adapted therapy. The outcomes of patients ceasing therapy guided by MRD assessment have not been described.

Methods: Eligible pts in the MASTER trial had NDMM requiring treatment, CrCl≥40 ml/min, adequate liver and heart function, ECOG performance status 0-2 with no age limit. There was a planned enrichment for pts with high-risk cytogenetic abnormalities (HRCA). Pts received 4 cycles of Dara-KRd as induction, AHCT, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status as previously reported. MRD was evaluated by next generation sequencing (NGS, ClonoSEQ®) in all pts at end of induction, post-AHCT, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negativity (<10^-5 as defined by IMWG) in the intent-to-treat (ITT) population. Pts received therapy until achievement of two consecutive MRD <10^-5 (i.e., post-induction and post-AHCT or post-AHCT and during consolidation). Pts with 2 consecutive MRD negative assessments entered treatment-free observation and MRD surveillance (“MRD-SURE”) with MRD testing 6 months after treatment cessation and yearly thereafter. Pts completing consolidation without 2 consecutive MRD-negative assessments received lenalidomide maintenance. Results are reported by risk profile based on the presence of 0, 1 or 2+ HRCA [gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)].

Results: The study accrued 123 participants. Fifty-three (43%) had no HRCA, 46 (37%) had 1 and 24 (20%) had 2+ HRCA. Median age was 60 y (36-79), 23% of pts were non-white, 20% had ECOG 2, 21% had high LDH, and 20% R-ISS3. Median follow up is 34.1 mo. Overall (N=123) 3-year PFS was 91%, 87% and 51% (Panel A, P<0.001) and 3-year OS 96%, 91% and 75% (P=0.004) for patients with 0, 1 and 2+ HRCA respectively. Disease was trackable by NGS-MRD in 118 (96%) pts. Of these, 81% achieved MRD negativity, and 71 % MRD < 10^-6. Among these 118 pts, 8% discontinued therapy prematurely (death, progression or withdraw of consent), 20% completed treatment and transitioned to lenalidomide maintenance and 71% reached 2 consecutive MRD negative assessments and entered MRD-SURE. Odds of reaching MRD-SURE was 66%, 82% and 63% for patients with 0, 1 or 2+ HR abnormalities respectively. Among the 84 patients who reached MRD-SURE, after median follow up post treatment cessation of 24.8 mo, 7 (8%) initiated lenalidomide-based therapy for MRD resurgence and 11 (13%) started treatment for disease progression. Sixty-six pts (79%) have remained off therapy, including 88%, 83% and 47% of patients with 0, 1 and 2+ HRCA. Four patients died after entering MRD-SURE, 2 from MM (21 and 24 mo. after progression) and 2 from unrelated causes (COVID-19 pneumonia and accidental fall). Two-year PFS from treatment cessation is 91%, 89% and 54% (Panel B, P=0.008) and 2-year OS 100%, 92% and 100% (P=0.51) for patients with 0, 1 or 2+ HRCA, respectively.

Conclusion: MM pts. with 0 or 1 HRCA reaching confirmed MRD negativity after quadruplet induction, AHCT and MRD-adapted consolidation have excellent PFS and OS in absence of maintenance therapy. Although the odds of achieving MRD-SURE were similar across risk strata, the risk of progression was higher among patients with ultra-high-risk MM (2+ HRCA) indicating the need for novel consolidation strategies. For the majority of patients with NDMM, quadruplet therapy, AHCT and MRD response-adapted treatment modulation provides the opportunity of durable treatment cessation without compromising disease control.