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Purpose: Prognostic Immunophenotyping in Myeloma Response (PRIMeR) is an ancillary study of minimal residual disease (MRD) assessment for multiple myeloma by next-generation multiparameter flow cytometry (MFC). Patients were enrolled on a three-arm randomized control trial (Blood and Marrow Transplants Clinical Trials Network 0702 Stem Cell Transplant for Myeloma in Combination of Novel Agents [STaMINA]; ClinicalTrials.gov identifier: NCT01109004)., Methods: Four hundred and thirty-five patients consented to the MRD panel, which included 10 monoclonal antibodies measured via six-color MFC. MRD was measured at baseline/preautologous hematopoietic cell transplant (BL/preAutoHCT), premaintenance (PM), and 1 year (Y1) after AutoHCT with a sensitivity of 10 -5 to 10 -6 . The primary objective was to assess MRD-negative (MRD neg ) at 1 year after AutoHCT and progression-free survival and overall survival (PFS/OS)., Results: Similar to the STaMINA results, at a median follow-up of 70 months, there was no significant difference in PFS/OS by treatment arm in the PRIMeR patients. MRD neg at all three time points was associated with significantly improved PFS, and MRD neg at Y1 had significantly longer OS. Multivariate analysis of PFS, adjusting for disease risk and treatment arm, demonstrated hazard ratios (HRs) in MRD-positive patients compared with MRD neg patients at BL, PM, and Y1 of 1.55 ( P = .0074), 1.83 ( P = .0007), and 3.61 ( P < .0001), respectively. Corresponding HRs for OS were 1.19 ( P = .48), 0.88 ( P = .68), and 3.36 ( P < .001). Patients with sustained MRD neg or who converted to MRD neg by Y1 had similar PFS/OS., Conclusion: To our knowledge, this first, prospective US cooperative group, multicenter study demonstrates that MRD neg at Y1 after AutoHCT with lenalidomide maintenance is prognostic for improved 6-year PFS and OS. Serial MRD measurements may direct trials to test how further therapy may improve long-term PFS and OS.

Optimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma (MM) in first relapse remains poorly defined. We therefore undertook a randomized phase II study evaluating the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) for this patient population. The overall response rate (ORR) for POM-DEX was 43.6% and 63.2% for IXA-POM-DEX. Depth of response, as measured by attainment of a very good partial response or better favored the triplet over the doublet, 28.9% vs 5.1%, respectively (p = 0.0063). A pre-planned interim analysis after 75% of the progression events had occurred demonstrated a progression-free survival (PFS) advantage favoring IXA-POM-DEX that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI] 4.8 - 13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI 7.7 - 26.0 months, hazard ratio 0.437 [upper 90% bound = 0.657]). ORR and median PFS for the 26 of 30 eligible patients who crossed over from the doublet to the triplet at progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the two groups. More hematologic toxicities were seen with the triplet, but non-hematologic adverse events were similar between the two arms. Our data support further testing of this all-oral triplet vs current standard triplet therapy in the context of phase III studies for patients with LEN-refractory disease in first relapse. This trial is registered at www.clinicaltrials.gov as NCT02004275., (Copyright © 2024 American Society of Hematology.)