Baseline characteristics, serological and measurable residual disease responses and outcomes in newly diagnosed multiple myeloma patients not planned for autologous stem cell transplant; Results from a prospective randomised study using MRD guided therapy

Abstract Introduction In recent times, Measurable Residual Disease(MRD) has emerged as a strong prognostic tool for Multiple Myeloma. It has potential to guide treatment which can include intensity, duration, and promote rational use of resources, especially in resource constrained settings. However studies on feasibility and utility remain limited. In this report, we discuss the baseline and serological characteristics associated with MRD results and further outcomes from a prospective study evaluating MRD guided therapy. Methods Patients who were newly diagnosed with Multiple Myeloma, ASCT ineligible and those who were started on VRd underwent a flow-MRD assessment provided that they achieved at least VGPR post 8 cycles of treatment. Patients who were MRD positive were randomized into two groups, one receiving standard maintenance therapy versus another which was planned for MRD guided consolidation with VRd/KPd for a maximum of 12 additional cycles until MRD was negative. Results A total of 279 patients were registered in this clinical trial between July 2022 and June 2024. Out of 279, 127 (45%) MRD evaluation could not be done. The most common reason was failure to achieve at least VGPR which was seen in 50 patients (17%). Other reasons included lack of fitness for the triplet regimen (32, 11%), early mortality (21,7%), presence of primary refractory disease (12, 4.3%), or if the patients were not keen on Bone marrow studies (7, 2.5%). 5 patients were excluded due to lack of feasibility of a BM MRD test. The median age of the remaining 152 patients who underwent MRD assessment was 55 years (range: 32-79), with 109 (72%) being male. At presentation, 86 had anemia (56.6%), 47 had hypercalcemia (30.9%), 142 had lytic bone lesions (93.4%) and renal dysfunction was observed in 24 patients (15.8%). 19 patients had RISS I (52.6%) while 80 (52.6%) and 41 (27%) had RISS II and RISS III respectively. Baseline Cytogenetics included presence of hyperdiploidy in 73 (48%), t(4;14) in 12 (7.9%), t(14;16) in 7 (4.6%), del 17p in 3 (2%), 1q gain/amplification in 44 (29%) and del1p was seen in 3 (2%) patients. In accordance with the IMWG response criteria, at the end of eight cycles, CR was achieved in 96 (64%) while VGPR was seen in 54 (36%). 60 (38.8)% patients reached MRD negativity at threshold of 10-5 while the remaining 92 (60.5% patients remained MRD positive. MRD positivity was significantly higher amongst patients who had VGPR in comparison to CR (52% vs 10%, p<0.001). On analysis of other baseline characteristics including R-ISS staging and presence of high-risk cytogenetics, no significant association was found. The median PFS and OS were not reached after a median follow up of 21.8 months. A total of 22 patients had serological progression of disease out of which 17 (18.5%) were MRD positive and 5 (8.5%) were MRD negative. PFS at 12 months for MRD positive patients was 74.7% and MRD positivity was significantly associated with poor PFS (ꭓ2 =6.111,p<0.013). A total of 6 deaths were observed, all due to disease progression. Four out of the six deaths occurred in the MRD positive cohort while two were seen in those with MRD negative (p value non significant). Conclusion Evaluation of MRD in our setting appears to be feasible and provides prognostically relevant results. MRD negativity was less frequent among patients achieving VGPR. Other baseline characteristics displayed no significant association with MRD status. MRD positivity was linked to poor PFS and data is still immature for OS analysis. A notable number of patients did not undergo MRD assessment after eight cycles primarily due to suboptimal response underscoring the need for more potent first-line regimes.