Multiple myeloma is the second most common blood cancer diagnosis, after non-Hodgkin lymphoma, in the US. Immunotherapy is a promising and innovative approach for myeloma treatment. It involves using monoclonal antibodies, CAR-T cells, or bispecific antibodies to boost the immune system’s ability to fight cancer cells. These therapies have shown remarkable results in patients who have failed other treatments. However, there is still room for improvement, as some responses are not lasting. 

The Phase III IFM2020-02-MIDAS trial evaluated a minimal residual disease (MRD)-driven strategy to guide consolidation and maintenance therapy in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Following induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (IsaKRD), patients were stratified based on MRD status at a threshold of 10⁻⁵ by next-generation sequencing (NGS). MRD-negative patients were randomized to receive either extended IsaKRD (Arm A) or autologous stem cell transplantation (ASCT) followed by IsaKRD (Arm B), while MRD-positive patients were randomized to either single ASCT plus IsaKRD (Arm C) or tandem ASCT (Arm D). All patients received subsequent maintenance, with lenalidomide for MRD-negative arms and isatuximab plus iberdomide for MRD-positive arms. The primary endpoint was MRD negativity at 10⁻⁶ prior to maintenance.

Among the 485 MRD-negative patients post-induction, MRD negativity at 10⁻⁶ before maintenance was achieved in 84% of patients in Arm A and 86% in Arm B (OR 1.17; 95% CI, 0.64–2.76; p = 0.64), indicating comparable deep response rates between prolonged IsaKRD and ASCT-based strategies. In the MRD-positive cohort (n = 233), pre-maintenance MRD negativity was observed in 40% of patients in Arm C and 32% in Arm D (OR 0.73; 95% CI, 0.42–1.25; p = 0.31), suggesting no significant advantage for tandem ASCT. During the consolidation phase, disease progression was rare (5 total events), and no new safety concerns were identified. With median follow-up of approximately 16 months across study arms, data on sustained MRD negativity and progression-free survival remain immature and will be reported in future analyses.

KOL insights

“In MRD-negative patients, transplant did not improve MRD outcomes compared to continued IsaKRD, and in MRD-positive patients, tandem transplant did not show any MRD advantage over single transplant.”– Expert Opinion

“MRD is a strong independent predictor of progression-free survival and overall survival in NDMM. Transplant improves PFS in Phase III trials compared to no transplant, but its benefits in patients who are already MRD-negative after induction remains unclear.” – Expert Opinion

Conclusion

IsaKRD, a quadruplet regimen combining isatuximab, carfilzomib, lenalidomide, and dexamethasone, is emerging as a potent frontline therapy for NDMM, particularly in transplant-eligible patients. It leverages the synergistic activity of the CD38 monoclonal antibody isatuximab and the second-generation proteasome inhibitor carfilzomib to deepen responses when used alongside immunomodulatory and corticosteroid backbones. The most direct competitor to IsaKRD is the Dara-KRd regimen (daratumumab, carfilzomib, lenalidomide, dexamethasone), which has demonstrated deep and durable responses in trials like MASTER and is being further evaluated in PERSEUS. Additionally, the widely adopted Dara-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone), supported by the GRIFFIN trial, remains the preferred standard of care in many frontline settings due to its favorable safety profile and broad accessibility.