Isa-KRd Induction Therapy Elicits Responses, MRD Negativity in Transplant-Eligible, Newly Diagnosed Myeloma

Six cycles of induction therapy with isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) generated responses and minimal residual disease (MRD) negativity, demonstrated manageable safety, and ensured successful stem cell collection in patients with newly diagnosed multiple myeloma eligible for transplant, according to data from an interim analysis of the phase 3 IFM2020-02 MIDAS study (NCT04934475).¹

Findings presented at the 21st IMS Annual Meeting showed that among the 757 patients who completed 6 cycles of Isa-KRD, the overall response rate (ORR) rate was 95%. In the intent-to-treat (ITT) population, 92% of patients had a very good partial response (VGPR) and 64% to 66% of patients achieved near complete response (nCR)/complete response (CR). In the per-protocol population (PP), 99% of patients achieved a VGPR or better and 69% to 71% of patients achieved nCR/CR.

A total of 751 patients had post-induction MRD and in the ITT population, the MRD negativity rate was 63% at 10-5 and 47% at 10-6, which was 66% and 50%, respectively, in the PP population.

“We found that this induction induced exceptionally high response and MRD negativity rates at 10-5, but also at 10-6.” said Aurore Perrot, MD, PhD, associate professor in hematology at the University of Toulouse, France, during a presentation of the data. “These rates are the highest reported to date; regarding MRD negativity at 63%, it is favorably compared to CASSIOPEIA [NCT02541383], GRIFFIN [NCT02874742], and IsKia [NCT03104842] at 4 years.”

During induction, 7 patients experienced disease progression, and 5 died. Of these, 1 death was due to disease progression, 2 were from cardiac adverse effects (AEs), and 2 resulted from other AEs. The most common grade 3 or grade 4 AEs reported were neutropenia in 25% of patients, thrombocytopenia in 5%, and infections in 7%. Peripheral neuropathy was observed in 6% of patients, with most cases being grade 1 or grade 2. Additionally, no new safety signals were observed.

Behind the Phase 3 MIDAS Trial

The phase 3 MIDAS trial is an ongoing study where investigators are evaluating an MRD-adapted consolidation and maintenance strategy following Isa-KRd induction. Patients will be separated into standard-risk and high-risk groups based on MRD negativity or positivity at 10-5 threshold post-induction. Those with standard risk will be randomly assigned to consolidation Isa-KRd with or without autologous stem cell transplant (ASCT) followed by lenalidomide maintenance. Those with high risk will be randomly assigned to receive ASCT plus Isa-KRd or tandem ASCT followed by isatuximab plus iberdomide as maintenance.

“The role of upfront transplant remains a topic of debate, and to date, no prospective trials have compared upfront transplant vs no transplant following quadruplet induction. We are convinced that risk-adapted strategies are needed,” said Perrot.

Eligible patients aged under 66 years underwent 6 cycles of 28-day treatment with Isa-KRd, consisting of isatuximab 10 mg/kg administered weekly for the first 4 weeks, then biweekly, carfilzomib at a dose of 20 mg/m² on day 1 of cycle 1, escalating to 56 mg/m² on days 1, 8, and 15, lenalidomide 25 mg daily from days 1 to 21, and dexamethasone 40 mg per week.

Cytogenetic risk was evaluated at diagnosis through next-generation sequencing (NGS), with a linear predictor (LP) score indicating high risk if it exceeded 1, based on factors including del(17p), t(4;14), del(1p32), gain 1q, trisomy 21, and trisomy 5. Peripheral stem cells (PSCs) were harvested after 3 cycles using G-CSF and plerixafor for mobilization. The response to treatment was assessed according to International Myeloma Working Group criteria, and MRD was measured using NGS techniques.

A total of 791 patients were enrolled across 72 centers between December 2021 and July 2023. The median patient age was 58.7 years (range, 25.4-66), the majority of patients were male (57%), and 61 patients (8%) met only SLiM criteria. Disease was classified as international staging system (ISS) stage III in 99 patients (13%) and as revised (R)-ISS stage III in 43 patients (5%). The t(11;14) translocation was found in 8% of patients. Only 5 patients had extramedullary disease at diagnosis, with 700 evaluated by PET-CT, and 53 patients (7%) had circulating plasma cells. “MRD status after induction was not consistently aligned with initial cytogenetic risk,” Perrot noted.

All 791 enrolled patients began Isa-KRd induction, with 766 (97%) receiving at least 1 course of PSC mobilization and 761 (99%) undergoing at least 1 apheresis over a median of 2 days. The median number of collected cells was 7 x 10-6 CD34-positive/kg, enabling the possibility of tandem transplantation in 721 patients.

“Longer follow-up is needed to further understand the significance of achieving MRD negativity in some particular subgroups,” concluded Perrot.

Reference

Perrot A, Touzeau C, Lambert J, et al. Efficacy and safety of Isa-KRd induction before response-adapted consolidation in transplant eligible newly diagnosed multiple myeloma: an interim analysis of the IFM2020-02 MIDAS study. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2023; Rio de Janeiro, Brazil. Abstract OA-54