Isa-KRd in Newly Diagnosed Multiple Myeloma: Results From the GMMG-CONCEPT Trial and the IFM 2020-02 MIDAS Study

Patients diagnosed with high-risk multiple myeloma persistently exhibit markedly inferior survival rates compared with patients without high-risk disease, despite the advancements in novel therapeutic agents available today.¹ The phase 2 GMMG-CONCEPT trial (NCT03104842) explored the induction and consolidation treatment of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd), along with Isa-KR maintenance therapy, in patients with high-risk newly diagnosed multiple myeloma (NDMM). This article reports the longer-term outcomes of the first cohort with a ≥4-year follow-up for survival and minimal residual disease (MRD) negativity.¹

A total of 153 patients with high-risk NDMM were divided into 2 arms. Arm A included patients who were transplant-eligible (TE) and aged ≤70 years (n=127), and arm B included transplant-ineligible (TNE) patients aged >70 years (n=26).¹ Arm A received 6 cycles of Isa-KRd plus high-dose chemotherapy and autologous stem cell transplant (ASCT), whereas arm B received 8 cycles of Isa-KRd. Both arms received Isa-KRd consolidation and Isa-KR maintenance.¹

MRD negativity was achieved at any time point by 83.5% of TE patients and 69.2% of TNE patients. Of the 106 TE and 18 TNE patients who achieved MRD negativity, 85 (80.2%; TE) and 13 (72.2%; TNE) achieved ≥1-year sustained MRD negativity.¹ Six years after treatment initiation, >50% of patients are alive and progression-free. Progressive disease or death <18 months after treatment initiation occurred in 29 patients. Multivariable time-dependent Cox regression analysis showed a prognostic progression-free survival benefit for MRD negativity versus non-MRD negativity with a hazard ratio of 0.11.¹

After a median follow-up period exceeding 4 years, >50% of patients with high-risk NDMM remain alive and free from disease progression 6 years following the commencement of treatment.¹ Achieving MRD-negative remission is of utmost importance for improving the prognosis in high-risk disease.¹

In patients diagnosed with TE NDMM, it is standard practice to administer induction therapy utilizing a quadruple regimen prior to undergoing ASCT.² Currently, there are no prospective studies that have evaluated the comparison between upfront ASCT and nonadministration of ASCT following quadruplet induction. The importance of upfront ASCT is still under scrutiny, indicating a need for risk-adapted approaches to ascertain its value post-quadruplet induction.

The phase 3 IFM 2020-02-MIDAS trial is currently underway, evaluating an MRD-adapted approach to consolidation and maintenance therapy subsequent to Isa-KRd induction.² Patients were divided into arms A and B and arms C and D based on standard risk (MRD <10^-5) and high risk (MRD >10^-5), respectively.² In the standard-risk group, patients were randomized 1:1 to receive either 6 cycles of Isa-KRd or ASCT plus 2 cycles of Isa-KRd. In the high-risk group, patients were randomized 1:1 to receive either ASCT plus 2 cycles of Isa-KRd or tandem ASCT.²

In the intention-to-treat (ITT) population, 92% of patients achieved a very good partial response or better and 64% to 66% of patients achieved a near-complete response or complete response.² In the ITT population, the post-induction MRD-negativity rate at 10^-5 was 63%. Subgroup analysis of MRD negativity did not result in a significant difference based on age, International Staging System (ISS) stage, revised ISS (R-ISS) stage, R2-ISS stage, International Myeloma Foundation linear predictor score, or International Myeloma Society/International Myeloma Working Group consensus definition. The most common hematologic adverse events of any grade included anemia (17%), thrombocytopenia (13%), and neutropenia (29%). The most common nonhematologic adverse events of any grade included gastrointestinal disorders (56%), infections (46%), and hepatobiliary disorders (13%).²

The results indicate that 6 cycles of Isa-KRd led to remarkably high rates of MRD negativity, achieving this at both a sensitivity level of 10^-5 and 10^-6.² Isa-KRd induction facilitates the successful collection of stem cells, with no emerging safety signals reported. Additional follow-up of the MIDAS cohort is necessary to validate these advantages in the final analysis.²

References

1. Leypoldt LB, Besemer B, Hänel M, et al. Isa-KRd in high-risk newly diagnosed multiple myeloma — 4-year-follow-up from the GMMG-CONCEPT trial. Presented at: 21st International Myeloma Society Annual Meeting. September 25-28, 2024; Rio de Janeiro, Brazil.
2. 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: 21st International Myeloma Society Annual Meeting. September 25-28, 2024; Rio de Janeiro, Brazil.