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
- 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.
- 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.