MInimal Residual Disease Adapted Strategy — MIDAS  

Multiple Myeloma Clinical Trial

Official title: MInimal Residual Disease Adapted Strategy: Frontline Therapy for Patients Eligible for Autologous Stem Cell Transplantation Less Than 66 Years; a Prospective Study

Status Active, not recruiting

Clinical Trial Summary

IFM 2020-02 will enroll patients eligible for ASCT less than 66 years. All patients will receive induction based on 6 cycles (28-day) of KRD-Isatuximab (Isa-KRD), in order to achieve deep responses and high MRD negativity rates. Patients will be classified at diagnosis according to cytogenetics (standard vs high-risk cytogenetics defined by the LP score including 17p deletion, t(4;14), del(1p32), gain 1q, trisomy 21 and trisomy 5).

Clinical Trial Description

According to international guidelines, outside clinical trials, frontline autologous stem cell transplantation (ASCT) is the standard of care for fit patients less than 71 years of age, who are newly diagnosed with multiple myeloma.

Triplet combinations are now the backbone of induction therapy prior to ASCT. KRD (Carfilzomib, Lenalidomide, Dexamethasone) is potentially the more active regimen.

Quadruplet combinations are under evaluation. The prospective phase 3 CASSIOPEIA trial conducted by the IFM and HOVON cooperative groups investigated the outcome of transplant-eligible patients treated with VTD (Bortezomib, Thalidomide, Dexamethasone) +/- Daratumumab administered both before (induction, 4 cycles) and after (consolidation, 2 cycles) single ASCT prepared by Melphalan 200 mg/m2.5 The addition of Daratumumab to VTD during induction induced significantly higher response rates, but also higher minimal residual disease (MRD) - negativity rates. The high response rates achieved after induction (MRD negativity rates at 10-5 by 8-color flow cytometry 35% (188/543) in the VTD-Dara arm vs 23% (125/542) after 4 cycles of VTD in the intent-to-treat population), but also after consolidation and before maintenance (MRD negativity rates at 10-5 by 8-color flow cytometry 63% in the VTD-Dara arm vs 43% in the VTD in the intent-to-treat population), translated into a significant improvement in progression-free-survival (PFS) in the Daratumumab arm of the study: 18-month PFS 93% vs 85% before maintenance, HR 0.47 (0.33-0.67), p < 0.0001. Cassiopeia is the first study showing a correlation between MRD negativity after induction (before ASCT) and PFS benefit, in the setting of quadruplet combination induction. Based on these results, VTD + daratumumab was recently approved by the FDA and EMA.

KRD has also been combined with Daratumumab in several phase 2 trials. Early results indicate that this quadruplet combination might potentially be the most effective regimen prior to ASCT in terms of response and MRD-negativity rates. Carfilzomib was administered intravenously weekly, on days 1, 8 and 15 of 28 day-cycles at the dose of 56 mg/m². Based on 70 patients, the MRD-negativity rate after four cycles of KRD-Daratumumab was 39% at a detection level of 10-5 by next generation sequencing (NGS). The weekly KRD-Daratumumab regimen was associated with low toxicity, and stem cell harvest was adequate. The rate of MRD negativity in 42 patients further improved after single ASCT, to 67% and 43% at a detection level of 10-5 and of 10-6 by NGS, respectively. Due to the short 7.9 months median follow-up time at the time of presentation, no PFS data were presented. At ASCO 2020, Weisel et al reported the results of induction based on 6 cycles of KRD plus Isatuximab, in patients with high-risk cytogenetics.8 In this interim analysis on the first 46 patients eligible for ASCT with high-risk disease, the overall response rate was 100%, including 60% MRD negativity at 10-5 by NGS after induction and before ASCT. No death on study was reported. No data are yet available regarding MRD negativity rates after ASCT or PFS. At ASH 2019, Landgren et al. reported the results of eight weekly KRD-Daratumumab cycles without ASCT in a small phase 2 study on 41 patients after a short median follow-up time of 8.6 months.

On the same intent-to-treat basis, MRD-negativity rate at a detection level of 10-5 by NGS was 61% and 65% in patients after six and eight cycles, respectively, including a very good partial response (VGPR) rate or better of 85% after 8 cycles and an overall response rate (ORR) of 100%. No death on study was seen. At the time of the report, no patient with MRD-negative disease had progressed. Despite the short follow-up time, based on the high rate of MRD-negativity and the 0% relapse rate achieved so far with this quadruplet combination, the authors of this small phase 2 series now propose to systematically delay ASCT in patients with standard-risk disease. This provocative recommendation requires validation in a phase 3 randomized trial comparing frontline versus delayed ASCT in patients with MRD-negative disease after induction.

Patients MRD positive after quadruplet induction are at higher risk of disease progression. For patients with high-risk (HR) disease, tandem ASCT has been proposed in order to improve PFS and overall survival (OS). In an integrated analysis of four phase III studies independently conducted by HOVON/GMMG, IFM, PETHEMA/GEM and GIMEMA European cooperative groups, in the era of Bortezomib-based induction regimens, double ASCT significantly improved PFS and OS in HR patients.

In the EMN02/HO95 study, in centers with a policy of double ASCT, patients were assigned to receive VMP (Bortezomib, Melphalan, Prednisone), single ASCT (ASCT-1) or two planned ASCTs (ASCT-2) to prospectively compare ASCT-1 with ASCT-2. Patients who received ASCT-2 had a prolonged PFS compared to those who received ASCT-1. Importantly, ASCT-2 overcame the adverse prognosis conferred by high-risk cytogenetics. In the same study, OS from the first randomization was significantly prolonged with ASCT-2 as compared with ASCT-1, a benefit also seen in subgroups of patients with adverse prognosis, including those with R-ISS stage II+III and high-risk cytogenetics. To date, no prospective trial has compared single vs tandem ASCT in HR patients in the era of quadruplet induction combinations.

After ASCT, a systematic maintenance is recommended by International Guidelines. Lenalidomide is approved in this setting, and proposed until progression. Other agents or combinations are under evaluation for maintenance, such as Ixazomib, Elotuzumab, Daratumumab or Isatuximab. Iberdomide is a next generation cereblon targeting agent, with antitumor and immunostimulatory activities in Lenalidomide- and Pomalidomide-resistant multiple myeloma. This oral agent, which could be the ideal agent for maintenance therapy, is currently tested after ASCT. Phase 2 and 3 randomized studies are currently investigating the combination of Lenalidomide with anti-CD38 monoclonal antibodies as maintenance therapy after autologous stem cell transplant. We assume that a fixed duration of maintenance using Iberdomide and Isatuximab will induce a high-rate of sustained MRD negativity. ;

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasm, Residual

• NCT number: NCT04934475
• Study type: Interventional
• Source: Intergroupe Francophone du Myelome
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 8, 2021
• Completion date: September 1, 2028