Daratumumab plus Ixazomib, Lenalidomide, and Dexamethasone as Extended Induction and Consolidation Followed by Lenalidomide Maintenance in Standard-Risk Transplant-Eligible NDMM

2021 Year in Review - Multiple Myeloma —February 23, 2022

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Multiple Myeloma

Results of a phase 2 IFM study demonstrated that quadruplet combination regimen of D-IRD as induction and consolidation therapy after ASCT followed by lenalidomide maintenance therapy was safe and resulted in increased depth of responses over time in standard-risk patients with NDMM.

The Intergroupe Francophone Du Myélome (IFM) phase 2 study (IFM 2018-01; NCT03669445) evaluated the safety and efficacy of the quadruplet combination regimen of daratumumab plus ixazomib, lenalidomide, and dexamethasone (D-IRD) as induction and consolidation, followed by autologous stem-cell transplantation (ASCT) before lenalidomide maintenance in patients with standard-risk newly diagnosed multiple myeloma (NDMM). Results of this trial were reported at the 2021 ASH Annual Meeting and summarized here.

From December 2018 to September 2019, the study enrolled patients with NDMM aged <66 years with standard-risk cytogenetics (defined by fluorescence in situ hybridization at diagnosis according to International Myeloma Working Group criteria) in 10 IFM centers. Eligible patients received six 21-day cycles of induction therapy consisting of daratumumab (16 mg/kg intravenously; cycles 1-4: days 1, 8, and 15; cycles 5-6: days 1 and 15) plus ixazomib (3 mg; days 1, 4, 8, and 11), lenalidomide (25 mg; days 1-14), and dexamethasone (40 mg; days 1, 8, and 15). Post-ASCT consolidation therapy consisted of four 28-day cycles with daratumumab (16 mg; days 1 and 15), ixazomib (4 mg; days 1, 8, and 15), lenalidomide (25 mg; days 1-21), and dexamethasone (20 mg; cycles 7-8: days 1, 8, 15, and 22; cycles 9-10: days 1 and 15). Single-agent lenalidomide maintenance was administered at 10 mg on days 1 to 21 of a 28-day cycle during 26 cycles. The primary end point was minimal residual disease (MRD) negativity (assessed by next-generation sequencing, sensitivity threshold of 10–6) after consolidation and before maintenance. Secondary objectives were toxicity, MRD negativity rates at other timepoints, response rates, progression-free survival, time to progression, and overall survival.

In total, the study enrolled 45 patients; of these, 42 patients completed induction, ASCT, and consolidation, while 37 patients started maintenance. The median age of the study population was 57 years; 40.9% of patients had a Multiple Myeloma International Staging System (ISS) score of 1, 38.6% had an ISS score of 2, and 20.5% had an ISS score of 3.

The MRD negativity rate (sensitivity of 10–6) after consolidation and before maintenance (primary end point) was 39.5%. At other timepoints, the MRD negativity rate (sensitivity of 10–6) after induction was 6.3%, after ASCT was 29.0%, and after maintenance was 30.3%. At a sensitivity of 10–5, the MRD negativity rate after induction was 28.1%, after ASCT was 34.4%, after consolidation was 51.4%, and after maintenance was 51.3%. All patients achieved a response (overall response rate, 100%), including complete response/stringent complete response of 53.4%, very good partial response of 40%, and partial response of 6.7%. The depth of response deepened over time in terms of International Myeloma Working Group categories and MRD negativity rates. At a median follow-up of 23.6 months, the 24-month progression-free survival rate was 93.3%; 24-month overall survival rate was 100%.

Grade 3/4 adverse events were reported in 26 (57.7%) patients; the most common grade 3/4 toxicities were neutropenia (31.1%), infections (15.6%), thrombocytopenia (11.1%), and gastrointestinal disorders (6.7%). Peripheral neuropathy was reported in 37.8% of patients and rash in 28.9%, all of which were grade 1/2 severity. Serious adverse events occurred in 15 (33.3%) patients. There were no reports of death; 1 secondary primary malignancy occurred (myelodysplastic syndrome).

Results of the phase 2 IFM study demonstrated that D-IRD as extended induction and consolidation therapy after ASCT was safe and resulted in increased depth of responses over time in standard-risk patients with NDMM.

Source: Perrot A, Lauwers-Cances V, Touzeau C, et al. Daratumumab plus ixazomib, lenalidomide, and dexamethasone as extended induction and consolidation followed by lenalidomide maintenance in standard-risk transplant-eligible newly diagnosed multiple myeloma (NDMM) patients (IFM 2018-01): a phase II study of the Intergroupe Francophone Du Myélome (IFM). Blood. 2021;138(suppl 1):464.

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