Daratumumab (Darzalex) plus ixazomib (Ninlaro), lenalidomide (Revlimid) and dexamethasone (Dara-IRd) as prolonged induction and consolidation therapy in newly diagnosed multiple myeloma eligible for standard risk transplantation resulted in increased rates of minimal residual disease (MRD)), according to the Phase 2 results of the IFM 2018-01 trial (NCT03669445) presented at the 2021 ASH annual meeting.

MRD negative specific to 10^-6 as determined by next-generation sequencing, was obtained by 39.5% (95% CI, 26.1% to 54.1%) of patients following treatment with Dara-IRd as induction and consolidation prolonged after autologous stem cell transplantation (ASCT). The 2-year progression-free survival rate (PFS) was 93.3% (95% CI, 80.7% to 97.8%) and 100% of people remained alive at assessment. These rates were lower than those seen with other quadruple diets for standard-risk multiple myeloma, said principal investigator Aurore Perrot, MD, PhD.

“Dara-IRd as a prolonged induction before and as a consolidation after transplantation was safe and allows to progressively deepen the responses in newly diagnosed multiple myelomas at standard risk”, said Perrot, of the Center Hospitalier Universitaire de Toulouse , Department of Hematology, Toulouse, France. “However, MRD negativity rates are lower, especially during post-induction assessment, than those obtained with Dara-VTd [daratumumab, bortezomib, thalidomide, and dexamethasone] and Dara-KRd [daratumumab, carfilzomib, lenalidomide, and dexamethasone], which should be favored in strategies adapted to MRD with a view to curing patients in transplant situations.

There were 45 patients enrolled to receive Dara-IRd, with 43 receiving ASCT and 42 receiving consolidation. Maintenance treatment with lenalidomide monotherapy was administered to 37 patients and was still ongoing at the time of analysis. The main causes of study discontinuation were disease progression (n = 3), adverse events (AEs; n = 2), and patient decision (n = 3).

In induction cycles 1 to 6 ixazomib was administered at 3 mg on days 1, 4, 8 and 11, lenalidomide was administered at a dose of 25 mg per day for days 1 to 14, dexamethasone was administered at 40 mg on days 1, 8 and 15 and daratumumab was administered at 16 mg / kg on days 1, 8 and 15 in cycles 1 to 4 and on days 1 and 15 for cycles 5 and 6. Cell mobilization for ASCT was obtained with intravenous cyclophosphamide at 3 g / m² with G-CSF at a rate of 10 g / kg per day. Melphalan at 200 mg / m² was given 2 days before the stem cell infusion and pegylated G-CSF was given 2 days after.

For consolidation, the ixazomib dose was increased to 4 mg on days 1, 8 and 15. Lenalidomide was administered 25 mg daily from day 1 to day 21 and dexamethasone was administered at 20 mg. on days 1, 8, 15 and 22. for cycles 7 and 8 and on days 1 and 15 for cycles 9 and 10. Daratumumab was administered at 16 mg / kg on days 1 and 15. After 10 total cycles of On induction and consolidation, patients switched to lenalidomide maintenance alone at 10 mg daily on days 1 to 21 for up to 2 years or until progression.

The median age of the patients included in the study was 57 years (range, 28-65) and 35.6% were at least 60 years old. Two-thirds of the patients were men (66.7%) and the stages of the International Staging System were balanced between stages I (40.9%), II (38.6%) and III (20.5% ). There were no patients enrolled with high-risk cytogenetics by fluorescence in situ hybridization, and the most common ECOG performance index was 0 (55.6%). Hemoglobin was less than 10 g / dL for 22.2% of patients.

The post-union objective response rate (ORR) according to the criteria of the International Myeloma Working Group (IMWG) was 97.7%. The rate of very good partial response (VGPR) or better was 95.3% and the rate of complete response (CR) or strict CR was 32.6%. After induction alone, the ORR was 97.6%, the VGPR or better was 78.0%, and the CR / sCR was 14.6%. After ASCT, ORR was 97.7%, VGPR or better was 90.0%, and CR / sCR was 25.0%. After 1 year of maintenance, the ORR was 95.2%, the VGPR or better was 92.8%, and the CR / sCR was 54.7%.

Although the MRD at 10-6 was the primary endpoint, the MRD at the IMWG cutoff of 10^-5 was also assessed for the study. According to these criteria, MRD-negativity after union and before maintenance was achieved by 51.4% of patients (95% CI, 36.8% to 65.7%). After induction alone, the MRD negativity rate of 10^-5 was 28.1% and 6.3% according to criteria 10-6. After ASCT, the MRD negativity rate of 10^-5 was 34.4% and 29.0% in 10^-6. After 1 year of maintenance, the MRD negativity rate was 51.3% according to criteria 10-5 and 30.3% according to definition 10-6.

The most frequently observed grade 3/4 AEs were neutropenia (31.1%), thrombocytopenia (11.1%), respiratory tract infections (8.8%) and gastrointestinal disorders (6, 7%). Adverse events of any grade included gastrointestinal disturbances (66.7%), respiratory tract infections (62.2%), peripheral sensory neuropathy (37.8%), and rash (28.9%) ). There was 1 case of a detected secondary primary malignancy, which was myelodysplastic syndrome.

“Due to its very safe profile, Dara-IRd could be used for standard-risk multiple myeloma patients with neurological or cardiovascular comorbidities,” noted Perrot.

Reference

Perrot A, Lauwers-Cances V, Touzeau C, et al. Daratumumab plus ixazomib, lenalidomide and dexamethasone as prolonged induction and consolidation followed by maintenance with lenalidomide in patients with newly diagnosed multiple myeloma (IFM 2018-01) eligible for a standard risk transplant (IFM 2018-01): a study phase II of the Francophone Myeloma Intergroup (IFM). Presented at the 2021 ASH Annual Meeting and Exhibition; December 11-14, 2021; Atlanta, Georgia. Abstract 464.