Daratumumab Plus IRd Induction, Consolidation Achieves High MRD-Negativity Rates in Standard-Risk Myeloma

Aurore Perrot, MD, PhD

In the phase 2 IFM 2018-01 trial (NCT03669445), daratumumab (Darzalex) plus ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone (Dara-IRd) as both induction and consolidation therapy achieved deepened minimal residual disease (MRD) rates in patients with standard-risk, transplant-eligible newly diagnosed multiple myeloma, according to data presented at the ASH Annual Meeting 2021.

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

“Dara-IRd as extended induction prior to and as consolidation following transplant was safe and allows gradually deepening responses in standard-risk newly diagnosed multiple myeloma,” said Perrot, of the the Centre Hospitalier Universitaire de Toulouse, Service d'Hématologie, Toulouse, France. “However, MRD-negativity rates are lower, especially at the 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 preferred in MRD-adapted strategies in a view to cure patients in transplant setting.”

There were 45 patients enrolled to receive Dara-IRd, with 43 receiving ASCT and 42 getting consolidation. Maintenance therapy with single agent lenalidomide was administered to 37 patients and remained ongoing at the time of the analysis. The main causes of study discontinuation were progressive disease (n = 3), adverse events (AEs; n = 2), and patients' decision (n = 3).

In cycles 1 to 6 of induction ixazomib was given at 3 mg on days 1, 4, 8, and 11, lenalidomide was administered at 25 mg daily for days 1 to 14, dexamethasone was dosed 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 achieved with intravenous cyclophosphamide at 3 g/m2 along with G-CSF at 10 μg/kg per day. Melphalan at 200 mg/m² was given 2 days prior to infusion of stem cells and pegylated G-CSF was given 2 days after.

For consolidation, the dose for ixazomib was increased to 4 mg on days 1, 8, and 15. Lenalidomide was given at 25 mg daily from day 1 to 21 and dexamethasone was given 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 induction and consolidation, patients were moved to maintenance lenalidomide alone at 10 mg daily on days 1 to 21 for up to 2 years or until progression.

The median age of patients enrolled in the study was 57 years (range, 28-65) and 35.6% were at least 60 years old. Two-thirds of patients were male (66.7%) and International Staging System stages were balanced between stage 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 status was 0 (55.6%). Hemoglobin was less than 10 g/dL for 22.2% of patients.

The post-consolidation objective response rate (ORR) by International Myeloma Working Group (IMWG) criteria was 97.7%. The very good partial response (VGPR) or better rate was 95.3% and the complete response (CR) or stringent CR rate was 32.6%. Following induction alone, the ORR was 97.6%, the VGPR or better was 78.0%, and CR/sCR was 14.6%. After ASCT, the ORR was 97.7%, the VGPR or better was 90.0%, and the 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 MRD at 10^-6 was the primary end point, MRD at the IMWG threshold of 10-5 was also assessed for the study. By this criteria, MRD-negativity following consolidation and before maintenance was achieved by 51.4% of patients (95% CI, 36.8%-65.7%). Following induction alone, the MRD negativity rate by 10^-5 was 28.1% and was 6.3% by the 10^-6 criteria. Following ASCT the rate of MRD negativity by 10^-5 was 34.4% and was 29.0% by 10^-6. After 1 year of maintenance, the MRD-negativity rate was 51.3% by the 10^-5 criteria and was 30.3% by the 10^-6 definition.

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 disorders (66.7%), respiratory tract infection (62.2%), peripheral sensory neuropathy (37.8%), and rash (28.9%). There was 1 case of a secondary primary malignancy detected, which was myelodysplastic syndrome.

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

_Reference

_{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). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 464.}