Ixazomib and Daratumumab Without Dexamethasone Shows Favorable Safety in Patients With Relapsed Myeloma and High Frailty Score

The phase 2 IDARA trial (NCT03757221) of the combination of daratumumab (Darzalex) plus ixazomib (Ninlaro) without dexamethasone demonstrated safety and preliminary efficacy of the combination in frail, elderly patients with relapsed or refractory multiple myeloma, according to data presented at the 63rd Annual American Society of Hematology Annual Meeting and Exposition.¹

Responses were promising, with 24% of patients overall achieving a very good partial response (VGPR) or better; in the group of patients with disease that is refractory to lenalidomide (Revlimid), that rate was 38%.

Frailty is typically associated with poor outcomes in patients with multiple myeloma given high rates of discontinuation from adverse effects (AEs), especially in the setting of relapsed disease. Both daratumumab and ixazomib are approved across various indications in multiple myeloma, and the combination of the 2 agents plus low-dose dexamethasone was previously shown to result in high response rates and improved quality of life in this patient population with frontline disease. However, treatment discontinuation remained high in frail subpopulations, which impacted both progression-free and overall survival (OS).₂

The current investigation aimed to determine if the IDARA combination is effective in an elderly subset of patients (>65 years) with relapsed or refractory disease who have a frailty score of 2 or more by the International Myeloma Working Group (IMWG) criteria, with a primary end point of VGRP or better. Other inclusion criteria included having 1 or 2 prior lines of therapy, disease that is naïve to both agents, and ECOG performance status of 2 or less, and adequate bone marrow and organ function.

Patients were treated with 28-day cycles on continuous therapy until disease progression with intravenous daratumumab at 16 mg/kg administered on days 1, 8, 15, and 22 for cycles 1 and 2, days 1 and 15 for cycles 3 through 6, and day 1 of each cycle thereafter. Oral ixazomib at 4 mg was administered on days 1, 8, and 15 of cycles 1 and 2, days 1, 8, and 15 of cycles 3 through 6, and days 1, 8, and 15 of each cycle thereafter.

In 55 patients examined, the median age was 82 years (range, 72-93), with 43 (78%) of those being 80 years of age or older. Most patients (76%) had an IMWG score of 2. International Staging System scores in 41 evaluable patients indicated that most had stage 2 (44%) or 3 (29%) disease. High-risk cytogenetics, indicated by the presence of t(4;14) and/or deletion 17p were noted in 15 out of 46 evaluable patients.

All patients had either 1 (65%) or 2 prior lines of therapy (35%). Of the patients who received lenalidomide in a prior line (67%), 19 (34%) were refractory to treatment. Most patients (64%) had also received bortezomib (Velcade) in a prior line of therapy.

In all patients evaluable for response (n = 50), the overall response rate (ORR), comprised of partial response or better, was 72%. In the lenalidomide-refractory group (n = 16), the ORR was 75%.

At a median follow-up of 7.6 months (95% CI, 3.8-11.2) in 50 evaluable patients, the median progression-free survival was 16 months (95% CI, 9.9-undefined). OS has yet to be determined.

In total, 30 patients (55%) were continued on treatment at the data cutoff. The 25 patients (45%) who discontinued therapy did so because of progressive disease (29%), AEs (13%), or withdrawal from the study (3%).

There were 2 treatment-related deaths, 1 from daratumumab-related bronchospasm and 1 from ixazomib overdose. Other deaths occurred due to second primary malignancy (2%), disease progression (5%), and infection (7%).

Grade 3 or higher AEs occurred in 23 patients (52%), including thrombocytopenia (16%), hypertension (7%), infection (5%), and gastrointestinal disorder (5%). Drug suspension or discontinuation resulting from ixazomib-related AEs included grade 3/4 thrombocytopenia (n = 2), grade 2 peripheral neuropathy (n = 1), skin rash (n = 1), sepsis (n = 1), and ixazomib overdose (n = 2).

The investigators concluded that the results support the safe use of the combination in this patient group.

References

1. Macro M, Touzeau C, Mariette C, et al. Ixazomib and Daratumumab without Dexamethasone (I-Dara) in Elderly Frail RRMM Patients. a Multicenter Phase 2 Study (IFM 2018-02) of the Intergroupe Francophone Du Myélome (IFM). Presented at: 63rd Annual American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 83. Accessed December 11, 2021. https://bit.ly/3ISkF3V
2. Stege CAM, Nasserinejad K, van der Spek E, et al. Ixazomib, daratumumab, and low-dose dexamethasone in frail patients with newly diagnosed multiple myeloma: The Hovon 143 Study. J Clin Oncol. 2021;39(25):2758-2767. doi:10.1200/JCO.20.03143