Ixazomib, Daratumumab, and Low-Dose Dexamethasone Induction in Frail Elderly Newly Diagnosed MM Patients

Non–transplant eligible newly diagnosed multiple myeloma (NDMM) patients who are frail have inferior overall survival (OS), primarily because of treatment discontinuation due to toxicity. As such, evaluation of less toxic effective therapies, such as the oral proteasome inhibitor ixazomib (Ixa) and the monoclonal anti-CD38 antibody daratumumab (Dara), is critical for this patient population as well as the elderly. This phase 2 study evaluates the efficacy and tolerability of Ixa-Dara with low-dose dexamethasone (Dex) in frail NDMM patients.

Sixty-five NDMM patients who were frail according to the International Myeloma Working Group Frailty Index were enrolled in this prospective, multicenter, phase 2 trial. Treatment consisted of nine 28-day induction cycles with Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (cycles 1-2: days 1, 8, 15, 22; cycles 3-6: days 1, 15; cycles 7-9: day 1), and Dex (in combination with Dara during cycles 1-2: 20 mg; 10 mg thereafter) followed by maintenance therapy with Ixa (days 1, 8, 15, 29, 36, and 43) and Dara (day 1) of 8-week cycles, until progression for a maximum of 2 years. The primary end point of the trial was overall response rate (ORR) on the induction treatment. Key secondary and safety outcomes included progression-free survival (PFS), OS, treatment discontinuation, and toxicity.

The patients’ median age was 81 years (range, 70-92 years), with 51% (33 patients) >80 years. Twenty percent (13 patients) were frail due to age only. Of those >80 years, 60% had additional frailty parameters such as comorbidities and/or instrumental activities of daily living dependency. During induction therapy, ORR was 78%, with 8% achieving stringent complete response, 28% achieving very good partial response, and 43% achieving partial response. After follow-up (median, 16.3 months; range, 8.5-26.9 months), median PFS was 13.8 months. At 12 months, OS was 78% (95% confidence interval, 66%-87%).

During induction therapy, treatment discontinuation occurred for 33 (51%) patients. Of these discontinuations, 6 were due to toxicity, 6 were due to intercurrent death (3 infections, 2 sudden deaths, and 1 acute renal failure due to diarrhea), 12 were due to progressive disease (PD), 4 were due to incompliance, and 5 were due to other reasons. PD also resulted in 5 patients not proceeding to maintenance therapy (9 total patients did not proceed). After maintenance follow-up (median, 16.7 months; range, 12.8-26.9 months), 38% of patients (12/32) discontinued treatment, 83% of which were due to PD. Toxicity grade 3 occurred in 32 patients (50%); hematologic adverse events (AEs) were limited, the most common of which was thrombocytopenia (grade 3, 19%; grade 4, 5%). Nonhematologic toxicity AEs were most commonly infections (grade 3, 19%; grade 4, 6%; grade 5, 2%), gastrointestinal (grade 3, 11%; grade 4, 2%), and cardiac (grade 3, 8%; grade 4, 3%).

Sixteen patients (25%) died, 6 of whom were due to PD (9%). Nonrelapse mortality occurred in the remainder of 10 patients (16%), 5 early (≤60 days) and 5 late (>60 days).

This study illustrated the efficacy of Ixa-Dara-Dex, with a high ORR (78%) and median PFS of 13.8 months. These results are favorable for this patient population compared with community-based data. However, toxicity and nonrelapse mortality resulting in discontinuation are still concerning.


  • Abstract and Poster EP929. EHA 2020. June 12, 2020. Efficacy and tolerability of induction treatment with ixazomib, daratumumab and low-dose dexamethasone in frail newly diagnosed multiple myeloma patients – results of the phase II HOVON 143 trial.

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