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Ixazomib, Daratumumab, and Low-Dose Dexamethasone Induction in Frail, Elderly Patients with NDMM

2020 Year in Review - Multiple Myeloma

Patients who were non–transplant eligible, newly diagnosed with multiple myeloma (NDMM) and frail have inferior overall survival (OS), primarily because of treatment discontinuation due to toxicity. Therefore, 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.

In this phase 2 study, the efficacy and tolerability of Ixa-Dara with low-dose dexamethasone (Dex) were evaluated in frail patients with NDMM.

Enrolled in this prospective, multicenter, phase 2 trial were 65 patients with NDMM who were frail according to the International Myeloma Working Group Frailty Index. 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 ≤2 years. 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.

Patients’ median age was 81 years (range, 70-92 years); 51% (33 patients) of patients were aged >80 years. Twenty percent (13 patients) were frail due to age only. Of those patients aged >80 years, 60% had additional frailty parameters, such as comorbidities and/or instrumental activities of daily living dependency. During induction therapy, ORR was 78%; 8% achieved stringent complete response, 28% achieved very good partial response, and 43% achieved partial response. After follow-up (median, 16.3; 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 patients (51%). Six of these discontinuations 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% due to PD. In 32 (50%) patients, toxicity grade 3 occurred; hematologic adverse events were limited, the most common of which was thrombocytopenia (grade 3, 19%; grade 4, 5%). The most common nonhematologic toxicity adverse events were 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 (25%) patients died; 6 due to PD (9%). In the remainder of 10 (16%) patients, nonrelapse mortality occurred: 5 early (≤60 days) and 5 late (>60 days).

The efficacy of Ixa-Dara-Dex was illustrated in this study; ORR rate (78%) was high, and median PFS rate was 13.8 months. These results are favorable for this patient population compared with those of community-based data. However, toxicity and nonrelapse mortality rates 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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