Results of the Phase 2 HOVON 143 Study of Induction Ixazomib, Daratumumab, and Low-Dose Dexamethasone in Intermediate-Fit Patients with NDMM

2021 Year in Review - Multiple Myeloma

Results of the phase 2 HOVON 143 study indicate that ixazomib, daratumumab, and dexamethasone is an effective and feasible regimen in intermediate-fit patients with non–transplant-eligible NDMM.

The prospective phase 2 HOVON 143 study investigated the efficacy and tolerability of the combination regimen of the proteasome inhibitor ixazomib plus the anti-CD38 monoclonal antibody daratumumab and low-dose dexamethasone in intermediate-fit patients with non–transplant-eligible newly diagnosed multiple myeloma (NDMM). Results of this study were reported at the 2021 ASH Annual Meeting and summarized here.

The study enrolled patients with non–transplant-eligible NDMM who were intermediate-fit according to the International Myeloma Working Group frailty index, with no severe cardiac dysfunction, chronic obstructive pulmonary disease (with a forced expiratory volume <50% of expected), or a creatinine clearance of <20 mL/min. Eligible patients were receiving nine 28-day induction cycles, consisting of ixazomib (4 mg on days 1, 8, and 15), daratumumab (16 mg/kg, cycles 1-2 on days 1, 8, 15, and 22; cycles 3-6 on days 1 and 15; and cycles 7-9 on day 1), and dexamethasone (on days of daratumumab 20 mg, cycles 1-2; 10 mg on subsequent cycles), followed by maintenance therapy of ixazomib (days 1, 8, 15, 29, 36, and 43) and daratumumab (day 1) for 8-week cycles until 2 years or earlier progression. The primary end point was overall response rate after 9 induction cycles; secondary end points were progression-free survival, overall survival (OS), event-free survival, and health-related quality of life (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and Quality of Life Questionnaire-Multiple Myeloma Module instruments).

A total of 65 eligible patients were enrolled in the study. The median age was 76 years (range, 65-80 years); 54% were male, 29% had a Charlson Comorbidity Index ≥2, 14% had a World Health Organization performance ≥2, 18% had International Staging System stage III, and 14% had high-risk cytogenetic abnormalities. A total of 30 (46%) patients did not proceed to maintenance therapy, mainly as a result of progressive disease (29%), toxicity (6%), noncompliance (5%), sudden death (2%), or other reasons (5%).

In the total population (N = 64), the overall response rate was 71%, including 23 very good partial responses and 1 complete response. After a median follow-up of 18.1 months, the median progression-free survival was 17.4 months; median OS was not reached, and 12-month OS rate was 92%. The median event-free survival was 5.3 months.

Of the 65 patients who received study treatment, 12% had grade ≥3 hematologic adverse events (AEs) and 51% had nonhematologic AEs. The most common nonhematologic grade ≥3 AEs were gastrointestinal (14%), central nervous system (11%), or infections (9%). Polyneuropathy was reported in 27 (42%) patients, of which 4 (8%) were of grade 3 severity. Treatment discontinuation caused by AEs were reported in 6% of patients that was attributed to the whole regimen, while 11% of patients discontinued ixazomib as a result of polyneuropathy.

During induction therapy, a statistically and clinically significant improvement in global health score/quality of life, role functioning, and future perspective were observed over time. In contrast, there was worsening of polyneuropathy over time.

Results of the phase 2 HOVON 143 study indicate that ixazomib, daratumumab, and dexamethasone is an effective and feasible regimen in intermediate-fit patients with non–transplant-eligible NDMM that was associated with an improvement in health-related quality of life. However, treatment discontinuation as a result of polyneuropathy attributable to ixazomib was cited as a concern.

Source: Groen K, Stege CAM, Nasserinejad K, et al. Ixazomib, daratumumab and low dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma (NDMM); results of induction treatment of the phase II HOVON 143 study. Blood. 2021;138(suppl 1):80.

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