Ixazomib, Daratumumab, and Low-Dose Dexamethasone in Frail Patients With Newly Diagnosed Multiple Myeloma: The Hovon 143 Study

Abstract

PURPOSE Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex). METHODS Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years. RESULTS The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age > 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or > 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles. CONCLUSION Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance.

Current approaches to management of newly diagnosed multiple myeloma

“…The Phase II HOVON 143 study enrolled 65 frail patients to receive 9 cycles of Dara‐Id induction followed by Dara‐I maintenance and found an ORR of 78% (95% CI: 73%–82%). At a median follow‐up of 22.9 months, the median PFS was 13.8 months and 1‐year OS was 78% (95% CI: 66%–87%, median OS not reached) 113 . There was also improvement in the quality‐of‐life measures during induction therapy, although treatment discontinuation because of toxicity did remain a concern.…”

“…At a median follow-up of 22.9 months, the median PFS was 13.8 months and 1-year OS was 78% (95% CI: 66%-87%, median OS not reached). 113 There was also improvement in the quality-of-life measures during induction therapy, although treatment discontinuation because of toxicity did remain a concern.…”

The EHA Research Roadmap: Malignant Lymphoid Diseases

“… 175 Thereafter, the first clinical trials were designed for intermediate and frail patients. 177 , 178 …”

Recent advances in the management of older adults with newly diagnosed multiple myeloma in Japan

“…Several clinical trials to develop optimal treatment regimens for frail patients have been conducted. For example, HOVON 143 was a phase II trial that evaluated the efficacy and safety of ixazomib, daratumumab and dexamethasone, targeting frail patients according to the IMWG frailty score ( 36 ). The primary endpoint was the ORR.…”

“…However, in 51% of the patients, induction therapy had to be discontinued prematurely because of toxicity or early death as the major reasons. An additional 12 patients discontinued ixazomib because of PN in 10 out of 12 patients even with low-grade severity (grade 1 or 2 in seven patients) ( 36 ). Therefore, it is important to consider that even low-grade AEs can affect treatment adherence in frail patients.…”