In the phase II Hovon 143 trial reported in the Journal of Clinical Oncology, Stege et al found that a regimen of ixazomib, daratumumab, and low-dose dexamethasone (Ixa-Dara-dex) was associated with a high response rate in frail patients with newly diagnosed multiple myeloma, but also a high rate of early discontinuation of treatment and early mortality. Survival outcomes differed across subgroups of frail patients.

Study Details

In the trial, 65 eligible patients were enrolled between September 2017 and December 2018 from sites in the Netherlands and Belgium. Frailty was determined according to the International Myeloma Working Group frailty index. Patients received nine 28-day induction cycles consisting of ixazomib at 4 mg (days 1, 8, and 15), daratumumab at 16 mg/kg (days 1, 8, 15, and 22 for cycles 1–2, days 1 and 15 for cycles 3–6, day 1 for cycles 7–9), and dexamethasone (on the days of daratumumab administration; cycle 1–2 = 20 mg, subsequent cycles = 10 mg), followed by maintenance therapy, consisting of 8-week cycles with ixazomib (days 1, 8, 15, 29, 36, and 43) and daratumumab (day 1) until disease progression or for a maximum of 2 years. The primary endpoint was overall response rate (partial response or better) on induction therapy.

Frailty was based on:

• Age > 80 years alone in 13 patients (20%)
• The frailty parameters ADL (activities of daily living), iADL (instrumental activities of daily living), or Charlson Comorbidity Index but not on age (age ≤ 80 years) in 32 (49%) patients
• Age > 80 years with additional frailty parameters in 20 (31%).

Key Findings

The overall response rate during induction was 78% (95% confidence interval [CI] = 73%–82%), including 5 patients (8%) with (stringent) complete response, 18 (28%) with very good partial response, and 28 (43%) with partial response.

Induction therapy was prematurely discontinued in 51% of patients, including in 6% due to treatment noncompliance, in 9% due to toxicity, and in 9% due to death (8% within 2 months; 80% of these deaths due to toxicity).

After median follow-up of 22.9 months, median progression-free survival was 13.8 months; 12-month overall survival was 78% among all patients.

Median progression-free survival and 12-month overall survival were: 21.6 months and 92% in patients who were frail based on age > 80 years alone; 13.8 months and 78% in patients aged ≤ 80 years with frailty based on other parameters; and 10.1 months and 70% in patients with frailty based on age > 80 years and additional parameters.  

Global health status or quality of life (GHS/QoL) was evaluated with the EORTC Quality of Life Questionnaire C30 at baseline and after induction cycles 3 and 9 for patients still receiving study treatment. Baseline GHS/QoL score was 54.1, improving to 65.8 after three cycles and to 71.5 after nine cycles. Improvements after three and nine cycles were statistically significant (P < .001) and clinically meaningful.

The investigators concluded, “Ixa-Dara-dex led to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing progression-free survival and overall survival, 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.”

Claudia A.M. Stege, MD, of Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Janssen Pharmaceuticals and Takeda Pharmaceutical Company Limited. For full disclosures of the study authors, visit ascopubs.org.