A prospective clinical trial involving frail patients with multiple myeloma shows for the first time that treatment with a new drug combination with lower toxicity induced high response rates and improved quality of life. However, a quarter of patients enrolled in the study discontinued therapy due to low-grade toxicity and incompliance. These findings support a novel frailty subclassification for more precise treatment guidance of patients with multiple myeloma.

Multiple myeloma is a disease usually affecting older patients who are often frail, according to the International Myeloma Frailty Index. The outcome of frail patients is poor mainly because many discontinue treatment due to toxicity. To address this issue, a national team led by Sonja Zweegman, Professor of Hematology, investigated a novel treatment regimen with an expected low-toxicity profile in a prospective phase II clinical trial.

Sixty-five frail patients with newly diagnosed multiple myeloma were treated with ixazomib-daratumumab-low dose dexamethasone. The overall response rate on induction treatment was high; 78%. The median progression free survival (PFS) was 13.8 months and 12-month overall survival 78%. Quality of life improved during the treatment, being clinically meaningful already after three induction cycles. However, 6% of patients discontinued therapy because of noncompliance, 9% because of toxicity, and 9% died (8% within 2 months, of which 80% because of toxicity), highlighting the need to identify which patients may respond negatively to treatment.

In order to define those patients, a new novel frailty subclassification was developed to distinguish between patients who are frail due to age alone, or frail due to additional frailty parameters. This was justified by the results that the median PFS and 12-month OS of 21.6 months and 92% in patients who were frail based on age alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients (≤80 or >80 years of age, respectively) who were frail based on additional frailty parameters.

This trial (1) provides a platform for the future design of trials for frail patients for more precise treatment guidance by proposing a frailty subclassification, and (2) indicates that frail patients have different side-effect profiles and might need a lower starting dose, only allowing dose increments in the absence of side effects.

Read the full article in the Journal of Clinical Oncology