New 2L+ Combination Therapy Shows Efficacy in RRMM Post-PI/IMiD

Multiple myeloma remains an incurable haematological malignancy, with patients invariably experiencing relapse and requiring subsequent lines of therapy. For those who have received at least two prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), treatment options become increasingly constrained, often associated with diminishing efficacy and accumulating toxicities.¹ The need for effective, tolerable regimens in this heavily pre-treated population is substantial, as progression-free survival (PFS) and overall survival (OS) continue to decline with each subsequent relapse.²

The Trial

A recent phase 3, open-label, multicentre trial investigated the efficacy and safety of a novel 2L+ combination therapy in adults with relapsed/refractory multiple myeloma (RRMM) who had received at least two prior lines of therapy, including a PI and an IMiD.³ The study enrolled 350 patients across 45 sites globally. Patients were randomised 2:1 to receive either the investigational combination therapy (n=233) or a physician's choice control regimen (n=117), which included established therapies such as carfilzomib-dexamethasone or pomalidomide-dexamethasone. Key eligibility criteria included documented progression on or within 60 days of their last therapy, measurable disease, and an ECOG performance status of 0-2.³

The primary endpoint was progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints included overall response rate (ORR), duration of response (DoR), overall survival (OS), and safety. Patients in the investigational arm received the combination therapy until disease progression or unacceptable toxicity. Baseline characteristics were balanced between the two arms, with a median age of 67 years, and approximately 60% of patients having received three or more prior lines of therapy. High-risk cytogenetics were present in 25% of the study population.³

The trial demonstrated a statistically significant improvement in PFS for patients receiving the investigational combination therapy compared to the control arm. The median PFS was 11.5 months (95% CI, 9.8-13.2 months) in the investigational arm, versus 6.8 months (95% CI, 5.5-8.1 months) in the control arm (Hazard Ratio [HR] = 0.62; 95% CI, 0.49-0.78; p < 0.001).⁴ The overall response rate (ORR) was also higher in the investigational arm at 65% (95% CI, 59-71%) compared to 38% (95% CI, 29-47%) in the control arm (p < 0.001). The median duration of response (DoR) was 9.1 months in the investigational arm versus 4.5 months in the control arm.⁴

Regarding safety, the most common grade 3 or higher adverse events (AEs) in the investigational arm included neutropenia (28%), thrombocytopenia (19%), and fatigue (12%). These rates were generally manageable and consistent with the known safety profiles of agents used in multiple myeloma. Discontinuations due to AEs occurred in 15% of patients in the investigational arm and 10% in the control arm. No new or unexpected safety signals were identified.⁵

While the OS data are not yet mature, the observed PFS and ORR benefits are clinically meaningful for this patient population. The trial's open-label design is a limitation, though the use of an independent review committee for PFS assessment mitigates some potential bias. Future research will focus on longer-term OS data and identifying biomarkers that predict response to this combination therapy. Further studies are also warranted to evaluate this regimen in earlier lines of therapy or in specific high-risk subgroups.⁵