Data being presented at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition show that triplet therapy is superior to doublet therapy for the treatment of patients with lenalidomide-refractory multiple myeloma (MM).

The evolving treatment landscape for MM, which has grown to include proteasome inhibitors (bortezomib, carfilzomib), monoclonal antibodies (daratumumab, isatuximab and elotozumab), and immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) has improved outcomes for this patient population.

“However, using lenalidomide as frontline treatment and maintenance therapy exposes greater numbers of patients to lenalidomide prior to relapse. Consequently, the treatment of lenalidomide-refractory disease is an increasing area of concern,” wrote Ghulam Rehman Mohyuddin, MD, Kansas University Medical Center, Kansas City, and colleagues.

Citing a lack of direct comparisons evaluating varying treatment regimens for lenalidomide-refractory MM, Dr Mohyuddin et al conducted a systematic review with the goal of identifying randomized controlled trials (RCTs) that included subgroup analysis of lenalidomide-refractory patients.

“The objective of our study was to compare the efficacy of novel treatment regimens in randomized trials for patients with lenalidomide-refractory MM using a network meta-analysis,” they wrote.

Using the keywords “multiple myeloma” and “RCT,” the investigators searched the MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials databases for studies published between January 2005, and December 2019. Only RCTs that had a primary outcome of progression free survival (PFS) were considered, and 2 independent investigators reviewed the studies and resolved any conflicts through mutual discussion.

“Network meta-analysis using random-effects model was performed to generate direct and indirect comparisons between various treatment groups. Frequentist method was used to rank the interventions and P-score was generated,” Dr Mohyuddin and colleagues explained.

“A higher P score (close to 1.00) corresponded to superior progression free survival. A P <.05 was considered statistically significant. Hazard ratios (HR) with 95% confidence interval (CI) were calculated,” they added.

Although the initial search yielded 1171 results, 123 RCTs were identified after duplicates, trials in progress, subset analysis, and non-randomized studies were excluded.

Ultimately, however, only 8 studies clearly reported outcomes of patients with lenalidomide-refractory disease, and 7 (n = 1698) were included in the final analysis of 2 discrete networks.

According to the findings, the combination regimens of pomalidomide plus bortezomib and dexamethasone (HR, 0.65; 95% CI, 0.50-0.84), daratumumab plus bortezomib and dexamethasone (HR, 0.36; 95% CI, 0.21-0.63), and daratumumab plus carfilzomib and dexamethasone (HR, 0.38; 95% CI, 0.21-0.69) all improved PFS compared with bortezomib plus dexamethasone.

These interventions were ranked from most efficacious as follows, with daratumumab plus bortezomib and dexamethasone (P of .8758) in first; daratumumab plus carfilzomib and dexamethasone (P of 0.8514) in second; pomalidomide plus bortezomib and dexamethasone (P of 0.4791) in third, carfilzomib plus dexamethasone (P of 0.2707) in fourth, and bortezomib plus dexamethasone (P of 0.0231) in fifth.

Furthermore, pomalidomide plus dexamethasone (HR, 0.50; 95% CI, 0.40-0.62), isatuximab plus pomalidomide and dexamethasone (HR, 0.30; 95% CI, 0.20-0.44) and elotozumab plus pomalidomide and dexamethasone (HR, 0.27; 95% CI, 0.16-0.45) were all shown to improve PFS compared with dexamethasone.

Of note, the ranking of these interventions from most efficacious was elotozumab plus pomalidomide and dexamethasone (P of .8716); then isatuximab plus pomalidomide and dexamethasone (P of .7932); and then pomalidomide plus dexamethasone (P of .3352).

“The results of our network meta-analysis of 1698 patients with lenalidomide refractory myeloma enrolled in seven randomized myeloma trials demonstrate that for lenalidomide refractory myeloma, triplet therapy is superior to doublet therapy,” Dr Mohyuddin and colleagues wrote.

“Regimens with the highest efficacy in this subset of patients were triplets containing monoclonal antibodies (such as daratumumab/elotozumab/isatuximab). There is a need for further randomized data to better ascertain the best standard of care for these patients,” they concluded.—Hina Porcelli

Mohyuddin GR, Hampton J, Aziz M, et al. A Systematic Review and Network Meta-Analysis of Randomized Data on Efficacy of Novel Therapy Combinations in Patients with Lenalidomide Refractory Multiple Myeloma. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 2557.