Efficacy and Safety of Third-Line or Later (3L+) Treatments, Including the CD38 Monoclonal Antibody Class, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): A Systematic Literature Review

Introduction: The treatment landscape for multiple myeloma is evolving rapidly. As such, there is a need to contextualize outcomes in light of prior therapies as well as disease and treatment characteristics. This makes comparisons across studies very challenging, especially in later lines of RRMM where the greatest heterogeneity is seen. We conducted a systematic literature review (SLR) to explore efficacy and safety outcomes across approved and investigational agents in 3L+ treatment of RRMM, including in patients who are refractory to anti-CD38 antibody therapy.

Methods: Searches were conducted on March 28, 2022, for publications (2008-2022) and unpublished/grey literature (2018-2020) reporting evidence from interventional studies in patients receiving RRMM treatment after ≥2 prior lines of therapy (LOTs). Studies were screened by 2 reviewers based on the PICOS framework. No geographical or language restrictions were applied. Results were synthesized descriptively.

Results: Overall, 147 unique studies met the eligibility criteria including 1 randomized controlled trial (RCT)/single-arm trial, 41 RCTs, 87 single-arm trials, 12 non-RCTs, and 6 pooled analyses. Median progression-free survival (PFS) and overall survival (OS) varied widely across studies. Of note however, the trial populations also differed substantially with regard to potential key modifiers of treatment outcomes. The shortest median PFS of 0.9 months (mo) over a median follow-up of 23 mo was seen in heavily pretreated patients, mostly refractory to lenalidomide (LEN). PFS was longest (up to 38.8 mo over a median follow-up of 44.3 mo) in patients who had had received as few as 2 prior LOTs and were not refractory to LEN. Median OS ranged from 6.4 mo (follow-up not reported), in patients who were exposed to at least 3 prior LOTs, to 54.3 months (over a median follow-up of 85 months) in patients who had received as few as 2 prior LOTs and were not LEN refractory. Similarly, overall response rates (ORRs) varied widely from 0% for patients who were LEN-refractory to 100% for those who were anti-CD38 refractory.

Of the 19 studies reporting data for anti-CD38 refractory patients, most enrolled <50 patients per trial and were Phase I or Phase I/II trials; only 2 were RCTs. Two trials had exclusively triple-class refractory populations (refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and an anti-CD38 monoclonal antibody); a further 10 trials included a subset of triple-class refractory patients (65-97% of total populations), and 5 studies enrolled broader populations but provided data for subgroups of triple-class refractory patients. Many of these studies provided safety or ORR data only, with only a few reporting median PFS and/or OS.

Overall rates of reported adverse events were high (94-100%) across trials providing such data. Anemia, thrombocytopenia, and neutropenia were the most frequently reported considering all 3L+ treatments.

Conclusions: This SLR identified a large body of data related to 3L+ treatments in RRMM. Considerable heterogeneity in previous treatment exposures and disease and patient characteristics were observed, along with substantial diversity in outcomes and endpoints reported. Careful consideration of these factors is relevant given how quickly the standard of care in early LOTs could change, which could impact treatment options for later LOTs. It is challenging to identify a standard of care for the 3L+ setting given the evidence observed, particularly due to heterogeneity in populations, subgroups, and outcomes. Treatment choice could therefore be dictated by multiple prognostic and patient characteristics. A network meta-analysis that considers these differences could facilitate robust quantitative comparative efficacy and safety evaluations for treatment options in RRMM.

Funding: GSK (study 214740)

Hanna:GSK: Current Employment, Current equity holder in publicly-traded company. Chorazy:GSK: Consultancy, Research Funding; Evidera: Current Employment. Iheanacho:GSK: Consultancy, Research Funding; Evidera: Current Employment. Gorsh:GSK: Current Employment, Current equity holder in publicly-traded company. Wang:GSK: Current Employment, Current equity holder in publicly-traded company. Paka:GSK: Current Employment, Current equity holder in publicly-traded company. Perera:GSK: Current Employment, Current equity holder in publicly-traded company.