Real-World Outcomes of Triple-Class Refractory, Penta-Exposed RRMM

Outcomes for patients with multiple myeloma (MM) that is triple-class refractory (TCR), meaning refractory to immunomodulators, proteasome inhibitors, and CD38 monoclonal antibodies, are particularly poor. Overall survival (OS) is measured in months.

Selinexor is a selective inhibitor of nuclear export compound targeting exportin 1 (XPO1), which is overexpressed in MM cells and essential for MM cell survival. In the STORM study, selinexor combined with low-dose dexamethasone (Sd) demonstrated promising efficacy in TCR, penta-exposed (PE) MM. Penta-exposed means that patients have received lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab.

The lack of efficacy outcome benchmarks in patients with TCR-PE MM is a concern. The retrospective MAMMOTH study, published in 2019 by Ghandi and colleagues in Leukemia, reports outcomes of patients with relapsed or refractory MM after becoming refractory to daratumumab, including a subset of patients who were TCR.

In this research initiative, a cohort of patients in the MAMMOTH data set who were comparable to patients in STORM were analyzed. The goal was to report “real-world” outcomes of TCR-PE patients who have received subsequent therapy. A total of 64 patients in STORM who received Sd after becoming TCR-PE were included, along with 128 patients in MAMMOTH who had TCR-PE MM and received subsequent therapy but who were not exposed to Sd.

Overall response rate (ORR) was evaluated using International Myeloma Working Group criteria. OS was assessed by Kaplan-Meier. In both cohorts, OS was assessed from the initiation of next line of therapy after TCR-PE criteria were met. A direct comparison between the 2 cohorts, including a multivariate model with adjustment for possible imbalances between cohorts, was presented. 

The 2 patient cohorts were similar in terms of age, number of prior lines of therapy (median, 6) and presence of high-risk cytogenetic abnormalities (50% in STORM and 54% in MAMMOTH). STORM patients had a longer time between MM diagnosis and post–TCR-PE therapy (6.4 years vs 5 years in MAMMOTH) and were more likely to be refractory to carfilzomib (97% vs 82% in MAMMOTH).

Patients in STORM who received Sd after reaching TCR-PE had an ORR of 33% and a median OS of 10.4 months. In contrast, patients in the MAMMOTH cohort received either monotherapy (5%) or a combination of 2 or more anti-MM agents (95%). They obtained an ORR of 25% with a median OS of 6.9 months. 

Despite inherent limitations in comparison of trial-eligible and real-world patients with TCR-PE MM, this matched cohort analysis suggests improved survival outcomes with Sd compared with other standard treatment options. However, the prognosis for patients with TCR-PE MM remains poor; there is a continued need for additional therapeutic advancements.  

Abstract FP-106: Cornell R, Parameswaran H, Tang S, et al. Real World vs. Clinical Trial Outcomes of Triple Class Refractory Penta-Exposed Multiple Myeloma (MM)

Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275.