New Analysis Aims to Characterize Patients With Best Carfilzomib Responses

A new analysis of 2 trials of carfilzomib (Kyprolis) in patients with multiple myeloma (MM) shows apparent little correlation between baseline patient characteristics and depth of responses to therapy.

Carfilzomib is a proteasome inhibitor approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) in combination with lenalidomide (Revlimid) and dexamethasone or dexamethasone alone. Two trials, ASPIRE and ENDEAVOR, led to the approval of the therapy.

In the ASPIRE trial, a regimen of carfilzomib, lenalidomide, and dexamethasone (KRd) was compared with lenalidomide plus dexamethasone. In the ENDEAVOR trial, combination carfilzomib and dexamethasone therapy (Kd) was compared with bortezomib (Velcade) and dexamethasone (Vd).

An international team of investigators, including Katja Weisel, MD, of the University Medical Center of Hamburg-Eppendorf, in Germany, wanted to find out whether the data from those trials would yield insights into which patients are most likely to respond best to carfilzomib-based therapies. They defined best responders as those with a complete response (CR) or greater. Their findings were published in Leukemia.

The team pulled patient characteristics and cross-referenced those data with progression-free survival (PFS), overall survival (OS), and safety data for the two trials. In a post-hoc analysis of both trials, CR or better correlated with longer PFS and OS compared with patients who achieved a very good partial response (VGPR) or a partial response (PR).

In ASPIRE, patients in the KRd arm with a CR or better had a median PFS of 50.4 months and a median OS of 67.0 months. Those who achieved VGPR or PR, meanwhile, had a median PFS and OS of 22.1 and 44.2 months, respectively.

Similarly, patients in the carfilzomib arm of the ENDEAVOR trial had a median PFS of 34.0 months versus 20.4 months if they achieved CR or better instead of VGPR/PR; the authors said median OS was not estimable in that study.

Notably, athough patients with CR or better had longer courses of treatment, that did not translate into a higher number of patients needing to discontinue carfilzomib-based treatment because of treatment-emergent adverse events.

Weisel and colleagues noted that a number of factors, including cytogenetics, serum albumin, serum lactate dehydrogenase (LDH), and β2-microglobulin have been identified as having prognostic value in patients with MM, although they said their prognostic role is less well-defined in RRMM. However, the only factor that appeared to correlate with CR in patients treated with carfilzomib was low LDH. That finding was based on data from the ASPIRE trial, since a similar analysis was not possible for the ENDEAVOR trial.

“Interestingly, no association was found between cytogenic risk status and >CR,” Weisel and colleagues wrote. “Similarly, in a preplanned subgroup analysis of ENDEAVOR evaluating Kd vs Vd by cytogenic risk, no association was observed between cytogenetic risk status and >CR.”

However, the authors said more study with more sensitive techniques, such as minimal residual disease, would be worthwhile.

While the study did not find multiple patient characteristics that appeared to be tied to achieving CR, the authors noted that patients in ENDEAVOR who achieved CRs or better tended to be younger and more likely to have undergone hematopoietic stem cell transplantation. The data also hint that patient frailty might be a factor.

“These patient characteristics also corroborate prior observations that best responders to carfilzomib-based treatment in ASPIRE and ENDEAVOR were somewhat fitter at baseline than those who achieved VGPR/PR,” they wrote.

Reference

Weisel K, Mateos MV, Gay F, et al. Efficacy and safety profile of deep responders to carfilzomib-based therapy: a subgroup analysis from ASPIRE and ENDEAVOR. Leukemia. Published online October 16, 2020. doi:10.1038/s41375-020-01049-5