Bortezomib Triplet Improves Outcomes in Newly Diagnosed Multiple Myeloma

Adding bortezomib to lenalidomide and dexamethasone improved progression-free and overall survival in patients with newly diagnosed multiple myeloma who were not planned for immediate stem-cell transplant, according to a new study.

“Combinations of lenalidomide or bortezomib with conventional anti–multiple myeloma drugs have produced higher overall response rates and excellent outcomes in both the relapsed and frontline setting,” wrote study authors led by Brian G. M. Durie, MD, of Cedars-Sinai Samuel Oschin Cancer Center in Los Angeles. They hypothesized that combining those two agents could provide better responses.

The new study was a phase III, randomized, open-label trial comparing bortezomib along with lenalidomide and dexamethasone to the latter two agents alone. Patients had previously untreated multiple myeloma, with ECOG performance status of 0–3. It included a total of 462 patients (of 525 randomized) across 139 institutions; the median follow-up period was 55 months. The results were published online ahead of print in Lancet Oncology.

The primary endpoint of improved progression-free survival was met. The median progression-free survival was 43 months with bortezomib, and 30 months without it, for a hazard ratio (HR) of 0.712 (96% CI, 0.560–0.906; P = .0018). Response duration was also improved with bortezomib, at a median of 52 months compared with 38 months with lenalidomide and dexamethasone alone.

The median overall survival was 75 months with bortezomib and 64 months with it, for an HR of 0.709 (95% CI, 0.524–0.959; P = .0125). When patients who left the study with intent for stem-cell harvest or transplant were excluded from the analysis, this result remained the same.

Grade 3 or worse neurological adverse events (AEs) were more frequent with bortezomib than without (33% vs 11%; P < .0001). The authors noted that if bortezomib were administered as it is today-subcutaneously-neuropathic side effects would likely be avoided. Other AEs were generally well balanced across the two groups.

“The median overall survival in our study of 75 months with [the combination] strongly supports the general notion that triplet therapy for induction adds value,” the authors wrote.

In an accompanying editorial, Heinz Ludwig, MD, and Michel Delforge, MD, PhD, of Wilhelminen Cancer Research Institute in Vienna and University Hospital Leuven in Belgium, respectively, wrote that the combination of bortezomib with lenalidomide and dexamethasone “can be established as an effective regimen for first-line treatment in transplant and non-transplant eligible patients.”

They noted, however, that this combination is currently being compared to another in an ongoing phase III trial. In that study, bortezomib’s place is taken by carfilzomib, a regimen that has resulted in high response rates and high rates of minimal residual disease negativity. These combinations in general, however, carry very high costs.

“Because multiple myeloma is not one uniform disease but molecularly a highly heterogeneous disease, new treatments will be developed that selectively target proteins or modify signaling pathways relevant for the pathogenesis in individual patients,” they wrote. “We have little doubt that this will have substantial effects on the outcome for future generations of myeloma patients.”