Appropriate selection of induction and consolidation chemotherapy regimens is essential to achieving the maximum response and improving outcomes for patients with multiple myeloma (MM) planning to undergo autologous stem cell transplantation (ASCT). Recent phase 2 trial results suggest that transplant-eligible MM patients may benefit from a new combination of agents for induction/consolidation therapy: carfilzomib, thalidomide, and dexamethasone (KTd).
“This is the first study to evaluate KTd in transplant-eligible patients with newly diagnosed MM and the first study in this setting to use a carfilzomib-based regimen as both an induction and consolidation treatment strategy,” the authors, led by Peter Sonneveld, MD, PhD, from the Erasmus University Medical Center in the Netherlands, wrote.
Dr. Sonneveld and colleagues examined the safety and efficacy of the KTd regimen in 91 previously untreated patients with MM. During KTd induction therapy, patients received four cycles of:
- carfilzomib 20/27 mg/m² (n=50), 20/36 mg/m² (n=20), 20/45 mg/m² (n=21), or 20/56 mg/m² (n=20) on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle
- thalidomide 200 mg on days 1-28
- dexamethasone 20 mg on days 1, 2, 8, 9, 15, and 16
During consolidation therapy, target doses were: carfilzomib 27 mg/m², 36 mg/m², 45 mg/m², or 56 mg/m² respectively, and thalidomide 50 mg.
The response after induction therapy was encouraging, the authors noted, with 90 percent of patients achieving at least a partial response (PR), 25 percent achieving a complete remission (CR), and 68 percent achieving at least a “very good partial response” (VGPR) – far exceeding the study’s primary endpoint of a ≥45 percent VGPR rate.
Furthermore, these responses were rapid and continued to increase with additional treatment, with 74 percent of patients achieving partial or greater response within the first induction cycle and 93 percent after two induction cycles.
After ASCT, consolidation treatment with KTd resulted in a substantial upgrade of response: 76 percent of patients achieved greater than VGPR, rising to 89 percent after four cycles of consolidation therapy. At 36 months, the progression-free survival rate was 72 percent (95% CI 60%–81%).
Overall, the KTd regimen was well tolerated: only five patients (5%) discontinued induction therapy because of excessive toxicity, and there were no toxicity-related treatment discontinuations during consolidation therapy. In general, for carfilzomib and thalidomide, more patients remained adherent to each of the study drugs – with no dose delays, reductions, or interruptions – during the consolidation period, compared to the induction period.
Focusing on neurotoxicity, polyneuropathy (PNP) was mostly grade 1/2, and the majority of cases were attributable to thalidomide; only 1 percent of patients experienced grade 3/4 PNP.
In this study, the maximum tolerated dose of carfilzomib in combination with thalidomide and dexamethasone was not reached. A fourth dosing cohort at carfilzomib 56 mg/m2 (n=20) is ongoing. The KTd regimen was “active, safe, and well tolerated” as induction/consolidation therapy in newly diagnosed MM patients planning to undergo ASCT, Dr. Sonneveld and investigators concluded.
Furthermore, KTd induction therapy did not adversely affect the feasibility of ASCT or hinder stem cell harvesting.
Currently, the most commonly used induction/consolidation therapy is a combination of bortezomib, thalidomide, and high-dose dexamethasone. However, the authors noted, given the increased risk of peripheral neuropathy and neurotoxicity profile of bortezomib with thalidomide, combination treatments based on alternative agents are a welcome addition to the frontline MM treatment armamentarium.
“The favorable peripheral neuropathy safety profile may allow for greater treatment adherence and more durable response,” the investigators wrote. “The data reported here support further clinical trials to validate the benefit of the KTd regimen for induction and consolidation therapy.”
- Sonneveld P, Asselbergs E, Zweegman S, et al. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2014 November 14. [Epub ahead of print]