Carfilzomib in Combination with Bendamustine and Dexamethasone (CBd) in Relapsed and/or Refractory Patients with Multiple Myeloma: The Phase I/II EMN09 Study

Introduction: Proteasome inhibitors (PI) lead to the accumulation of defective ribosomale products (DRiPs) and apoptosis of malignant plasma cells. Bendamustine (Benda) is a bifunctional molecule possessing alkylating and purine analoga activity and may increase the level of DRiPs. This provides the rationale for the CBd protocol combining Benda, an agent with a favorable profile of side effects, with carfilzomib (Carf), a PI with limited neurotoxicity and low dose dexamethasone (dex).

Methods: The study included relapsed and/or refractory multiple myeloma (MM) patients with at least two lines of prior therapy. A 4 week cycle consists of Benda 70 mg/ m² fixed dose at day 1 and 8 and Carf/dex on day 1,2,8,9,15,16 with additional 20 mg/ m²dex on day 22 and 23. After receiving 8 cycles, responding patients continued with maintenance therapy scheduled with Carf/dex only on two consecutive days every 14 days until progression.

Results: Conducted as EMN09 study of the European Myeloma Network, in the phase I part of this Italian-Dutch-German trial the first six patient were entered at the starting level of Carf 27 mg/m² (within the first cycle Carf on day 1 and 2 was reduced to 20 mg/m²). Initially, pronounced lymphopenia of grade 4 in 3 of 6 patients was seen but without clinical equivalent. Therefore, Carf doses in the CBd combination were escalated to 36 mg/m² for the next 7 patients. Dose limiting toxicity with 2 cases of pneumonia was observed at that dose level. Encouraging results with 9 of 12 evaluable patients responding at least with a PR, including 4VGPR and 1 CR, were obtained. Since responses at the Carf 36 mg/m² level occurred in a similar frequency as with the non-escalated Carf dose, for this older pretreated patient population it was decided to stay for the phase II part with the initial Carf 27 mg/m². Currently, 38 patients are evaluable in phase I and II. The patient population with an age up to 77 years (median 67 years) and 5.5 years from initial diagnosis to study entry had received up to 9 lines of prior therapy. Already 55% of patients achieved PR or better including 32% with ≥VGPR. One patient is in ongoing CR for more than 2 years. Peripheral polyneuropathy was absent. No safety signal occurred for renal function. Cardiac toxicity including a case of fatal myocarditis and cardiac infarction was around 10% and 8% of the patients developed venous thromboembolism. The infection rate (21% of grade ≥3) appeared not unusual in such a heavily pretreated population. However, anti-infective prophylaxis and immunoglobulin support may be necessary.

Conclusions: The ongoing EMN09 phase I/II trial suggests that CBd provides an effective well tolerated therapy even for older patients with relapsed MM, many of whom may have from prior therapies persisting side effects like polyneuropathy. Despite intense pretreatment, today frequently patients will have received little previous chemotherapy. Thus, the CBd combination may be a valuable treatment option for those relapsing patients not candidates for aggressive approaches.