A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma

Abstract

This phase 1/2 study in patients with newly diagnosed multiple myeloma (N = 53) assessed CRd--carfilzomib (20, 27, or 36 mg/m2, days 1, 2, 8, 9, 15, 16 and 1, 2, 15, 16 after cycle 8), lenalidomide (25 mg/d, days 1-21), and weekly dexamethasone (40/20 mg cycles 1-4/5+)--in 28-day cycles. After cycle 4, transplantation-eligible candidates underwent stem cell collection (SCC) then continued CRd with the option of transplantation. The maximum planned dose level (carfilzomib 36 mg/m2) was expanded in phase 2 (n = 36). Thirty-five patients underwent SCC, 7 proceeded to transplantation, and the remainder resumed CRd. Grade 3/4 toxicities included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); peripheral neuropathy was limited to grade 1/2 (23%). Most patients did not require dose modifications. After a median of 12 cycles (range, 1-25), 62% (N = 53) achieved at least near-complete response (CR) and 42% stringent CR. Responses were rapid and improved during treatment. In 36 patients completing 8 or more cycles, 78% reached at least near CR and 61% stringent CR. With median follow-up of 13 months (range, 4-25 months), 24-month progression-free survival estimate was 92%. CRd was well tolerated with exceptional response rates. This study is registered at http://www.clinicaltrials.gov as NCT01029054.

Figures

Figure 1

Study design and treatment schema. *Assessment on days 1 and 15 of cycle 1 and day 1 of each subsequent cycle using modified IMWG Uniform Criteria with the addition of nCR. †Patients achieving a PR after cycle 4 underwent SCC and then continued CRd with the option to proceed to ASCT. ‡Initial dose of 20 mg/m2 during cycle 1 days 1-2 for all patients regardless of dose cohort. §At the discretion of the investigator, patients could receive 4 mg of dexamethasone orally or intravenously on days 2, 9, and 16 (cycles 1 and 2) before the infusion of carfilzomib if signs of tumor flare-up were present. ¶Or the last tolerated dose. ASCT indicates autologous stem cell transplantation; CRd, carfilzomib, lenalidomide, dexamethasone; LEN, lenalidomide monotherapy; and PR, partial response.

Figure 2

Patient flow. Median duration of treatment (N = 53); 12 cycles (range, 1-25). One cycle = 28 days. ASCT indicates autologous stem cell transplantation; CRd, carfilzomib, lenalidomide, dexamethasone; LEN, lenalidomide monotherapy; and SCC, stem cell collection.

Figure 3

Change in M-protein levels compared with baseline. Error bars indicate SD.

Figure 4

PFS (N = 53).