In a phase I/II trial of patients with newly diagnosed multiple myeloma (MM), 55 percent of patients treated with the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) achieved stringent complete response (sCR) and 79 percent achieved three-year progression-free survival (PFS), but a proportion of patients had no response or experienced disease progression.1 These patients could benefit from the addition of autologous hematopoietic cell transplantation (AHCT), according to results of a trial reported at the 15th International Myeloma Workshop.2
The phase II trial, conducted by Andrzej Jakubowiak, MD, PhD, director of the myeloma program at The University of Chicago in Chicago, Illinois, and colleagues, tested the hypothesis that combining KRd with AHCT would further improve response and outcomes.
Seventy transplant-eligible patients with newly diagnosed MM requiring treatment were enrolled. Patients received four 28-day cycles of KRd induction (historical KRd) followed by high-dose melphalan AHCT. At 70 to 90 days post-AHCT, patients received another four cycles of KRd consolidation:
- Carfilzomib – 36 mg/m2 or last tolerated dose (LTD) on days 1, 2, 8, 9, 15, 16
- Lenalidomide – 15 mg on days 1 to 21, with the option to escalate to 25 mg after one cycle
- Dexamethasone – 20 mg or LTD weekly
After consolidation therapy, patients then received maintenance therapy with KRd for 10 cycles (cycles 8-18); the carfilzomib dose schedule was modified to days 1, 2, 15, and 16. Study protocol recommended single-agent lenalidomide after KRd maintenance.
Among the 62 patients evaluable for the current analysis, baseline median age was 61 years (range = 40-79 years) and 38 percent had high-risk cytogenetics. Forty-eight of these patients proceeded to AHCT after four cycles, 37 completed KRd consolidation, and eight had completed KRd maintenance.
Outcomes were compared between patients who underwent AHCT and the historical KRd group who did not undergo transplant. “Added benefit” with AHCT was defined as at least a 30-percent improvement in sCR over the eight cycles of the historical KRd group; a greater than 50-percent improvement in sCR would “support further evaluation,” Dr. Jakubowiak and colleagues added.
sCR rates in the current study were similar to those in the earlier phase I/II study through four cycles of induction, but KRd plus AHCT demonstrated a greater rate of sCR than KRd alone. At each stage of treatment (induction, consolidation, and maintenance), KRd plus AHCT demonstrated an added benefit (TABLE).
After a median follow-up of 13 months, PFS at 24 months was 98 percent. Notably, PFS exceeded 90 percent in both studies (TABLE).
“Treatment has been well tolerated,” the authors reported, with adverse events in the phase II trial consistent with those reported in the earlier phase I/II trial. “The addition of AHCT does not appear to add significant toxicity post-transplant.”
“Recognizing limitations of cross-study comparisons, the sCR rate was markedly higher with KRd plus AHCT versus historical KRd without ASCT and met the pre-specified target of promising results that support further studies,” Dr. Jakubowiak and colleagues concluded, adding that these findings will need confirmation in a larger, randomized trial.
- Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-9.
- Jakubowiak AJ, Griffith K, Jasielec JK, et al. Carfilzomib (CFZ, Kyprolis®), lenalidomide (LEN, Revlimid®), and dexamethasone (DEX) (KRd) combined with autologous stem cell transplant (ASCT) shows improved efficacy compared with KRd without ASCT in newly diagnosed multiple myeloma (NDMM). Abstract OP-003. Presented at the 15th International Myeloma Workshop, September 23, 2015; Rome, Italy.
|TABLE. Responses in Patients Receiving KRd With and Without AHCT|
|Phase I/II Study of KRd without AHCT (N=53)||Phase II Study of KRd with AHCT (N=62)*|
|Median follow-up||13 months||11 months|
|*Rates for 48 patients at 4 cycles; 37 at 8 cycles; and 8 at 18 cycles|