Carfilzomib-Based Quadruplet Regimen Beats Triplet Approach in Newly Diagnosed Myeloma

Induction with the quadruplet regimen of carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone (KCRD) led to deeper responses and longer progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM), compared with a response-adapted triplet regimen of cyclophosphamide, lenalidomide or thalidomide, and dexamethasone (CTD/CRD). Improvements in response were seen both before and after autologous hematopoietic cell transplantation (AHCT), the researchers noted. These findings were reported at the 17th International Myeloma Workshop.

“Our findings in a large number of genetically characterized patients confirm and extend previous findings that suggested a benefit of exposure to proteasome inhibitor and immunomodulatory drug combinations for high-risk subgroups of patients,” presenter Charlotte Pawlyn, PhD, of the Institute of Cancer Research in London, told ASH Clinical News. “Carfilzomib, a new type of irreversible proteasome inhibitor, has fewer side effects than the first-generation inhibitors, which has improved the capacity to combine multiple agents to generate well-tolerated combinations that can be given safely and, as a result, outcomes have significantly improved without increasing toxicity for patients.”

The phase III Myeloma XI trial randomized 1,056 patients with newly diagnosed, transplant-eligible MM to receive 28-day cycles of either KCRD or CTD/CRD prior to AHCT.

The quadruplet KCRD therapy consisted of the following:

  • intravenous carfilzomib 36 mg/m2 on days 1-2, 8-9, and 15-16
  • twice-daily cyclophosphamide 500 mg on days 1-8
  • twice-daily lenalidomide 25 mg on days 1-21
  • twice-daily dexamethasone 40 mg on days 1-4, 8-9, and 15-16

Patients with a suboptimal response to CTD/CRD underwent response-adapted intensification to either a bortezomib-containing triplet (CVD) or no CVD.

Per study protocol, at three months following AHCT, a maintenance randomization was performed to compare lenalidomide with observation.

Treatment with the quadruplet regimen was associated with a significantly longer PFS than triplet therapy (hazard ratio = 0.63; 95% CI 0.51-0.76; p<0.001). At three years, the PFS rate was 64.5% in the KCRD group, compared with 50.3% in the CTD/CRD group (p<0.0001). The researchers added that KCRD also was associated with deeper response rates both before and after AHCT (p<0.0001), although these data were not provided.

The response and survival benefits with KCRD were seen across risk groups, the investigators added, including among patients with high-risk molecular risk disease, defined as the presence of t(4;14), t(14;16), t(14;20), del17p, or gain1q.

Patients appeared to tolerate all treatment regimens, Dr. Pawlyn noted, with no additional toxicity observed in the quadruplet regimen.

According to the authors, a greater pro-portion of patients randomized to KCRD induction proceeded to AHCT, compared with patients who received response-adapted induction. Also, in an analysis restricted to those who had completed AHCT, KCRD induction was still associated with longer PFS.

Limitations of the study include the short follow-up duration, as well as the inclusion of only patients with newly diagnosed MM.

“While not directly compared in this study, these responses are similar to recently studied combinations of anti-CD38 antibodies with the first-generation proteasome inhibitor bortezomib and immunomodulatory drugs seen in the CASSIOPEIA and GRIFFIN trials,” Dr. Pawlyn added. “Longer follow-up of all these studies will give us more information regarding comparative outcomes once median PFS and overall survival endpoints have been reached.”

Study authors report relationships with Celgene, Merck, and Amgen, which sponsored this trial.

Reference

Pawlyn C, Davies F, Cairns D, et al. Quadruplet KCRD (carfilzomib, cyclophosphamide, lenalidomide and dexamethasone) induction for newly diagnosed myeloma patients. Abstract OAB-002. Presented at the 17th International Myeloma Workshop, September 12, 2019; Boston, Massachusetts.

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