Combination Ibrutinib, Carfilzomib, and Dexamethasone Is Promising for Relapsed/Refractory MM

In a phase I dose-finding study, two-thirds of patients with relapsed/refractory multiple myeloma (MM) responded to the triplet combination of ibrutinib plus carfilzomib and dexamethasone, according to results published in Leukemia & Lymphoma. Ajai Chari, MD, of the Tisch Cancer Institute at Mount Sinai in New York, and co-authors also reported that the combination had a “manageable safety profile.”

The multicenter, open-label, phase I/IIb PCYC-1119 study enrolled 43 patients with MM (median age = 63 years; range = 44-83 years) who had received two or more prior lines of therapy, including bortezomib and an immunomodulatory drug (IMiD). Patients were excluded from the trial if they were refractory or non-responsive to prior carfilzomib.

The median time from MM diagnosis to trial enrollment was 4.2 years (range = 0.5-25.3 years), and patients had received a median of three prior lines of therapy (range = 2-9 therapies). Most (70%) had received a prior autologous hematopoietic cell transplantation. Participants were refractory to bortezomib (74%), lenalidomide (72%), and pomalidomide (28%), and 60 percent were refractory to both a proteasome inhibitor and IMiD. Twenty-three percent of patients had high-risk cytogenetics, including 19 percent with t(4;14), 9 percent with t(11;14), and 7 percent with del17p mutation.

In a 3+3 dose-escalation design, participants were assigned to the following cohorts and treated with 28-day cycles of:

  • ibrutinib 560 mg; carfilzomib 27 mg/m2; no dexamethasone (cohort 1, n=3)
  • ibrutinib 560 mg; carfilzomib 36 mg/m2; no dexamethasone (cohort 2a, n=5)
  • ibrutinib 560 mg; carfilzomib 36 mg/m2; dexamethasone 20 mg (cohort 2b, n=17)
  • ibrutinib 840 mg; carfilzomib 36 mg/m2; dexamethasone 20 mg (cohort 3b, n=18)

The first 13 patients completed the doselimiting toxicity (DLT) observation period, and an additional 30 patients were enrolled during the dose-expansion phase to cohorts 2b and 3b.

All trial participants experienced at least one any-grade, treatment-related adverse event (AE), and 37 patients (86%) experienced a grade ≥3 AE. The researchers observed no DLTs during the dose-escalation phase, so the recommended phase II dose (primary endpoint) was ibrutinib 840 mg with carfilzomib 36 mg/m2 and dexamethasone adjusted for age.

The most common hematologic AEs were anemia (35%), thrombocytopenia (28%), and neutropenia (9%); the most common non-hematologic grade ≥3 AEs were hypertension (23%), pneumonia (19%), fatigue (16%), and diarrhea (14%). “The low incidence of grade 3 neutropenia [(n=9 any-grade; n=7 grade ≥3)] and thrombocytopenia [n=28 any-grade; n=12 grade ≥3)] is encouraging, as myelosuppression is common with other agents used in this population,” the authors reported.

Thirteen patients (30%) discontinued treatment because of AEs, and this was consistent across all cohorts, the researchers reported. Four participants discontinued treatment because of grade ≥3 pneumonia, which the authors said was possibly related to both ibrutinib and carfilzomib.

“Despite known cardiac toxicities associated with carfilzomib and ibrutinib as individual agents, the cardiac AEs with the combination did not meet DLT criteria and were manageable with re-challenge or dose reduction,” the researchers observed. Five patients (12%) required an ibrutinib dose reduction, and eight (19%) required a carfilzomib dose reduction.

The median time on study was 20.5 months for all patients (range not reported), and at the time of analysis, one patient remained on study. Other than AEs, reasons for treatment discontinuation included progressive disease (n=18; 42%), patient withdrawal (n=6; 14%), and investigator decision (n=5; 12%).

Thirteen deaths occurred from progressive disease (n=8), infections (n=4), and metastatic non small–cell lung cancer (n=1). Two deaths related to infection occurred after subsequent anti-cancer therapy.

Of the 42 patients who were evaluable for response (secondary endpoint), the clinical benefit rate (defined as at least a minimal response) was 76 percent and the overall response rate (defined as at least a partial response) was 67 percent (see TABLE). At the time of analysis, 29 percent of patients with a partial response or better (n=8/28) were alive and their disease had not progressed.

The overall progression-free survival (PFS) was 7.2 months (range = 0.2-20.3 months). In the expansion cohorts 2b and 3b, median PFS was 8.1 months (range = 1.4-16.3 months) and 6.4 months (range = 0.2-20.3 months). The median overall survival was not reached in any cohorts.

In high-risk patients (defined as those with either del17p and/or t[4;14]), the median PFS was 8.1 months (range = 1.1-15.6 months), with an estimated one-year PFS rate of 30 percent, which, the authors highlighted, was similar to responses seen in patients with standard-risk disease. “Additionally, the median PFS in patients refractory to prior IMiDs and proteasome inhibitors was 6.4 months (range = 0.2-20.3 months), with an estimated one-year PFS rate of 33 percent and was comparable with those who were not double-refractory.”

Adding ibrutinib to a standard backbone treatment of carfilzomib and dexamethasone “resulted in promising and durable responses,” the authors concluded, noting that this early-phase study is limited by its small patient population. An ongoing phase IIb study is assessing the pharmacodynamics of this combination.

The corresponding authors report no conflicts of interest. Pharmacyclics, an AbbVie Company, provided editorial support.

Reference

Chari A, Larson S, Holkova B, et al. Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma. Leuk Lymphoma. 2018 April 4. [Epub ahead of print]

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