KPd Triple-Combination Shows Potential in Refractory Multiple Myeloma

Charles M. Rudin, MD, PhD

Andrzej J. Jakubowiak, MD, PhD

A regimen consisting of carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone (KPd) merits further investigation for the treatment of patients with multiple myeloma whose disease progresses while on lenalidomide (Revlimid) in the earlier stages of disease.

At the end of 1 cycle of KPd, more than 60% of patients had already achieved partial response (PR) or better, reported Andrzej J. Jakubowiak, MD, PhD, at the 2016 ASCO Annual Meeting. At 2 years, the rate of progression-free survival (PFS) is “encouraging,” he said, approaching 13 months.

An increasing number of patients with multiple myeloma are receiving lenalidomide-based regimens as first- and second-line therapy. Evidence-based choices for patients progressing on lenalidomide-based therapy with multiple prior lines of treatment are limited, as most studies have excluded these patients from enrollment.

Carfilzomib and pomalidomide, and their combination with dexamethasone, had shown promising tolerability and activity in heavily pretreated patients with multiple myeloma, including those refractory to lenalidomide. This makes KPd an attractive option in less heavily pretreated patients that have progressed on lenalidomide-based therapies, said Jakubowiak, Professor of Medicine Director, Myeloma Program University of Chicago Medical Center.

These observations led to the design of a multicenter, single-arm, phase I/IIb study to evaluate the safety and efficacy of KPd in relapsed/refractory multiple myeloma, with a focus on lenalidomide-refractory and proteasome inhibitor-naïve/sensitive patients.

The primary objective of phase I was to establish the maximum tolerated dose (MTD) of carfilzomib with pomalidomide and dexamethasone, and of phase II, to explore the efficacy at the determined MTD, defined as PR after 4 cycles.

Eligible patients included those with relapsed/refractory multiple myeloma with at least one prior line of therapy. Lenalidomide-refractory disease was required for first relapse. A proteasome-naïve or —sensitive population was required for the primary efficacy analysis.

The phase I dose escalation scheme to determine MTD examined four dose levels in which pomalidomide was administered at 3 to 4 mg on days 1 to 21; carfilzomib was given intravenously at 20 to 36 mg/m²on days 1, 2, 8, 9, 15, 16 during cycles 1 to 8, and on days 1, 2, 15, 16 during cycle 9 and afterward; and dexamethasone was dosed at 40 mg weekly from cycles 1 to 4, and 20 mg weekly from cycles 5 to 8; in 28-day cycles.

In phase I, the study protocol was deigned to enroll a total of 40 patients but was expanded by 2 patients to enhance the accuracy of MTD determination. MTD was defined as the probability of dose-limiting toxicity closest to but not exceeding 25%.

In phase II, planned enrollment was 30 lenalidomide-refractory but proteasome-naïve or —sensitive patients treated at the MTD for primary efficacy analysis.

The overall patient population consisted of 56 patients; the primary efficacy population consisted of 46 patients, including 21 at MTD. Years from multiple myeloma diagnosis were 5.3 years in the overall population and 6.1 years in the primary study population. Thirty-five percent and 29%, respectively, had high-risk disease, and 14% and 12%, respectively, had deletion 17p.

About 80% of the study cohort received 2 or more prior lines of therapy, and approximately 40% received 3 or more prior lines. Ninety-two percent of the patients met criteria for refractory disease, the vast majority of whom were refractory to lenalidomide.

Dose-limiting toxicities were experienced by 1 of 3 patients at dose level 1, 4 of 26 at dose level 2, and 4 of 13 at dose level 3. All dose-limiting toxicities were asymptomatic cytopenias (8 grade-3 neutropenias and 1 grade-4 thrombocytopenia). The probability estimate of dose-limiting toxicity at level 3 was 24.8%, which was closest to the preselected 25%. This dose was established as the MTD and therefore was chosen to advance to phase II. Dose level 3 was carfilzomib, 27 mg/m²on a twice weekly schedule; pomalidomide, 4 mg on days 1 to 21; and dexamethasone, 40/20 mg weekly.

Most adverse events were grade 1 or 2, with anemia, neutropenia, and thrombocytopenia as the most common hematologic toxicities. Gastrointestinal adverse events, musculoskeletal pain, and fatigue, each occurred in about 60% of patients, and infection and dyspnea each occurred in slightly more than 40% of patients. Hypertension, mostly grade 1 or 2, occurred in 25% of patients.

The median treatment duration was 9.5 cycles; 82% completed 4 cycles and 57% completed 8 cycles. Thirty-six percent of patients remain on treatment. The main reason for discontinuation was progressive disease (83%).

After 4 cycles, 72% of all response-evaluable patients and 73% of the primary study population had a PR or better.

“Importantly, responses were very rapid,” said Jakubowiak.

At the end of 1 cycle, 65% of all response-evaluable patients and 61% of the primary study population were already in PR or better. Depth of response improved with continued treatment. On intent-to-treat analysis, 84% achieved PR or better, with 21 of 30 planned patients being treated at MTD.

After a median of 17.9 months of follow-up, median PFS in the overall study population was 12.9 months and median overall survival had not been reached. At 24 months, 78% of patients were still alive.

With only limited data on the activity of established regimens in patients with multiple myeloma who progress on lenalidomide, further exploration of the KPd regimen in a randomized setting is warranted, said Jakubowiak.

Rosenbaum CA, Stephens LA, Kukreti V, et al. Phase 1/2 study of carfilzomib, pomalidomide, and dexamethasone (KPd) in patients (Pts) with relapsed/refractory multiple myeloma (RRMM): A Multiple Myeloma Research Consortium multicenter study. Presented at: ASCO 2016; June 3-7, 2016; Chicago. Abstract 8007.