Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma

Abstract

• This is the first clinical trial to investigate CPD in multiple myeloma.• Results suggest that the regimen is a well-tolerated and highly active combination for patients with relapsed/ refractory multiple myeloma.Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone (CPD) in an open-label, multicenter, phase 1, doseescalation study. Patients who relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib IV on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m 2 ), pomalidomide once daily on days 1 to 21 (4 mg as the initial dose level), and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m 2 , pomalidomide 4 mg, dexamethasone 40 mg). Hematologic adverse events (AEs) occurred in ‡60% of all patients, including 11 patients with grade ‡3 anemia. Dyspnea was limited to grade 1/2 in 10 patients. Peripheral neuropathy was uncommon and limited to grade 1/2. Eight patients had dose reductions during therapy, and 7 patients discontinued treatment due to AEs. Two deaths were noted on study due to pneumonia and pulmonary embolism (n 5 1 each). The combination of CPD is well-tolerated and highly active in patients with relapsed/refractory multiple myeloma.

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

“…Early-phase studies of carfilzomib, pembrolizumab, isatuximab, or cyclophosphamide in combination with pom-dex reported ORRs ranging from 50% to 65%. [23][24][25][26] While ORR was slightly higher in a phase 1 study of bortezomib plus pom-dex (72%), only 13 patients had been evaluated for response, and the study population was bortezomib naïve. 27 Larger, randomized, controlled studies will be required to determine the potential benefit of these regimens, overall and in high-risk patients.…”

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

“…Pomalidomide is indicated in patients who have received at least two previous therapies including bortezomib and lenalidomide (Table 1) (Celgene Corporation POMALYST, 2016;Celgene Europe Ltd., 2016a) and is thus a treatment option at second or later relapse. New triplet combinations based on the addition of a PI to pomalidomide plus dexamethasone have shown promising efficacy in phase I/II studies (Hofmeister et al, 2013;Shah et al, 2015;Voorhees et al, 2015); however, to date, no phase III trial data are available for these combinations.…”

“…The novel combination of pomalidomide plus carfilzomib and dexamethasone has also shown efficacy in heavily pretreated patients. The phase I dose-escalation study of this combination, in which all patients were refractory to lenalidomide and most (91%) were also refractory to bortezomib, reported an ORR of 50% and median OS of 20.6 months (Shah et al, 2015).…”

Developments in the Field of Myeloma in the Last Decade

“…• Proteasome inhibitors: carfilzomib [18,19] and ixazomib [20] • IMIDs: pomalidomide [19] • Monoclonal antibodies: daratumumab [21,22] elotuzumab [23] • HDAC inhibitors: panobinostat [24] Conclusion and the Future There has been remarkable improvement in our ability to manage multiple myeloma. Standard-risk patients live beyond five years of disease progression and overall survival is improving too, a reflection of the highly effective newer molecules.…”