Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy

Abstract

In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m 2 on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m 2 ), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progressionfree survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; Xgrade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (Xgrade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at

Therapy for Relapsed Multiple Myeloma

“…54,157 Therefore, we recommend a combination of carfilzomib, pomalidomide, and dexamethasone (KPd) 57 or daratumumab, bortezomib, and dexamethasone (DVd) 37 for fit patients who relapse while receiving, or soon after discontinuing, lenalidomide maintenance. In contrast, for patients who relapse while receiving maintenance therapy with bortezomib or soon after discontinuing bortezomib maintenance, we recommend therapy with daratumumab, lenalidomide, and dexamethasone (DRd).…”

Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma

“…Carfilzomib is currently being investigated in combination with other agents (eg, immunomodulatory agents, histone deacetylase inhibitors, corticosteroids, and/or alkylating agents) for treatment of patients with newly diagnosed MM [17][18][19][20][21][22] as well as patients with relapsed and/or refractory MM. [23][24][25][26][27] Specifically, the combination of carfilzomib with lenalidomide and dexamethasone (KRd) has been shown to be safe and tolerable with encouraging activity in patients with newly diagnosed MM 18,22 and also in patients with relapsed MM. 28 In particular, low rates of PN have been reported using KRd as a frontline regimen (23% all grades, 5.7% grade $2).…”

The Proteasome Inhibitor Carfilzomib Suppresses Parathyroid Hormone-induced Osteoclastogenesis through a RANKL-mediated Signaling Pathway

“…The first generation proteasome inhibitor bortezomib has been used as an effective therapy for the treatment of multiple myeloma, a disease characterized by an increase in the numbers and activity of osteoclasts and a decrease in the number and function of osteoblasts adjacent to tumor cells in the bone marrow (8). Carfilzomib (CFZ), a next generation selective proteasome inhibitor, exhibits potent antimyeloma efficacy and decreased toxicity when compared with bortezomib and has been recently approved in the United States for the treatment of relapsed and refractory multiple myeloma (9). Both bortezomib and CFZ have been shown to directly inhibit osteoclast formation and bone resorption in vitro (10,11), and bortezomib was reported to inhibit PTH-induced Rankl mRNA expression in osteoblasts (12).…”