Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia

• Published in: Blood 2014-07, Vol.124 (4), p.503-510
• Main Authors: Treon, Steven P., Tripsas, Christina K., Meid, Kirsten, Kanan, Sandra, Sheehy, Patricia, Chuma, Stacey, Xu, Lian, Cao, Yang, Yang, Guang, Liu, Xia, Patterson, Christopher J., Warren, Diane, Hunter, Zachary R., Turnbull, Barry, Ghobrial, Irene M., Castillo, Jorge J.
• Format: Article
• Language: English
• Subjects: Aged; Antibodies, Monoclonal, Murine-Derived - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Dexamethasone - administration & dosage; Female; Follow-Up Studies; Humans; Immunoglobulin G - metabolism; Immunoglobulin M - metabolism; Male; Middle Aged; Oligopeptides - administration & dosage; Peripheral Nervous System Diseases - metabolism; Peripheral Nervous System Diseases - mortality; Peripheral Nervous System Diseases - prevention & control; Prognosis; Prospective Studies; Remission Induction; Rituximab; Survival Rate; Waldenstrom Macroglobulinemia - drug therapy; Waldenstrom Macroglobulinemia - metabolism; Waldenstrom Macroglobulinemia - mortality
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-03-566273

Bortezomib frequently produces severe treatment-related peripheral neuropathy (PN) in Waldenström's macroglobulinemia (WM). Carfilzomib is a neuropathy-sparing proteasome inhibitor. We examined carfilzomib, rituximab, and dexamethasone (CaRD) in symptomatic WM patients naïve to bortezomib and rituximab. Protocol therapy consisted of intravenous carfilzomib, 20 mg/m2 (cycle 1) and 36 mg/m2 (cycles 2-6), with intravenous dexamethasone, 20 mg, on days 1, 2, 8, and 9, and rituximab, 375 mg/m2, on days 2 and 9 every 21 days. Maintenance therapy followed 8 weeks later with intravenous carfilzomib, 36 mg/m2, and intravenous dexamethasone, 20 mg, on days 1 and 2, and rituximab, 375 mg/m2, on day 2 every 8 weeks for 8 cycles. Overall response rate was 87.1% (1 complete response, 10 very good partial responses, 10 partial responses, and 6 minimal responses) and was not impacted by MYD88L265P or CXCR4WHIM mutation status. With a median follow-up of 15.4 months, 20 patients remain progression free. Grade ≥2 toxicities included asymptomatic hyperlipasemia (41.9%), reversible neutropenia (12.9%), and cardiomyopathy in 1 patient (3.2%) with multiple risk factors, and PN in 1 patient (3.2%) which was grade 2. Declines in serum IgA and IgG were common. CaRD offers a neuropathy-sparing approach for proteasome inhibitor-based therapy in WM. This trial is registered at www.clinicaltrials.gov as #NCT01470196. •Carfilzomib, rituximab, and dexamethasone (CaRD) produce overall and CR/VGPR responses in 87% and 36% of frontline WM patients, respectively.•CaRD activity was not impacted by MYD88 and CXCR4 mutations and represents a neuropathy-sparing option for treating WM patients.