Carfilzomib-based combinations for Waldenström macroglobulinemia: Real-world experience from a single center.

Abstract

e19080 Background: Waldenström Macroglobulinemia (WM) is the most common lymphoplasmacytic lymphoma (LPL). Bortezomib is a reversible inhibitor of the 26S proteasome and one of the mainstays of treatment for WM. One limitation in this therapy is peripheral neuropathy (PN) as an adverse effect, which can compound those patients with pre-existing IgM-associated neuropathy. Carfilzomib, a second-generation proteasome inhibitor has been used off-label for WM and carries less risk of PN but a small risk of cardiotoxicity. Methods: We performed a single-center retrospective study of patients seen at the John Theurer Cancer Center in Hackensack, NJ. We reviewed 43 records of patients with biopsy-confirmed WM treated with carfilzomib-based regimens from July 2012 to January 2026 under a protocol approved by our IRB. Outcomes included ORR per the 6th International Workshop on WM, progression-free survival (PFS) as time from first cycle to either progression of disease or death, overall survival (OS) using the Kaplan-Meier method, and relapse following treatment. PN, cardiac toxicity and discontinuation rates were collected. Results: 29 patients were male (67.4%), 40 were Caucasian (93%) and 3 were Asian (7.0%). Median values at diagnosis: hemoglobin 10.0 g/dL, platelets 227x10^9/L, beta-2-microglobulin 2.6 mg/dL, IgM 2408 mg/dL [IQR 973-5435]. Median age at treatment was 67.2 years. Revised IPSSWM risk stratification was calculable for 36 patients, of whom 12 were low-risk (33.3%), 17 were intermediate-risk (47.2%) and 9 were high-risk (25%). 10 had systemic amyloidosis. Bone marrow involvement was available for 37 patients with a median of 30% [IQR 20-60%]. Of the 36 patients tested, 33 had MYD88 p.L265P (91.7%). ORR was 40/43 (93%), and 32/43 were alive at last follow-up (74.4%) with median follow-up of 66.2 months. 24 patients were progression-free at 120 months (55.8%). In total, 3 patients had complete response (CR, 6.9%), 18 had partial response (VGPR, 41.9%), 18 patients had partial response (PR, 41.9%), 1 had minimal response (MR, 2.3%), 2 had stable disease (4.7%) and 1 had progression of disease (2.3%). Median IgM after treatment was 161.5 mg/dL [IQR 98-413]. 1 patient developed atrial fibrillation and 1 developed heart failure that resolved after carfilzomib withdrawal. 3 patients developed PN attributed to carfilzomib, 6 with pretreatment PN were diagnosed with IgM-associated neuropathy, 2 had anti myelin associated glycoprotein neuropathy and 1 developed PN after switching from carfilzomib to bortezomib. 2 patients stopped treatment due to toxicity, 1 cardiac and 1 non-cardiac. Conclusions: Carfilzomib-based treatment regimens are effective with a favorable safety profile in our population. One patient experienced characteristic cardiac toxicity and demonstrated full recovery of cardiac function. PN was attributable to carfilzomib in a small fraction of cases.