Antitumor Activity of Bortezomib (PS-341; Velcade) in a Phase II Study of Patients with Previously Untreated or Treated Waldenstrom’s Macroglobulinemia (WM).
Authors: Chen Christine I. , White Darrell , Kouroukis C. Tom , Stewart A. Keith , Howson-Jan Kang , Larratt Loree , Powers Jean , Eisenhauer Elizabeth 
Published: October 2019

Background: WM is a clonal disorder of lymphoplasmacytoid cells that shares features with lymphoma and myeloma. It is generally considered an indolent lymphoma hence traditional first-line treatments include single-agent alkylators (RR 50–80%) or purine analogues (RR 70–80%). For relapsed/refractory disease, purine analogues lead to responses in only 30% of pts. Newer agents such as rituximab or thalidomide have moderate activity. Regardless of regimen, responses tend to be partial and transient. Bortezomib is a proteasome inhibitor that has shown activity in myeloma. Objective responses were reported in phase I studies of lymphoma, including WM, making this agent of interest to evaluate.

Methods: Eligible pts for this ongoing multicentre study must have symptomatic WM (Hb <110g/L; symptomatic lymphadenopathy; hepatomegaly and/or splenomegaly; or hyperviscosity) and received <3 prior chemotherapy regimens (rituximab allowed as a 3rd regimen). Pts receive bortezomib 1.3 mg/m2 IV bolus twice weekly x 2 wks on a 3 wk cycle until PD or 2 cycles beyond CR/stable PR. Planned accrual = 25 pts.

Results: Sixteen pts are enrolled thus far. Demographics: median age 63 (range 46–87), M:F ratio = 9:7, ECOG 0:1:2 ratio = 5:10:1. Eight of 16 pts were chemonaive; 8 previously treated (prior regimens: chlorambucil, cladribine, fludarabine, CHOP). At study entry, most pts (12/16) had IgM levels >30g/L (range 11.2–79.8), measurable nodal disease (10/16 pts), and Hb levels <110g/L (10/16 pts). Responses have been observed: 3 confirmed PR (≥50% decrease in both IgM and bidimensional disease), 10 SD, no CR (of 13 evaluable pts). PR in 3 pts was reached after 3, 4, and 8 cycles, respectively. No pts have progressed on treatment. A ≥50% decrease in IgM alone with lagging nodal responses has been observed in another 3 pts. Therefore, a total of 6/13 pts (46%) have achieved PR based on paraprotein response alone. Hematologic improvements (Hb increases ≥ 10g/L) were observed in 9/13 pts (69%). Most common toxicities: fatigue (69%), sensory neuropathy (61.5%), headache (54%), myalgias (61.5%). Neuropathy is described as tingling, numbness, or pain in feet/legs generally within 2–4 cycles. Gr 3 neuropathy developed in 4 pts (none had clinical neuropathy at baseline). Four pts were removed from study due to neuropathy. Reversibility of neuropathy is pending longer followup. Other Gr 3 toxicities: thrombocytopenia (3/13), myalgias (2/13), neutropenia (2/13). Thrombocytopenia and neutropenia were transient, mandating a dose reduction in only 1 pt (neutropenia). Gr 3 myalgias (leg cramps) led to drug discontinuation in 1 pt with rapid resolution. No Gr 4 toxicities have been reported.

Conclusions: Bortezomib appears to have activity in WM with objective responses in 3 of 13 pts and SD in 10 additional pts evaluable thus far. Despite prompt IgM reductions and hematologic improvements, objective responses are slow due to lags in nodal reductions. Bortezomib is well-tolerated although sensory neuropathy is common. These interim results are promising and encourage further study of this drug in WM.