Phase II Study of Bortezomib in Waldenstrom’s Macroglobulinemia: Results of WMCTG Trial 03-248.

In this multi-center phase II study, 27 patients with the consensus panel definition of Waldenstrom’s macroglobulinemia received bortezomib as a single agent. All but one patient had relapsed/or refractory disease, and the median number of prior therapies was 2 (range 0–3). Intended therapy consisted of 8 cycles of bortezomib at 1.3 mg/m² on days 1,4,8,11. Twenty-six patients have completed therapy and are eligible for evaluation. The median age for this group was 62 (44–79 years) and baseline laboratories were as follows: serum IgM: 4,565 (1,067–9,330 mg/dl); bone marrow (BM) involvement 30% (1–95%); and hematocrit 34.9% (25.6–45.3%). Following a median of 6 cycles of therapy, serum IgM levels decreased in 25/26 patients to a median of 2,685 (125–5,650 mg/dl), while hematocrit rose in 20/26 patients to a median of 37.2% (30.9–46.3%). The overall response rate was 84.6%, with 11 and 11 patients achieving a minor (<25% decrease in IgM) and partial (<50% decrease in IgM) response, respectively, using consensus panel criteria. Post therapy bone marrow biopsies were not required for response determination, but were available for 8 patients who demonstrated a median decrease in bone marrow involvement from 37.5%(range 20–55%) to 17.5% (range 5–48%). However, in 3 of 8 patients discordance between serum IgM levels, bone marrow involvement and/or adenopathy was demonstrated including in one patient who demonstrated a decrease in serum IgM levels from 2,291 to 618 mg/dL whilst bone marrow involvement rose from 25% to 48%. With a median follow-up of 8 months, 10 patients have demonstrated progressive disease. In general, therapy was well tolerated with grade III/IV toxicities as follows: neutropenia (15%); sensory neuropathies (12%); thrombocytopenia (8%); pleural effusion (4%); neuropathic pain (4%); diarrhea (4%); infection (8%); anorexia (8%); and fatigue (4%). The results of these studies demonstrate that bortezomib is an active agent in the salvage setting for patients with WM, and may independent of direct tumor cell killing inhibit secretion of IgM in some patients. Moreover, BM biopsies and CT scans (if baseline adenopathy or splenomegaly were present) should be considered to assess response in WM patients receiving bortezomib. In view of these results, a phase II study of bortezomib in combination with dexamethasone and rituximab has been initiated in patients with WM.