A phase ii trial of thalidomide in the treatment of relapsed multiple myeloma (mm) with laboratory correlative studies

Aim: A phase II trial of thalidomide in relapsed MM with laboratory correlative studies examining bone marrow (BM) angiogenesis and plasma cell proliferation. Methods: 32 patients (pts), 22 male and 10 female, with relapsed MM were treated between April 1999 and July 2000. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, then increased as tolerated by 200 mg/day every 2 weeks, up to a maximum daily dose of 800 mg/day. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or greater, and confirmed by repeat measurements at least 2 weeks apart. BM angiogenesis was studied in a blinded manner using immunohistochemical staining for CD34 to identify microvessels in 27 pts (84%). Microvessel density (MVD) was estimated by determining the average number of vessels in 3 hot spots examined at 400x magnification. Angiogenesis was also visually graded as low, intermediate and high. Plasma cell (PC) proliferation was studied using a slide based immunofluorescent bromodeoxyuridine incorporation assay (plasma cell labeling index; PCLI). Results: The median age was 67 years (range, 36-78). All pts had failed prior chemotherapy and 5 (16%) had failed stem cell transplantation. Response is still being evaluated, and currently 26 patients with at least two cycles of data are évaluable for response. 10 responses were confirmed, yielding a response rate of 38%. No complete responses were seen. Major grade 3 toxicities were sedation (10%) and neuropathy (10%). One pt each had grade 3 constipation, rash and vertigo. Pre-treatment MVD ranged 5-47 per 400x field (median 20). Angiogenesis grade was high in 52%, intermediate in 30%, and low in 18%. No significant changes were observed in MVD following treatment in 4 responders on whom at least 2 BM samples were available for study. Pre-treatment MVD and angiogenesis grade did not appear to be associated with response to therapy. Response rates were significantly higher in pts with a high PCLI (1) compared to those with a low PCLI, 57% versus 21%, respectively, (p=0.02). Conclusions: Thalidomide is effective in the treatment of relapsed MM with a response rate of 38% in this study. Its mechanism of action remains unclear. These results suggest that a high PCLI is a potential predictor of response to therapy.