Salvage Therapy With Thalidomide In Patients With Advanced Relapsed/Refractory Multiple Myeloma

Abstract

Background and Objectives. Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high‐dose therapy. Thalidomide, a glutamic acid derivative with anti‐angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients. Design and Methods. From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty‐six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after greater than or equal to 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty‐one (93.8%) patients were in stage 111, median beta2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200 mg every other week to a maximum of 800 mg/day. Results. The median administered dose of thalidomide was 400 mg/day. WHO grade> II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed greater than or equal to 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed greater than or equal to 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow‐up, 15/28 patients are alive and progression‐free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre‐treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 ± 165 pg/mL vs 227.11 ± 70 pg/mL, p = 0.04). Interpretation and Conclusions. These data confirm that thalidomide is active in patients with advanced relapsed/ refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.

First-line thalidomide–dexamethasone therapy in preparation for autologous stem cell transplantation in young patients (<61 years) with symptomatic multiple myeloma

“…Remarkable antimyeloma efficacy, reported to be about 30% with thalidomide alone 8,9 and 50% with added dexamethasone 10,11 in advanced and refractory MM, provided the basis for recent clinical trials aimed at investigating the role of these drugs as first-line therapy for patients with symptomatic MM. [12][13][14] The aim of this prospective, multicenter study was to evaluate the efficacy and toxicity of thalidomide and dexamethasone administered as primary therapy in patients with symptomatic MM, and to determine the effect of this combination therapy on stem cell collection and engraftment.…”

“…19 Response rates of about 30% reported by Singhal et al 8 were confirmed by others groups. 9,[20][21][22][23] Addition of dexamethasone to thalidomide in patients who failed to benefit from prior therapy, including both thalidomide and dexamethasone given as single agents, further increased responses, up to an overall response rate of 50-55%. 10,11 These data suggested a synergy between thalidomide and dexamethasone and prompted several groups to explore this combination also in patients with previously untreated MM.…”

The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma

“…[4][5][6][7][8][9][10] One of the most active and promising drugs for this subset of patients is thalidomide, which has provided an overall response rate of around 45%. [11][12][13][14][15][16][17][18] In an attempt to increase this response rate, several groups, including our own, have investigated the efficacy of combining thalidomide with other agents. We designed a protocol (ThaCyDex) that includes thalidomide together with oral cyclophosphamide and dexamethasone.…”

Targeted treatments to improve stem cell outcome: old and new drugs

“…6 Since then, thalidomide has been widely used as a single agent in heavily pretreated and relapsed or refractory multiple myeloma. [7][8][9][10][11][12][13][14][15][16][17] In vitro studies revealed synergistic activity between dexamethasone (Dex) and thalidomide. 18 Combining thalidomide and Dex in clinical trials clearly represented an advance in treatment options for relapsed MM with overall responses up to 55%.…”