This report of a phase 2 trial of thalidomide (THAL) (200 mg/d; 200 mg increment every 2 weeks to 800 mg) for 169 patients with advanced myeloma (MM) (abnormal cytogenetics (CG), 67%; prior autotransplant, 76%) extends earlier results in 84 patients. A 25% myeloma protein reduction was obtained in 37% of patients (50% reduction in 30% of patients; near-complete or complete remission in 14%) and was more frequent with low plasma cell labeling index (PCLI) (below 0.5%) and normal CG. Two-year eventfree and overall survival rates were 20% ؎ 6% and 48% ؎ 6%, respectively, and these were superior with normal CG, PCLI of less than 0.5%, and ␤ 2 -microglobulin of 3 mg/L. Response rates were higher and survival was longer especially in high-risk patients given more than 42 g THAL in 3 months (median cumulative dose) ( IntroductionThalidomide (THAL) represents the first new class of active agents in the treatment of multiple myeloma (MM) since the introduction of melphalan and glucocorticoids more than 3 decades ago. 1 Its possible antitumor mechanisms in MM include a direct effect on MM and/or bone marrow stromal cells, 2 modulation of MM stromal cell adhesion, 3 suppression of MM cell-sustaining cytokines, 4 antiangiogenic effects by repression of vascular endothelial growth factor and basic fibroblast growth factor pathways, 5 and immunomodulation such as induction of T H1 T-cell response with secretion of interferon-␥ and interleukin-2. 6 More recently, synergistic apoptotic signaling of THAL and dexamethasone has also been observed. 7 We now report on the follow-up of all 169 patients enrolled in a phase 2 trial for advanced and refractory MM. Study designBetween December 1997 and December 1998, 169 consecutive eligible patients with extensively pretreated and progressive MM were enrolled in a phase 2 trial. THAL (50-mg capsules) (Celgene, Warren, NJ) was started at a daily dose of 200 mg and escalated by 200 mg every 2 weeks to 800 mg according to tolerance. Patients with cardiopulmonary or renal dysfunction were not excluded; liver function tests could not exceed twice the upper limit of normal. All patients were enrolled at a single institution and provided written informed consent in keeping with institutional and Food and Drug Administration guidelines.Baseline and follow-up laboratory tests were performed as previously outlined. 1 Patients kept a diary to document the occurrence and severity of toxicities. Follow-up visits were scheduled every 3 months, and more than 90% of patients adhered to this.Study endpoints included paraprotein responses (PPRs) in serum and/or urine of at least 25%, 50%, 75%, or 90%; complete remission (CR) was defined by absence of monoclonal protein on immunofixation analysis. 1 Patients with a PPR less than 25% and those discontinuing treatment before response could be assessed (minimum of 4 weeks of therapy) were considered to have failed treatment; all results were evaluated on an intent-to-treat basis. Relapse criteria have been previously reported. 1 Survival distributions (Kapl...

In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options.

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Summary:Patients with myeloma relapsing after tandem transplant have a poor survival and treatment options are limited. The role of additional salvage transplant procedures for these patients is unknown. To evaluate the benefit and identify prognostic factors, the outcome of 76 consecutive patients with recurrent myeloma after tandem transplant receiving salvage transplants (ST) was analyzed. Prior to ST, 23 patients (30%) had shown chemosensitive response to preceding salvage chemotherapy: two complete remissions (CR); eight near CRs (nCR: only immunofixation positive); 13 partial remissions (PR у75% reduction in M protein). Fifty received an autologous transplant, 22 a sibling-matched allogeneic transplant, and four a matched-unrelated allogeneic transplant. Overall response after ST was 59%: eight CRs (11%); 14 nCRs (18%); 23 PRs (30%). Overall survival (OS) at 2 years was 19%; 2 year eventfree survival rate (EFS) 7%. On univariate analysis for survival, only pre-transplant chemosensitive relapse (P Ͻ 0.05), serum albumin Ͼ3 g/dl (P = 0.001), normal LDH (P = 0.04), and long interval between the second transplant and relapse/progression were significant beneficial factors. In a Cox proportional hazard model, chemosensitive relapse, and albumin Ͼ3 g/dl were significant for better OS: hazard ratio (HR) 1.4, 1.7, respectively, while normal LDH, and absence of CA13 were significant for better EFS: HR 1.8, 1.7, respectively. Patients with albumin Ͼ3 g/dl who had chemosensitive disease before ST (n = 16) had a median survival of 16 months, compared to 7 months (n = 34) and 2 months (n = 26) for patients with only one (n = 34) or no favorable prognostic factors (n = 28), respectively (P Ͻ 0.001). Their survival at 2 years post-ST was 43%, 17% and 11%, respectively. Our study suggests further transplantation should only be considered in the setting of a clinical trial in patients with favorable prognostic factors. Long-term myeloma control has become possible since high-dose therapy (HDT) with melphalan was introduced in the mid-1980s.1 Treatment-related mortality of HDT has decreased to less than 3% with autologous peripheral blood stem cell support and improved supportive care. 2,3 In newly diagnosed myeloma, about 40% of patients achieve CR, resulting in a significant increase in EFS and OS when compared to conventional therapy. [4][5][6] Further intensification of HDT by using tandem transplantation was apparently associated with progressive increase in CR rate and additional survival benefit.6 A recent randomized trial by IFM (IFM-94 02) showed significant improvement in both EFS and OS with tandem transplantation compared to a single transplant. This difference only became apparent after 42 months of follow-up.

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