Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy.
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...
The occurrence of deep-vein thrombosis (DVT) in patients with newly diagnosed multiple myeloma, who were randomly assigned to receive identical induction chemotherapy with or without thalidomide, are reported in this study. The 2 study arms were comparable with respect to key myeloma prognostic factors and known risk factors for DVT. One hundred patients received induction chemotherapy including 4 cycles of continuous infusion of combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin, and each patient completed at least one induction cycle. DVT developed in 14 of 50 patients (28%) randomly assigned to receive thalidomide but in only 2 of 50 patients (4%) not given the agent (P ؍ .002). All episodes of DVT occurred during the first 3 cycles of induction. Administration of thalidomide was resumed safely in 75% of patients receiving anticoagulation therapy. Thus, thalidomide given in combination with multiagent chemotherapy and dexamethasone is associated with a significantly increased risk of DVT, which appears to be safely treated with anticoagulation and does not necessarily warrant discontinuation of thalidomide. (Blood. 2001;98: 1614-1615)
Summary. Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine . 176´8 mmol/ l) at the time of autologous stem cell transplantation (auto-SCT), including 38 patients on dialysis. The median age was 53 years (range: 29±69) and 26% had received more than 12 months of prior chemotherapy. CD34
Summary. Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.
The feasibility and efficacy of autologous stem cell transplantation (auto‐SCT) in patients aged ≥ 70 years was analysed. Newly diagnosed (n = 34) and refractory multiple myeloma (n = 36) patients were studied. The median age was 72 years (range: 70–82·6). CD34+ cells were mobilized with chemotherapy and granulocyte colony‐stimulating factor (G‐CSF) (n = 35) or G‐CSF alone (n = 35), yielding medians of 11·8 × 106 versus 8 × 106cells/kg respectively (P = 0·007). Because of excessive mortality (16%) in the first 25 patients who received melphalan 200 mg/m2 (MEL‐200), the dose was subsequently decreased to 140 mg/m2 (MEL‐140). Median times to absolute neutrophil count (ANC) > 0·5 × 109/l and to platelets > 20 × 109/l were 11 and 13 d respectively. Thirty‐one patients (44%) received tandem auto‐SCT. Complete remission (CR) was 20% after the first SCT and 27% after tandem SCT. Median CR duration was 1·5 years and was significantly longer for patients with ≤ 12 months of prior chemotherapy (2·6 versus 1·0 years, P = 0·0008). The 3‐year event‐free survival (EFS) and overall survival (OS) (+ standard error, SE) were projected at 20% + 9% and 31% + 10% respectively. Tandem SCTs positively affected EFS (4·0 versus 0·7 years; P = 0·003) and OS (4·0 versus 1·4 years; P = 0·02) compared with single auto‐SCT. In conclusion, MEL‐140 is less toxic and appears equally as efficacious as MEL‐200 in elderly patients. The benefits of tandem SCT in this patient population need further evaluation in a randomized trial.
Summary Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow‐up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0·002), postenrolment (P < 0·001) and at relapse (P = 0·004); elevations of serum C‐reactive protein (CRP) (P = 0·003) and lactate dehydrogenase (P = 0·029), anaemia (P = 0·029) and they more often completed two transplants within 12 months (P = 0·019). Postenrolment overall survival (OS) and event‐free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0·001 and 0·037 respectively) and in the presence of low CRP at baseline (P = 0·001 and 0·017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0·001), IgA isotype (P = 0·002), International Staging System stage 3 (P = 0·014), and when patients had two protocol transplants prior to relapse (P = 0·038). Ten‐year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high‐dose melphalan, were applied together upfront for the management of myeloma.
Standard allogeneic stem cell transplant (allo-SCT) regimens have been associated with a high transplant-related mortality (TRM) in multiple myeloma (MM). Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. We report on 16 poor-risk MM patients receiving allo-SCT from an HLA-matched (n ؍ 14) or mismatched (n ؍ 2) sibling following conditioning with melphalan 100 mg/m 2 (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n ؍ 9) or 2 (n ؍ 7) prior autotransplants. Donor lymphocyte infusions (DLIs) were given to 14 patients with no clinical evidence of graft versus host disease (GVHD) either to attain full donor chimerism (n ؍ 4) or to eradicate residual disease (n ؍ 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day
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