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.
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.
The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m (MEL 200). Higher doses of melphalan 220-260 mg/m, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose-response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.
7608 Background: Autologous stem cell transplantation (ASCT) using melphalan 200 mg/m2 is a standard part of inital therapy in younger multiple myeloma (MM) patients (pts). We have previously reported an augmented regimen of melphalan 280 mg/m2 with the cytoprotectant agent amifostine (AF) to try to improve the anti-tumor response without increased mucosal toxicity (The Hematol J 2003; 4[suppl]: S207). We now update our experience with this regimen. Methods: Pts without disease progression and adequate organ function (creatinine clearance at least 60 cc/min) were eligible. Pts were treated as part of phase I-II trials approved by each center’s institutional review board. AF 740 mg/m2 was given IV over 5–15 min 24 hr and 15 min prior to melphalan 280 mg/m2 (infused over 15 min). Blood stem cells were reinfused 24 hrs later. The primary endpoint was response rate at day 100. Regimen-related toxicity using the Seattle criteria, progression-free (PFS) and overall survival (OS) were also assessed. Results: 24 pts were transplanted between 5/99–7/02. Median age was 50 (32–65) yrs; 1 pt had primary amyloidosis; median beta2-microglobulin level at diagnosis was 1.98 (0.88–11.80) mg/L. Prior therapy included VAD in 14, dexamethasone alone in 7 plus other regimens in 7. Day 100 responses compared with with pre-ASCT values included CR in 11, near CR (immunofixation positivity only) in 1, VGPR (greater than 90% reduction in serum M protein) in 3, PR in 5 and stable disease in 3. Maximum grade of mucositis was 2 (5 pts); no grade 3 or 4 toxicity was seen. The median day of ANC recovery to 0.5 x 109/L and median day of last platelet transfusion were 11 (6–16) and 10 (7–32), respectively. 4 received thalidomide (1 briefly), while 1 was treated with maintenance alpha interferon after day 100. Median follow-up is 52 (9–72) mos. 7 pts are alive without progression, including 5 in CR and 2 in PR. 16 have progressed at a median of 15 (7–36) mos post-ASCT. 8 have died from MM (7) or lung cancer (1). The 4 yr actuarial PFS is 28% (95% C.I. 34–76%) and OS 58% (95% C.I.11–47%). Conclusions: 1) Melphalan 280 mg/m2 with AF is well-tolerated; 2) the CR + nCR + VGPR rate of 62% warrants further evaluation, perhaps as part of tandem transplants or in conjuction with novel agents. [Table: see text]
Bcl-2 acts as an important regulator of the mitochondrial pathway of apoptosis and promotes resistance of MM cells to chemotherapy. The Bcl-2 antisense oligonucleotide G3139 specifically targets Bcl-2 and may enhance the anti-tumor efficacy of Dex and Thal. In this trial G3139 was administered at 5 mg to the first 3 Pts and then 7 mg/kg/d by IVCI for 7d of 21d cycle. On day 4, Pts started Dex 40 mg daily for 4 d and Thal 100-400 mg as tolerated. After 3 cycles, responding Pts continued G3139 on a 5-week cycle with Dex 20 mg x 4d and Thal at the tolerated daily dose for up to 1 yr with an optional second yr for responding Pts. Thirty-three Pts treated to date had the following characteristics: median age 60 yrs (range: 28- 76), 22 males; 16 Pts had complex karyotypes; 14 Pts had B2M > 2.5 g/dl; LDH >1.5 normal in 7 Pts; Cr >1.5 mg/dl in 6 Pts; platelets <100,000/ul in 4 Pts. Pts had received a median of 3 prior regimens (range 2-4) including auto-SCT. Seventeen Pts had received prior Thal for a median duration of 6.5 mos. (range 2–8); 11 had no response or progressed on Thal. G3139/Thal/Dex regimen was well tolerated. The median number of cycles per Pt was 8 (range: 1–16). Toxicities included reversible increase in Cr from a median of 1.2 (0.6–2.5) at baseline to 1.5 (range: 0.9–2) at cycle 6. G3139 dose was decreased (3–5 mg/kg/d) for Cr elevations in teh majority of Pts. Thrombocytopenia <100K occurred between cycle 1 and 2 (P= 0.008), and was reversible. Other toxicities (>grade 2) included fatigue, neutropenia, fever, electrolyte disturbance, muscle cramps, rash, hypotension, constipation and infections. Only 3 Pts maintained 400 mg/d of Thal, most Pts required dose reduction to 50–200 mg/d due neuropathy. Thirty Pts were evaluable for response; 24 Pts (80%) had documented responses, including 2 CR, 4 near-CR (+ immunofixation) and 12 PR; 6 had minimal response and 6 Pts had PD. The median duration of response is 13 mos. The estimated PFS is 12 mos and the median OS is 17.4 mo. The upper limits of the 95% confidence interval for PFS and OS have not been reached. At a median follow up of 1 yr (range 1.5–16.6 mo), 7 Pts had died and 26 are alive, of them 16 Pts continue on the study. Responding Pts had an early and significant increase in polyclonal IgM from a median baseline of 35.5 mg/dl (range: 8–75) to 94 (45–211) after cycle 3 (P=0.005), suggesting activation of the innate immune system. CD138+ cells were isolated from BM aspirates pre-treatment, and on d 4 or 7, and 28. Western blot analysis of Bcl-2 protein demonstrated demonstrated a decrease in Bcl-2 levels after normalization for protein loading by densitometry in 3 of 7 Pts with sufficient cells for analysis. The change of Bcl-2 protein levels did not correlate with response. Real time quantitative RT-PCR analysis was subsequently used to evaluate changes in Bcl-2 gene expression. Of 9 Pts evaluated, 6 demonstrated a significant decrease in Bcl-2 mRNA expression when normalized against GAPDH; 5 of them had a clinical response. In conclusion, G3139, Dex and Thal regimen is well tolerated in relapsed MM Pts. G3139 was associated with significant decrease in Bcl-2 gene expression in some Pts. G3139 appears to over-come resistance to Dex/Thal with impressive clinical responses in relapsed/refractory MM patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.