Phase 2 Study of Pegylated Liposomal Doxorubicin, Vincristine, Decreased-Frequency Dexamethasone, and Thalidomide in Newly Diagnosed and Relapsed-Refractory Multiple Myeloma (original) (raw)
British Journal of Haematology, 2008
Relapsed/refractory myeloma has a poor outcome because of multi-drug resistance, patient low-performance status and toxicity of conventional chemotherapy. To improve results, standard chemotherapeutics and drugs targeting the microenvironment are applied at the same time. Bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to other drugs and overcome drug-resistance. Notably, doxorubicin and bortezomib may reciprocally increase their efficacy. Thus, to improve outcome whilst minimizing therapy-related toxicity, liposomal doxorubicin was added to a bortezomib-based combination. From January 2004, relapsed/refractory myeloma patients referred to our Institution received bortezomib 1.0 mg/m(2) i.v. twice weekly for 2 weeks in a 28-d cycle for up to six cycles, oral dexamethasone 24 mg with the standard scheduling and thalidomide 100 mg continuously (VTD). From January 2005, liposomal doxorubicin, 50 mg/m(2) (30 mg/m(2) for patients older than 75 years), was added on day 4 of each cycle [VTD plus Myocet (MyVTD)]. In total, 70 patients were treated: 28 received VTD and 42 MyVTD. Baseline demographic and clinical characteristics were similar between the two groups. Toxicity was manageable although more pronounced with MyVTD. The overall response rate (81% vs. 50%, P = 0.009), time to progression (19 vs. 11 months, P = 0.01) and progression-free survival (15 vs. 8 months, P = 0.001) were significantly higher with MyVTD regimen, suggesting an improved quality of response.
Clinical Lymphoma, 2003
In patients with multiple myeloma (MM) who may ultimately receive active therapy, the combination of VAD (vincristine, doxorubicin, and dexamethasone) has been shown to be effective. However, the use of VAD is complicated by inherent risks that result from the use of central venous catheters, steroid toxicity, and by doxorubicin-associated adverse events such as cardiotoxicity and alopecia. To address these issues, a phase II trial investigating the combination of vincristine, pegylated liposomal doxorubicin, and reducedschedule oral dexamethasone in the first-line treatment of patients with MM has been conducted. Patients with symptomatic, newly diagnosed MM were treated with intravenous (I.V.) pegylated liposomal doxorubicin 40 mg/m 2 and vincristine 2 mg on day 1, along with dexamethasone 40 mg/day given either I.V. or orally for 4 days, every 4 weeks for a minimum of 6 cycles. Responses were reported in 29 patients (88%), and an additional 3 patients achieved stable disease. The median time to maximal response was 5.8 months (range, 0.7-13.6 months), and median overall survival time is estimated to be 60 months. This treatment regimen was well tolerated, and the most common grade 3/4 adverse events included hand-foot syndrome (21%), neutropenia (30%), anemia (21%), and mucositis (12%). Based on these results, the vincristine/liposomal doxorubicin/dexamethasone regimen appears to be effective and well tolerated in the first-line treatment of MM.
2002
Introduction: Thalidomide has recently proven to be a useful drug for treatment of refractory and relapsed multiple myeloma patients, up to 35% of whom achieve remission. However, little is known about the potential additive or synergistic eect upon its association with other drugs with proven ecacy in MM. Material and methods: The present pilot study was designed to evaluate the toxicity and response rate of the association of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 22 refractory or relapsed MM patients. The protocol scheduled the administration of thalidomide at escalating doses (200 to 800 mg/day), daily oral cyclophosphamide (CTX) (50 mg/day) and pulsed dexamethasone (40 mg/day, four days every three weeks). Results: Adverse eects were moderate (grade 42) with only two patients in whom treatment was withdrawn due to neuropathy and severe somnolence. Infections were recorded in six patients, four requiring hospitalization for intravenous antibiotic therapy. No cases of thrombocytopenia grade 52 were noted. Other side eects included grade 42 constipation (29%), somnolence (35%) or dizziness (12%). In addition, one case of meralgia paresthetica and one with a deep venous thrombosis were noted. Two cases displayed hyperglycemia and myopathy attributed to dexamethasone, which was solved upon changing to prednisone. With a median follow-up of 12 months, 17 patients were evaluable for response; 13 (77%) responded to the therapy, including nine cases (53%) with a 450% M-component reduction (two of them with a complete remission). Only two responders have already progressed, with a projected event free survival of 51% at 12 months. Seven patients have died due to disease progression (n=5), sudden death (n=1) and infection (n=1). Conclusion: This study shows that ThaCyDex is a feasible and promising therapeutic approach for patients with relapsed/refractory MM.
Blood Cancer Journal, 2016
The goal of initial treatment for transplant eligible patients with multiple myeloma (MM) is to achieve the deepest possible response in an effort to attain prolonged event-free survival after transplant. There has been an excellent response to the threedrug regimens of agents approved for upfront use (Table ), including bortezomib/IMiD (thalidomide or lenalidomide) dexamethasone (VTD or VRD) and bortezomib/cyclophosphamide/ dexamethasone (VCD). We had previously treated patients with three cycles each of two sequential three-drug regimens, VCD, then VTD, and reported an overall response rate of 92%, with a CR rate of 26%. 1 Another three-drug regimen, liposomal doxorubicin/ bortezomib/dexamethasone (DVD) also resulted in a good overall response rate of 71.5% ⩾ PR, and 20% CR in previously untreated patients. 2 Our objective in developing the bortezomib, cyclophosphamide, pegylated liposomal doxorubicin and dexamethasone regimen was to improve the depth of response and overall response rate compared to three-drug regimens. In addition, the study was designed to improve ease of administration by use of weekly dosing rather than the typical twice weekly dosing (that is, days 1, 4, 8 and 11) of bortezomib (the standard dosing at study inception). The efficacy of this four-drug regimen was examined in newly diagnosed, transplant eligible patients, with a secondary objective of evaluating rates of successful stem cell mobilization and survival after transplant. This study was conducted with approval of the University of Washington-Fred Hutchinson Research Center Cancer Consortium Institutional Review Board, and the Institutional Review Boards of the Seattle Cancer Care Alliance Network sites. Written informed consent was obtained from all patients. The trial was registered as NCT00849251 on www.clinicaltrials.gov. This study was comprised of two cohorts. After a pilot phase to assess tolerability in the relapsed setting (cohort 1), then newly diagnosed patients were enrolled (cohort 2). Relapsed, refractory patients with multiple myeloma who had failed at least one prior regimen, not including dexamethasone alone, were eligible to enroll in cohort 1. Newly diagnosed patients with previously untreated MM other than prior dexamethasone that did not exceed a total dose of 320 mg were eligible for cohort 2. Patients who were 18 years and older with quantifiable monoclonal protein or light chain identified by serum protein electrophoresis, urine protein electrophoresis or serum-free light-chain assay were enrolled. Eastern Cooperative Oncology Group performance status was 0-2. Patients were required to have adequate blood counts, renal, hepatic and cardiac function. Patients with uncontrolled infection were excluded, as were patients with grade 2 or higher neuropathy, prior cumulative dose of 400 mg/m 2 of doxorubicin or equivalent, patients with hypersensitivity to boron or bortezomib, those who were pregnant or lactating, patients with other cancers with limited exceptions, or patients who had undergone prior autologous or allogeneic transplant.
American Journal of Hematology, 2014
A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up 5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m 2 on day 1), dexamethasone (40 mg on days 1-4), and intravenous vincristine (2 mg on day 1). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM (ClinicalTrials.gov number, NCT00091624).
Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma
The Hematology Journal, 2004
Purpose: The efficacy of low-dose thalidomide (THAL) plus dexamethasone (DEX) has been evaluated in myeloma. The clinical outcome of patients treated with THAL-DEX was compared with that of a control group treated with conventional chemotherapy (CC). Experimental design: A total of 120 relapsed/refractory patients to one (52%), or two or more (48%) lines of chemotherapy were treated with THAL 100 mg/day (continuous) and DEX 40 mg (days 1-4 of each month). Their clinical outcome was compared to a control group of 120 patients frequency matched for serum b2-microglobulin levels and Durie and Salmon clinical stage. Clinical characteristics were homogeneous in the two groups. Results: In patients treated after one line of chemotherapy, THAL-DEX significantly improved outcome. Median progression-free survival (PFS) was superior in THAL-DEX group versus CC group (17 months versus 11 months, P ¼ 0.0024). The median survival for THAL-DEX patients has not to been reached, but the probabilities of survival at 3 years were 60% after THAL-DEX and 26% after CC (P ¼ 0.0016). The clinical outcome of patients receiving THAL-DEX or CC after two or more lines of chemotherapy, was similar. In the THAL-DEX group, the median PFS was 11 months compared to 9 months in the CC group (P ¼ NS). No differences in overall survival (OS) were observed (median OS 19 months for both THAL-DEX and CC). Conclusions: As first salvage regimen, THAL-DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL-DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit.
American Journal of Hematology, 2014
Our previous phase I/II trial of pegylated liposomal doxorubicin (PLD), low-dose dexamethasone, and lenalidomide in patients with relapsed and refractory myeloma showed an overall response rate of 75%, with 29% achieving ≥VGPR. Here, we investigated this combination (PLD 30 or 40 mg/m 2 intravenously, day 1; dexamethasone 40 mg orally, days 1-4; lenalidomide 25 mg orally, days 1-21; administered every 28 days) in a phase II study in patients with newly diagnosed symptomatic multiple myeloma to determine its efficacy and tolerability (ClinicalTrials.gov NCT00617591). At best response, patients could proceed with high-dose melphalan or with maintenance lenalidomide and dexamethasone. In 57 patients, we found that the overall response rate and rate of very good partial response and better on intent-to-treat, our primary endpoints, were 77.2% and 42.1%, respectively, with responses per the International Myeloma Working Group. Median progression-free survival was 28 months (95% CI 18.1-34.8), with 1-and 2-year overall survival rates of 98.1 and 79.6%. During induction, grade 3/4 toxicities were neutropenia (49.1%), anemia (15.8%), thrombocytopenia (7%), fatigue (14%), febrile neutropenia (8.8%), and venous thromboembolic events (8.8%). During maintenance, grade 3/4 toxicities were mainly hematologic. We found this combination to be active in patients with newly diagnosed myeloma, with results comparable to other lenalidomide-based induction strategies without proteasome inhibition. In addition, maintenance therapy with lenalidomide was well tolerated.
British journal of haematology, 2018
Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3-29·0 + months). Overall response rates for patients in Phase 2 were 39% and 3...
Clinical Oncology and Cancer Research, 2009
OBJECTIVE Though doxorubicin is highly active in the treatment of multiple myeloma, its toxicity profi le limits its therapeutic index. We performed this study to evaluate the effi cacy and safety of pegylated liposomal doxorubicin (PLD, Caelyx ® ), vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma (MM) patients in a Chinese population. METHODS This was an open-label, single-arm study in which newly diagnosed patients with MM received PLD 40 mg/m 2 intravenously on Day 1, vincristine 1.4 mg/m 2 intravenously (maximum 2 mg) on Day 1, and 40 mg of dexamethasone (intravenously or orally) from Day 1 to Day 4. Treatment was repeated every 28 days for at least 4 cycles. RESULTS In the intent-to-treat (ITT) analysis, the overall response rate was 68.29%, and the complete remission rate was 10.98%. The incidence of all adverse events was 46.34%. The most common non-hematologic toxicities were palmar-plantar erythrodysesthesia (13.4%) and stomatitis (6.1%). CONCLUSION PLD, vincristine, and a reduceddose dexamethasone combination (DVd) is an effective and safe regimen in newly diagnosed MM patients in a Chinese population.
Leukemia, 2004
We evaluate the efficacy of the oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 71 refractory/relapsed multiple myeloma patients, including a prognostic analysis to predict both response and survival. Patients received thalidomide at escalating doses (200-800 mg/ day), daily cyclophosphamide (50 mg/day) and pulsed dexamethasone (40 mg/day, 4 days every 3 weeks). On an intentionto-treat basis and using the EBMT response criteria, 2% patients reached complete response (CR), 55% partial response (PR) and 26% minor response (MR) yielding a total response (CR þ PR þ MR) rate of 83% after 3 months of therapy. After 6 months of therapy, responses were maintained including a 10% CR. The 2-year progression free and overall survival were 57 and 66%, respectively. A favorable response was associated with b 2 microglobulin p4 mg/dl, platelets 480 Â 10 9 /l and nonrefractory disease. Regarding survival, low b 2 microglobulin (p4 mg/dl), age (p65 years) and absence of extramedullary myelomatous lesion were associated with a longer survival. Major adverse effects included constipation (24%), somnolence (18%), fatigue (17%) and infection (13%). Only 7% of patients developed a thrombo-embolic event. ThaCyDex is an oral regimen that induces a high response rate and long remissions, particularly in relapsing patients with b 2 microglobulin p4 mg/dl and p65 years.