Survival Effect of Venous Thromboembolism in Patients With Multiple Myeloma Treated With Lenalidomide and High-Dose Dexamethasone

2010 ◽  
Vol 28 (1) ◽  
pp. 132-135 ◽  
Author(s):  
Maurizio Zangari ◽  
Guido Tricot ◽  
Latha Polavaram ◽  
Fenghuang Zhan ◽  
Ashlie Finlayson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Venous Thromboembolism ◽  
Retrospective Analysis ◽  
The United States ◽  
Phase Iii ◽  
High Dose ◽  
Time To Progression ◽  
High Dose Dexamethasone ◽  
Survival Effect

Purpose We conducted a retrospective analysis of the survival effect of venous thromboembolism (VTE) development in patients with multiple myeloma (MM). Methods Two identically designed, multicenter, double-blind, phase III clinical trials (MM-009 and MM-010) were conducted in Europe and the United States to assess the effect of lenalidomide in combination with dexamethasone versus dexamethasone plus placebo in patients with relapsed or refractory MM, after failing at least one prior line of treatment. In this retrospective analysis, we evaluated incidence and survival effect of thromboembolism in 353 patients randomly assigned to receive 25 mg of lenalidomide on days 1 through 21 of a 28-day cycle, plus 40 mg of oral dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 for the first four cycles; after the fourth cycle, 40 mg of dexamethasone was administered on days 1 through 4 only. Results Seventeen percent of patients experienced a thromboembolic episode. The development of VTE did not significantly affect overall survival (P = .90) or time to progression (P = .34). No significant survival impact was observed in a subgroup of patients who received prophylactic anticoagulation (overall survival P = .7, time to progression P = .1). Conclusion Patients with MM treated with lenalidomide and high-dose dexamethasone who developed a VTE did not experience shorter overall survival or time to progression.

Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7521-7521 ◽  
Author(s):  
D. M. Weber ◽  
C. Chen ◽  
R. Niesvizky ◽  
M. Wang ◽  
A. Belch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Response Rate ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Time To Progression ◽  
Prognostic Features ◽  
High Dose Dexamethasone ◽  
Grade 3

7521 Background: Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with dexamethasone (Dex). Methods: In this phase 3, multicenter, double-blind trial, 354 patients (pts)with relapsed or refractory MM were treated with Dex 40 mg daily on days 1–4, 9–12, 17–20 every 28 days and were randomized to receive either lenalidomide (Len) 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning with cycle 5, Dex was reduced to 40 mg daily on days 1–4 only, every 28 days. Patients were stratified with respect to B2M (≤ 2.5 vs. > 2.5 mg/mL), prior stem cell transplant (none vs. ≥ 1), and number of prior regimens (1 vs > 1). The treatment arms were well balanced for prognostic features. Results: The overall response rate was greater with Len-Dex than with Dex-placebo (59.4% vs. 21.1%; p < 0.001). Complete responses were achieved in 12.9% of pts treated with Len-Dex and 0.6% of pts treated with Dex-placebo. The median time to progression (TTP) for pts treated with Len-Dex was 11.1 months compared to 4.7 months for pts treated with Dex-placebo (p < 0.000001). Median overall survival was higher with Len-Dex (not reached) compared to Dex-placebo (24 months) (hazard ratio 1.76, p = .0125). Grade 3–4 neutropenia was more frequent with combination therapy than with Dex-placebo (24% vs. 3.5%), however ≥ grade 3 infections were similar in both groups. Thromboembolic events occurred in 15% of pts treated with Len-Dex and in 3.5% of pts treated with Dex-placebo. Atrial fibrillation occurred in 8 pts and CHF developed in 4 pts treated with Len-Dex. Conclusions: Considering the ease of oral administration, higher response rate, longer time to progression and overall survival benefit, the combination of lenalidomide-dexamethasone may very well represent the treatment of choice for early refractory or relapsing multiple myeloma. The relatively infrequent side effects should not detract from these improvements, but the use of prophylactic antithrombotic therapy should be considered for patients treated with the combination of lenalidomide and dexamethasone. [Table: see text]

Lenalidomide Plus High-Dose Dexamethasone Provides Improved Overall Survival Compared to High-Dose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of 2 Phase III Studies (MM-009, MM-010) and Subgroup Analysis of Patients with Impaired Renal Function.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3547-3547 ◽  
Author(s):  
Donna Weber ◽  
Michael Wang ◽  
Christine Chen ◽  
Andrew Belch ◽  
Edward A. Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Renal Function ◽  
Creatinine Clearance ◽  
Subgroup Analysis ◽  
Impaired Renal Function ◽  
Phase Iii ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Duration Of Response

Abstract Lenalidomide is a novel, orally administered immunomodulatory drug (IMiD) that has single-agent activity against multiple myeloma (MM) and additive effects when combined with dexamethasone. We have previously reported improved response (OR), time to progression (TTP) and overall survival (OS) with lenalidomide-dexamethasone (Len-Dex) compared to dexamethasone-placebo (Dex) based on the results of 2 phase III trials (MM-009, North American, 353 pts; MM-010, Europe, Australia, and Israel, 351 pts). In both trials patients with relapsed or refractory MM not resistant to dexamethasone, were treated with dexamethasone 40 mg daily on days 1–4, 9–12, and 17–20 every 28 days and were randomized to receive either lenalidomide 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning at cycle 5, Dex was reduced to 40 mg daily on days 1–4 only, every 28 days. Patients were also stratified with respect to B2M (≤2.5 vs. > 2.5 mg/mL), prior stem cell transplant (none vs. ≥ 1), and number of prior regimens (1 vs > 1). At a median follow-up from randomization of 17.1 mos (MM-009) and 16.5 mos (MM-010), both studies continue to show significant improvement with Len-Dex compared to Dex in OR (MM-009: 61% vs 20.5%, p<.001; MM-010: 59.1% vs. 24%, p<.001, respectively), TTP (MM-009: 11.1mos vs. 4.7mos, p<.001; MM-010: 11.3mos vs. 4.7mos, p<.001, respectively), and OS (MM-009: 29.6mos vs. 20.5mos, p<.001; MM-010: not estimable vs 20.6mos, p<.001, respectively). Pooled data from both trials demonstrates a significant improvement in duration of response for pts achieving ≥ PR with 122/216 pts (56.5%) who received Len-Dex continuing in remission (med. duration of response not reached but > 68.1 wks) compared to only 22/76 pts (28.9%) treated with dexamethasone alone (med. duration of response 22.1 wks, p<.001). An additional subgroup analysis was performed on pts with impaired creatinine clearance (cr cl). No significant difference in response rate, TTP, or OS was noted for patients with cr cl above or below 50 ml/min who were treated with Len-Dex, but for 16 pts with cr cl <30ml/min, med. TTP and OS was shorter than for those with cr cl >30ml/min, but still significantly higher than for pts treated with Dex. Grade 3–4 thrombocytopenia was significantly higher in pts with impaired renal function (<50ml/min, 13.8%; >50ml/min 4.6%, p<.01; <30ml/min, 18.8%, >30 ml/min, 5.5%, p<.05), but there was no difference for G3–4 neutropenia at either cutoff. Phase I–II evaluation to establish appropriate dosing in pts with cr cl < 30ml/min, particularly with respect to thrombocytopenia is warranted, but should not underscore improved OR, TTP, and OS for pts treated with Len-Dex regardless of creatinine clearance.

Thromboprophylaxis in Multiple Myeloma Patients Treated with Lenalidomide - a Systematic Review

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2321-2321 ◽  
Author(s):  
Fatimah Al-Ani ◽  
Martha L Louzada ◽  
Jose Maria Bastida Bermejo ◽  
Maria Victoria Mateos
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Expert Opinion ◽  
Advisory Board ◽  
Risk Of Bias ◽  
Phase Iii ◽  
High Dose ◽  
Pooled Data ◽  
High Dose Dexamethasone

Abstract Background Lenalidomide in combination to steroid therapy, including high-dose dexamethasone (RD), low-dose dexamethasone (Rd) or triple therapy of melphalan, prednisolone, lenalidomide (MPR), has shown to be an effective and well-tolerated treatment for patients with newly diagnosed multiple myeloma (NDMM) and relapsed refractory multiple myeloma (RRMM). Lenalidomide is associated with an increased risk of venous thromboembolism, and studies have consistently demonstrated the need for venous thromboembolism (VTE) prophylaxis in patients receiving these combinations. However, the optimal approach to thromboprophylaxis has not yet been established. Objective In this systematic review we sought to compare the efficacy of aspirin (ASA) or low molecular weight heparin (LMWH) in the prevention of VTE in patients with myeloma using lenalidomide- based therapy. Methods A systematic literature search strategy was used to identify potential studies on MEDLINE, EMBASE, and CENTRAL using an OVID interface. The methodological quality of the selected cohort studies was assessed according to Newcastle-Ottawa Quality Assessment Scale, and risk of bias of randomised controlled trials (RCTs) was assessed according to risk of bias assessment tool from the Cochrane Handbook. The primary outcome measure was the incidence rate of VTE while using ASA or LMWH. Results Out of 247 studies, 6 met our inclusion criteria with a total of 1126 participants including a total of 5 phase III RCTs, and one retrospective study. Overall, all studies show high quality: In 4 of the 5 RCTs type of randomization was clearly reported, outcome assessment was blinded, and withdrawal rates were reported, and the remaining RCT was an abstract. In 4 RCTs the intervention and comparator arms were related to anti-myeloma treatment regimens. Pooled data of studies of NDMM treated with lenalidomide based regimen with ASA prophylaxis show a VTE rate of 98 of 915 (10.7%) [95% CI: 8.86-12.88] (Table1). In NDMM and RRMM patients treated with lenalidomide, VTE rate on LMWH prophylaxis was 3 of 211 (1.4%) [95% CI: 0.48-4.09] (Table2). The relative risk (RR) of VTE in patients receiving ASA compared to LMWH was 7.5 (95% CI: 2.41-23.53, p =0.0005). Overall, the rate of VTE was 1.4 (95% CI: 1.14 - 1.69) per 100 patient-cycles of anti-myeloma treatment. A subgroup analysis on patient using ASA showed a similar risk of 1.5 (95% CI: 1.24 - 1.84).The incidence of VTE in those using ASA while on RD was 52 of 195 (26.6%) [95% CI: 20.9-33.2], while VTE rate in those receiving Rd was 27 of 262 (10.3%) [95% CI: 7.18-14.58] demonstrating a statistically significant higher risk for patients on RD [RR=2.5 (95% CI: 1.68- 3.96), p <0.0001]. Furthermore, VTE rate with MPR therapy while on ASA was 19 of 458 (4.1%) [95% CI: 2.67-6.38]. Pooled data of studies revealed that patients who received lenalidomide and dexamethasone alone (RD+Rd) had a significantly higher risk of VTE compared to those on MPR while on ASA (RR=6.4 [(95% CI: 4.11- 9.91), p< 0.0001]). Conclusion The study showed that the most frequent thromboprophylaxis of choice for patients with myeloma on lenalidomide-based therapy is ASA. However, ASA may not confer appropriate protection against VTE, especially in patients using high dose dexamethasone. On the other hand, the risk of VTE in patients receiving MPR and ASA was low and ASA may be a safe option for these patients. More studies comparing the safety of ASA to other anticoagulants such as LMWH or direct oral anticoagulants are warranted. Table 1. Rate of VTE using ASA in NDMM with different lenalidomide based regimens. Rx: treatment; 95% CI: 95% confidence interval. Study Design Rx N VTE rate: N (%) 95% CI Zonder, 2010 Rajkumar, 2010 Phase III RCT RD 195 52 (26.6) 20.9-33.2 Larocca, 2011 Rajkumar, 2010 Phase III RCT Rd 262 27 (10.3) 7.18-14.58 Palumbo, 2012 Stewart, 2014 Phase III RCT MPR 458 19 (4.1) 2.67-6.38 Total 915 98 (10.7) 8.86-12.88 Table 2. Rate of VTE using LMWH in myeloma patients (NDMM or RRMM) on lenalidomide-based regimen. 95% CI: 95% confidence interval. Paper Design Induction Setting N VTE rate: N (%) 95% CI Klein, 2008 Retrospective cohort RD RRMM 45 1(2.2) 0.39-11.57 Larocca, 2011 Phase III RCT Rd NDMM 166 2(1.2) 0.33-4.28 Total 211 3(1.4) 0.48-4.09 Disclosures Louzada: pfizer: Consultancy, Other: advisory board and expert opinion; janssen: Consultancy, Other: advisory board and expert opinion; Celegene: Consultancy, Other: advisory board and expert opinion.

Baseline Thrombophilic Alterations and Risk of Venous Thromboembolism in 266 Multiple Myeloma Patients Primarily Treated with Thalidomide and High-Dose Dexamethasone.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3997-3997
Author(s):  
Elena Zamagni ◽  
Lelia Valdre ◽  
Michela Cini ◽  
Cristina Legnani ◽  
Patrizia Tosi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Protein C ◽  
Low Dose ◽  
Autologous Transplantation ◽  
Phase Iii ◽  
High Dose ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Dose Warfarin

Abstract Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.

Melphalan-Prednisone-Thalidomide to Newly Diagnosed Patients with Multiple Myeloma: A Placebo Controlled Randomised Phase 3 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 78-78 ◽  
Author(s):  
Anders Waage ◽  
Peter Gimsing ◽  
Gunnar Juliusson ◽  
Ingemar Turesson ◽  
Peter Fayers
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Randomised Trial ◽  
High Dose ◽  
Time To Progression ◽  
Phase 3 ◽  
Double Blind ◽  
Free Survival ◽  
Starting Dose

Abstract Previously untreated patients with multiple myeloma were included in this double-blind randomised trial. Patients not eligible for high dose treatment in Norway, Sweden and Denmark were recruited. The study started in 2002 and accrual of patients stopped 1st of May 2007. Date of analysis was 1st of June 2007. The treatment was randomized between melphalan/prednisone/thalidomide and melphalan/prednisone/placebo. Starting dose of thalidomide was 200 mg escalating to 400 mg. There was no recommendation for prophylaxis for venous thromboembolism. Endpoints were overall survival, event free survival, response, time to progression and quality of life. Interim analysis for safety was performed in 2004 by an independent commitee. Altogether 362 patients with mean age 75 (49–92) years were included, 55% males. The incidence of venous thromboembolism in the blinded treatment arms was 7%. The study will be unblinded and results will be available September 2007.

Effect of Venous Thrombotic Events on Overall Survival in Multiple Myeloma: Analysis of Thrombotic Events Occurring in E4A03A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma, a Trial Coordinated by the Eastern Cooperative Oncology Group (ECOG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1740-1740 ◽  
Author(s):  
Susanna Jacobus ◽  
Shaji Kumar ◽  
Natalie Scott Callander ◽  
Rafat Abonour ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Low Dose ◽  
Standard Dose ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
The Impact

Abstract Background: Venous thrombotic events (VTE) are a common complication of therapy with the lenalidomide plus dexamethasone regimen. The incidence of VTE with RD is approximately 20%, and can be lowered with the use of effective thromboprophylaxis, avoidance of erythropoietin, and the use of lower doses of dexamethasone. The goal of this study was to determine the impact of VTE on overall survival of patients with newly diagnosed myeloma by studying events occurring in ECOG E4A03 phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1–21 every 28 days plus dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The trial initially did not mandate routine thromboprophylaxis, but recommended that such treatment be considered. After the first 264 patients were enrolled the trial was amended to require mandatory thromboprophylaxis of aspirin for all patients, with a recommendation to use stronger thromboprophylaxis with either warfarin (target INR 2–3) or low molecular weight heparin among patients in the RD arm. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 30 months. Overall VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 18.5% of patients; 25.6% in Arm A and 11.4% in Arm B. Rates for the first 4 cycles of treatment were 20.2% in Arm A and 8.2% in Arm B, P&lt;0.01. Rates did not change substantially before and after the prophylaxis amendment. A partial response (PR) or higher was seen in 82.1% of pts who experienced VTE compared with 74.6% of pts who did not experience VTE, P=0.19. Overall VGPR rates also were not inferior. Pts who had VTE, however, had significantly higher other grade 3–5 toxicities such as hyperglycemia (14.6% vs 7.5%, P=0.051), cardiac ischemia (4.9% vs 0.8%, P=0.002), non-neuropathic weakness (13.4% vs 6.4%, P=0.039), infection/pneumonia (17.1% vs 11.1%, P=0.138) and fatigue (18.3% vs 10.5%, P=0.060). In a Cox PH model, VTE status as a time-varying covariate was marginally significant: HR 1.54 95%CI (0.96–2.47), P=0.074, suggesting patients that develop VTE have a higher hazard of death. Conclusions: The occurrence of VTE may adversely affect the survival of patients with newly diagnosed myeloma receiving Rev-Dex. VTE was associated with a higher frequency of other serious adverse events. Prevention of VTE events is a priority. Besides lowering the dose of dexamethasone, studies investigating optimum thromboprophylaxis are needed.

A Randomized Phase III Trial of Lenalidomide Plus High-Dose Dexamethasone Versus Lenalidomide Plus Low-Dose Dexamethasone in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 799-799 ◽  
Author(s):  
S. Vincent Rajkumar ◽  
Susanna Jacobus ◽  
Natalie Callander ◽  
Rafael Fonseca ◽  
David Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
M Protein ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
High Dose Dexamethasone

Abstract Background: Lenalidomide has shown efficacy in patients with relapsed myeloma in phase II and III clinical trials, and is currently being investigated as initial therapy for the disease. We report results of a phase III trial comparing lenalidomide plus high-dose dexamethasone (Dex) versus lenalidomide plus low-dose Dex as first line therapy in newly diagnosed multiple myeloma (MM). Methods: Pts with newly diagnosed, untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO on days 1–21 every 28 days. In addition, patients in the high-dose Dex arm (Arm A) received Dex 40 mg on days 1–4, 9–12, and 17–20 PO every 28 days, while pts in the low-dose Dex arm (Arm B) received Dex 40 mg on days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was best response at 4 months on intent to treat basis. At 4 months pts could go off study for stem cell transplant or elect to continue therapy until progression. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If the serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses need to be confirmed at least 4 weeks apart. Patients with disease progression or not responding to lenalidomide within 4 months switched to thalidomide with the same dose of dexamethasone they were receiving (Arms C and D, respectively). An independent Data Monitoring Committee approved release of these results. Results: 445 pts were enrolled: 223 randomized to Arm A and 222 to Arm B. Median age was 65 yrs. Serious adverse event data based on expedited reporting (AdEERS) is available on all pts (see table). Common adverse events of Grade 3 or higher were thromboembolism (18.4% in arm A vs 5.4% in Arm B), infection/pneumonia (18.8% vs 9.0%) and hyperglycemia (5.8% vs 1.8%). Incidence of any grade 4 or higher toxicity was 22.0% in Arm A vs 12.6% in Arm B. Response data is being analyzed. Conclusions: Lenalidomide plus two different schedules of Dex was investigated in this phase III trial. Preliminary results suggest that toxicity rates are higher in the high-dose Dex arm. The differences in the response rates between the two arms will dictate future trials and clinical practice. Major Toxicties (AdEERS) Toxicity Arm A (n=223) Arm B (n=222) Cardiac ischemia (Grade &gt;=3) 2.7% 0.5% Hyperglycemia (Grade &gt;=3) 5.8% 1.8% Infection/Pneumonitis (Grade &gt;=3) 18.8% 9.0% Neuropathy (Grade &gt;=3) 0.9% 0.9% Thromboembolism (Grade &gt;=3) 18.4% 5.4% Any non-Hem toxicity (Grade &gt;=3) 53.4% 36.0% Any toxicity (Grade &gt;=4) 22.0% 12.6% Death (Grade 5) 4.5% 1.4%

Relapsed/Refractory Multiple Myeloma Patients Treated with Lenalidomide/Dexamethasone Who Achieve a Complete or near Complete Response Have Longer Overall Survival and Time to Progression Compared with Patients Achieving a Partial Response.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3598-3598 ◽  
Author(s):  
Jean-Luc Harousseau ◽  
Donna Weber ◽  
Meletios Dimopoulos ◽  
Marta Olesnyckyj ◽  
Zhinuan Yu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Partial Response ◽  
Adverse Events ◽  
Complete Response ◽  
Response To Therapy ◽  
Phase Iii ◽  
Time To Progression ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response

Abstract Background: There is ongoing debate about what would be considered an acceptable response to therapy in patients with relapsed/refractory multiple myeloma (MM). Lenalidomide (Len) is an immunomodulatory compound. Two recent phase III randomised trials (MM-009 and MM-010) showed Len in combination with Dexamethasone (Dex) provided significantly better overall response (OR), complete response (CR), overall survival (OS) and time to progression (TTP) compared with Dex alone in patients with relapsed/refractory MM. Approximately 60% of patients achieved an OR (61% in MM-009 and 60% in MM-010), including a CR in 15% (14% and 16%, respectively), Median OS was ≥29.5 months (29.5 and not yet reached) and median TTP was ≥11.1 months (11.1 months and 11.3 months, respectively). Here, we compare outcomes in patients with a CR or near CR (nCR) vs those with a partial response (PR). Methods: Data for patients who received Len/Dex in the MM-009 or MM-010 studies were pooled for this analysis. Patients received Len (25 mg/day on days 1–21 of every 28-day cycle) and Dex 40mg PO q.d. on days 1–4, 9–12, and 17–20 (for the first four cycles). After 4 cycles, Dex 40 mg/day was administered only on days 1–4. Response to therapy, TTP, OS, duration of response, and time to response, as well as adverse events were assessed. Response rate and TTP are based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Results: Of 353 patients treated with Len/Dex, 214 (61%) had PR or better (86 with CR/nCR; 128 with PR). Baseline characteristics were comparable between patient groups; most patients had stage III disease (63% vs 66%) and an Eastern Cooperative Oncology Group (ECOG) score of 0–1 (83% vs 90%). More patients with CR/nCR had received ≥2 prior antimyeloma regimens/stem cell transplant than patients with PR (88% vs 70%). Patients with CR/nCR had significantly longer median TTP and OS compared with those with PR (Table). The median duration of response was significantly higher among patients with CR/nCR (not yet reached vs 38 weeks; p&lt;0.001). Fewer patients with CR/nCR relapsed compared with those with PR (38% vs 43%). The times to CR/nCR and PR were comparable. The most common grade 3–4 adverse events were neutropenia (43% vs 41%), thrombocytopenia (13% vs 16%), anaemia (12% vs 9%) and pneumonia (12% vs 6%). Rates of febrile neutropenia were low (1% vs 3%). Conclusion: Len/Dex treatment is associated with longer OS and TTP in patients with relapsed/refractory MM who achieve a CR than in patients who achieve a PR. Len/Dex CR/nCR (n=86) PR (n=128) P value Median OS (weeks) &gt;132.7 &gt;118.1 &lt;0.01 Median TTP (weeks) &gt;65.1 46.0 &lt;0.001 (n=84) (n=126) Duration of response (weeks) NE 38 &lt;0.001 Time to response (weeks) 10.2 10.9 NE = not yet evaluable

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