We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus ...dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, P<0.001), complete response rate (15.0 vs 2.0%, P<0.001), time to progression (median of 13.4 vs 4.6 months, P<0.001) and duration of response (median of 15.8 months vs 7 months, P<0.001) compared with dexamethasone-placebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low beta(2)-microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.
This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with ...lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response.
Patients (n=353) received lenalidomide (25 mg/day for 21 days of each 28-day cycle) plus dexamethasone (40 mg on days 1-4, 9-12, and 17-20 for four cycles, and only on days 1-4 after the first four cycles). Time to response, duration of response, time-to-progression, overall survival, and adverse events were investigated for patients who had a complete or very good partial response and compared with those of patients who had a partial response.
At the time of unblinding, 32% of patients had achieved a complete or very good partial response and 28% had a partial response. Half (50.5%) of the patients who had a partial response as their initial response achieved a complete or very good partial response with further treatment. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased with delayed achievement of a partial response (by cycle 4 versus later); however, it remained clinically significant. With an extended follow-up of 48 months, the median response duration, time-to-progression, and overall survival were longer in patients with a complete or very good partial response than in those with a partial response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, P<0.001; not reached versus 44.2 months, P=0.021, respectively). The benefit of a complete or very good partial response was independent of when it was achieved.
Continuing treatment with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provided deeper remissions and greater clinical benefit over time for patients in this study.
Abstract Background: In two randomized phase III trials (MM-009 and MM-010), lenalidomide plus dexamethasone significantly prolonged time to progression and overall survival (OS) in patients with ...relapsed/refractory multiple myeloma compared with dexamethasone alone. In both trials the treatment was continued until disease progression or unacceptable toxicity. We conducted a subanalysis to determine if continuing therapy after achieving ≥ partial response (PR) improved survival. Patients and Methods: Data were collected on 212 patients who were treated with lenalidomide plus dexamethasone and achieved ≥ PR. Kaplan-Meier survival estimates were compared between patients on continued treatment versus patients discontinuing therapy because of adverse events, withdrawal of consent, or other reasons. Time-dependent multivariate regression analyses were used to determine the benefit of continuing treatment with lenalidomide. Results: A total of 174 patients received continued treatment until disease progression or death, and 38 patients discontinued therapy without progression. There was a trend toward longer median OS in patients who continued therapy (50.9 months vs. 35.0 months; P = .0594). When controlling for the number of previous antimyeloma therapies, β2 -microglobulin levels, and Durie-Salmon stage (which adversely affected survival in these patients), continued lenalidomide treatment (HR, 0.137; 95% CI, 0.045-0.417; P = .0005) or each additional cycle of lenalidomide (HR, 0.921; 95% CI, 0.886-0.957; P < .0001) were both associated with longer survival. Conclusion: Continued lenalidomide treatment until disease progression after achievement of ≥ PR is associated with a significant survival advantage when controlling for patient characteristics. These findings should be confirmed in a prospectively designed trial.
Lenalidomide, an oral immunomodulatory drug that is similar to thalidomide but has a different safety profile, has clinical activity in relapsed or refractory multiple myeloma.
Patients in the United ...States and Canada who had received at least one previous therapy for multiple myeloma but who required additional treatment were randomly assigned to receive either 25 mg of lenalidomide or placebo on days 1 to 21 of a 28-day cycle. Both groups also received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles. After the fourth cycle, 40 mg of dexamethasone was administered only on days 1 to 4. Safety, clinical response, time to progression, and overall survival were assessed.
We assigned 177 patients to the lenalidomide group and 176 to the placebo group. Complete, near-complete, or partial responses occurred in 108 patients (61.0%) in the lenalidomide group and in 35 patients (19.9%) in the placebo group (P<0.001); complete responses occurred in 14.1% and 0.6%, respectively (P<0.001). The median time to progression was 11.1 months in the lenalidomide group and 4.7 months in the placebo group (P<0.001). Median overall survival times in the two groups were 29.6 months and 20.2 months, respectively (P<0.001). Grade 3 or 4 adverse events were reported in 85.3% of the lenalidomide group and in 73.1% of the placebo group; these events resulted in study discontinuation in 19.8% and 10.2%, respectively. Grade 3 or 4 neutropenia and venous thromboembolism were more common in the lenalidomide group than in the placebo group (41.2% vs. 4.6% and 14.7% vs. 3.4%, respectively; P<0.001 for both comparisons).
Lenalidomide plus dexamethasone is superior to placebo plus dexamethasone in patients with relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00056160 ClinicalTrials.gov.).
Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus ...dexamethasone in the treatment of relapsed or refractory multiple myeloma.
Of 351 patients who had received at least one previous antimyeloma therapy, 176 were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive placebo on days 1 to 21 of a 28-day cycle. In addition, all patients received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles and subsequently, after the fourth cycle, only on days 1 to 4. Patients continued in the study until the occurrence of disease progression or unacceptable toxic effects. The primary end point was time to progression.
The time to progression was significantly longer in the patients who received lenalidomide plus dexamethasone (lenalidomide group) than in those who received placebo plus dexamethasone (placebo group) (median, 11.3 months vs. 4.7 months; P<0.001). A complete or partial response occurred in 106 patients in the lenalidomide group (60.2%) and in 42 patients in the placebo group (24.0%, P<0.001), with a complete response in 15.9% and 3.4% of patients, respectively (P<0.001). Overall survival was significantly improved in the lenalidomide group (hazard ratio for death, 0.66; P=0.03). Grade 3 or 4 adverse events that occurred in more than 10% of patients in the lenalidomide group were neutropenia (29.5%, vs. 2.3% in the placebo group), thrombocytopenia (11.4% vs. 5.7%), and venous thromboembolism (11.4% vs. 4.6%).
Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00424047 ClinicalTrials.gov.).
This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% ...were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.
This subset analysis of data from two phase III studies in patients with relapsed or refractory multiple myeloma (MM) evaluated the benefit of initiating lenalidomide plus dexamethasone at first ...relapse. Multivariate analysis showed that fewer prior therapies, along with β2‐microglobulin (≤2.5 mg/L), predicted a better time to progression (TTP; study end‐point) with lenalidomide plus dexamethasone treatment. Patients with one prior therapy showed a significant improvement in benefit after first relapse compared with those who received two or more therapies. Patients with one prior therapy had significantly prolonged median TTP (17.1 vs. 10.6 months; P = 0.026) and progression‐free survival (14.1 vs. 9.5 months, P = 0.047) compared with patients treated in later lines. Overall response rates were higher (66.9% vs. 56.8%, P = 0.06), and the complete response plus very good partial response rate was significantly higher in first relapse (39.8% vs. 27.7%, P = 0.025). Importantly, overall survival was significantly prolonged for patients treated with lenalidomide plus dexamethasone with one prior therapy, compared with patients treated later in salvage (median of 42.0 vs. 35.8 months, P = 0.041), with no differences in toxicity, dose reductions, or discontinuations despite longer treatment. Therefore, lenalidomide plus dexamethasone is both effective and tolerable for second‐line MM therapy and the data suggest that the greatest benefit occurs with earlier use.
Introduction: The incidence of subsequent primary malignancies (SPM) associated with lenalidomide treatment of multiple myeloma (MM) outside the context of maintenance therapy post-melphalan is ...unknown. Three clinical trials reported modest, statistically significant increased risks of SPM associated with lenalidomide treatment in MM patients (Palumbo et al, N Engl J Med, 2012; Attal et al, N Engl J Med, 2012; McCarthy et al, N Engl J Med, 2012). Although these randomized trials are well controlled for potential confounders, they represent a unique population of patients and a specific juxtaposition of lenalidomide use with melphalan; as such, their results are not necessarily generalizable to the broader MM patient population. To investigate whether lenalidomide is associated with an increased risk of SPM in MM patients within a clinical setting in the United States, we conducted a retrospective cohort study of 1,653 MM patients treated with or without lenalidomide at the Moffitt Cancer Center (“MCC”) in Tampa, FL.
Methods: Patients treated for MM at MCC from 2004-2012 were identified through Moffitt’s enterprise wide data warehouse combining clinical information from several sources, including the Cancer Registry, electronic medical records and disease-specific databases. Among 1,653 MM patients, ages 18 and older, 51 cases of SPM were verified by two hematologists for confirmation of MM and SPM diagnoses. Incidence rates and 95% confidence intervals (CI) for SPM were estimated using a Poisson distribution. Cox proportional hazards ratios (HR) and 95% CIs were calculated to estimate the age-adjusted association between lenalidomide treatment and SPM in the overall cohort, and stratified by ISS. Additional details on lenalidomide treatment and potential confounders were obtained through medical chart abstraction for SPM cases and a subset of MM patients from the baseline cohort who had not developed SPM; these controls were matched to cases 2:1 on age at MM diagnosis (+/- 5 years), gender, follow-up time (+/- 6 months), and date of diagnosis (+/- 1 year). Associations between lenalidomide and SPM in the nested case-control analysis were estimated using odds ratios (OR) and 95% CIs adjusted for age at MM diagnosis, bone marrow transplantation, creatinine levels and personal history of cancer.
Results: Overall, 1,653 MM patients were followed for an average of 40 months, including patients treated with (n=846) or without (n=807) lenalidomide. Incident SPMs were observed for 15 patients treated with lenalidomide (0.55 per 100 person-years) and 36 patients treated without lenalidomide (1.27 per 100 person-years), corresponding to an HR of 0.44 (95% CI=0.24-0.80) (Figure 1). Of the 51 SPMs observed, 37 were solid tumors comprising 14 different types, including 9 and 28 in the lenalidomide and no lenalidomide groups, respectively (HR=0.55, 95% CI=0.15-0.69). Of the 14 hematological SPMs observed, 8 were in the lenalidomide group versus 6 in the no lenalidomide group (HR=0.90, 95%CI = 0.31-2.63). Similar associations between lenalidomide and SPM were observed for MM patients with ISS = 1 (HR=0.26, 95% CI=0.06-1.21) and for MM patients with ISS = 2 or 3 (HR=0.20, 95% CI=0.02-1.62). Of the 51 SPM cases and 102 matched controls included in the nested case-control analysis, 33.3% and 74.5% were treated with lenalidomide, respectively (adjusted OR=0.03, 95% CI=0.002-0.34). Similar associations were observed for lenalidomide given as part of first line treatment versus subsequent treatment, and for lenalidomide given alone or in combination with other drugs. (8 cases and 46 controls received melphalan in addition to lenalidomide.) There was no association between lenalidomide and SPM among those treated for >9.1 months (OR=0.05, 95% CI=0.01-0.43), the median treatment duration among controls.
Conclusion: Lenalidomide treatment was not associated with an increased risk of SPM among a large cohort of MM patients. It is important to note that in this clinical setting (in 2004-2012) the use of lenalidomide in combination with melphalan and in the maintenance setting was a rare event. This may be a critical factor in the contrast between the results of this study and in the increase in SPMs reported in randomized clinical trials.
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Rollison:Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide given as treatment for non-del(5q) MDS and/or multiple myeloma . Komrokji:Celgene: Consultancy, Research Funding. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fulp:Celgene, Inc.: Research Funding. Fisher:Celgene, Inc: Research Funding. Baz:Celgene: Research Funding; BMS: Research Funding; Millenium: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding. Olesnyckyj:Celgene: Employment, stock options Other. Kenvin:Celgene: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. Dalton:Celgene, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria. Shain:L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau; Envision/Celgene: Research Funding, Speakers Bureau.
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