Long-term health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma receiving lenalidomide and dexamethasone.

The FIRST trial demonstrated that continuous therapy with lenalidomide and dexamethasone (Rd) prolongs overall survival (OS) and improves health-related quality of life (HRQoL) during the first 18 months of therapy in newly diagnosed multiple myeloma (NDMM) patients. However, patient-reported HRQoL data were not collected after 18 months. We therefore estimated HRQoL scores based on time-varying data collected during progression-free follow-up after 18 months. During the initial 18 months of Rd, observed changes from baseline were within the 95% confidence interval of the predictive models at 33 of 35 time points across 7 HRQoL scores. Predicted scores after 18 months of therapy showed that observed HRQoL improvements during therapy were maintained or improved. Therefore, the survival gain observed with Rd does not come at a cost of declining HRQoL during continuous therapy beyond 18 months, supporting long-term Rd as a standard of care for initial myeloma therapy.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

[Lenalidomide and low-dose dexamethasone therapy for Japanese patients with newly diagnosed multiple myeloma: updated results of the MM-025 study].

In a Japanese phase II study (MM-025), the efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) were confirmed at a median follow-up of 14.2 months in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem cell transplantation. In the present report, we analyzed the follow-up data from the abovementioned study. Treatment was stopped for all 26 patients after a median follow-up of 31.3 months, and the median treatment duration was approximately 25 months. The overall response rate was 87.5%, and the complete response rate was 20.8%. The median duration of response and progression-free survival were 30.7 and 31.6 months, respectively. The median overall survival has not yet been reached. At least one grade 3/4 adverse event was experienced by 23 patients (88.5%), and 18 patients (69.2%) experienced serious adverse events. There were no treatment-related deaths. Therefore, the efficacy and safety of Rd were confirmed in transplant-ineligible Japanese patients with newly diagnosed multiple myeloma at the present follow-up period.

Continuous treatment with lenalidomide and low-dose dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma in Asia: subanalysis of the FIRST trial.

The phase 3 FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial demonstrated that lenalidomide plus low-dose dexamethasone (Rd) until disease progression (Rd continuous) is an effective treatment option for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Given genetic differences between Asian and Western populations, this subanalysis of the FIRST trial examined the safety and efficacy of Rd (given continuously or for 18 cycles [Rd18]) and MPT (melphalan, prednisone, thalidomide) in 114 Asian patients from Mainland China, South Korea and Taiwan. Efficacy and safety with Rd continuous in Asian patients were consistent with those in the overall study population. The overall response rates were 77·8% for Rd continuous, 57·5% for MPT and 65·8% for Rd18. The risk of progression or death was reduced by 39% with Rd continuous versus MPT and by 35% with Rd continuous versus Rd18. Rd continuous improved the 3-year survival rate compared with MPT (70·2% vs. 56·4%) and Rd18 (58·1%). Common grade 3/4 adverse events in the Rd continuous and MPT arms were neutropenia (25·0% vs. 43·6%), infection (19·4% vs. 28·2%) and anaemia (19·4% vs. 15·4%), respectively. Thromboembolic event rates were low, and no second primary malignancies were observed. Rd continuous is safe and effective in transplant-ineligible Asian patients with NDMM.

Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial.

Purpose This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age. Patients and Methods Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v > 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators. Results Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P < .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P < .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous-treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions. Conclusion Results support Rd continuous treatment as a new standard of care for stem-cell transplantation-ineligible patients with newly diagnosed MM of all ages.

Lenalidomide and low-dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma: A phase II study.

In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation.

Impact of renal impairment on outcomes with lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 trial in transplant-ineligible patients with multiple myeloma.

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.

Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.

BACKGROUND: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS: As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma.

PURPOSE: Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its efficacy in a wide range of hematologic malignancies, we conducted a phase II trial (NHL-001) of single-agent lenalidomide in indolent non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety. RESULTS: Forty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively). CONCLUSION: Oral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.

Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with a poor prognosis following first relapse. We present a subgroup analysis of an open-label phase II trial investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL. Oral lenalidomide 25 mg was self-administered once daily on days 1-21 every 28 d for up to 52 weeks, according to tolerability or until disease progression. The primary endpoint was overall response rate (ORR) and secondary endpoints were duration of response, progression-free survival (PFS) and safety. Among 15 patients with MCL with a median disease duration of 5.1 years and a median of four prior treatments, the ORR was 53%. Three patients (20%) had a complete response and 5 (33%) had a partial response. The median duration of response was 13.7 months and median PFS was 5.6 months. Four of five patients who relapsed after transplantation and two of five patients who previously received bortezomib responded to lenalidomide. The most common grade 4 adverse event was thrombocytopenia (13%) and the most common grade 3 adverse events were neutropenia (40%), leucopenia (27%) and thrombocytopenia (20%). In conclusion, oral lenalidomide monotherapy is well tolerated and active in relapsed or refractory MCL.

Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma.

PURPOSE: The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL. PATIENTS AND METHODS: Patients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety. RESULTS: Forty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%). CONCLUSION: Oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.