Jay Mei

Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma

BACKGROUND Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma. METHODS We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival. RESULTS The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. CONCLUSIONS MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).

Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: results of a randomized phase III trial

The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).

Phase I study of single-agent CC-292, a highly selective Bruton's tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia.

B-cell receptor (BCR) signaling plays a key role in the pathogenesis of B-cell malignancies, mediating the survival and proliferation of malignant B cells.[1][1],[2][2] Clinical studies have shown that Bruton’s tyrosine kinase (BTK) inhibitors are well tolerated, with promising clinical activity.

Factors that influence health-related quality of life in newly diagnosed patients with multiple myeloma aged ≥ 65 years treated with melphalan, prednisone and lenalidomide followed by lenalidomide maintenance: results of a randomized trial

Abstract In the MM-015 trial, melphalan–prednisone–lenalidomide followed by lenalidomide maintenance (MPR-R) significantly prolonged progression-free survival versus melphalan–prednisone (MP) in newly diagnosed patients with multiple myeloma aged ≥ 65 years. Health-related quality of life (HRQoL), a secondary endpoint of MM-015, was also improved with MPR-R. This sub-analysis evaluated the impact of individual predictive factors on HRQoL. Patients completed HRQoL questionnaires at baseline, every third cycle and at progressive disease (PD)/treatment discontinuation. In a mixed-effects model female gender, advanced age and PD negatively affected HRQoL while better treatment responses showed positive effects. Compared to PD, HRQoL during MPR-R treatment was statistically significantly better in two of six preselected domains both of which were also clinically meaningful. HRQoL scores at end of treatment were all either improved or not statistically significantly different versus baseline. In conclusion, continuous treatment with MPR-R, which delays PD, appears to be associated with clinically meaningful improvements in HRQoL.

Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial)

Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial)

Safety and efficacy of different lenalidomide starting doses in patients with relapsed or refractory chronic lymphocytic leukemia: results of an international multicenter double-blinded randomized phase II trial*

Abstract The objective of this study was to evaluate the safety and efficacy of different lenalidomide starting doses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). CLL patients were randomized to receive lenalidomide at initial doses of 5, 10, or 15 mg/d (N = 103). Doses were escalated by 5 mg every 28-d up to a maximum of 25 mg/d; dose reductions in up to 5 mg decrements were permitted. The most common grade ≥3 adverse events (AEs) were neutropenia and thrombocytopenia. Ten patients died during therapy (four deaths considered as related to lenalidomide); 12 patients experienced second primary malignancies. The most common cause for treatment discontinuation was AEs. Overall response rates were similar across arms. Progression-free survival and overall survival rates were longer in patients who escalated treatment (to 15 or 20 mg/d) versus those who did not. Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL.

Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial

Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105).