Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study

Abstract

Background Lenalidomide is an effective treatment for myeloma and has been studied in a range of combination regimens worldwide. The results of these studies have suggested that prolonged exposure to lenalidomide is important to improve outcomes both as a maintenance agent post-transplant (Attal M et al NEJM 2012, McCarthy et al NEJM 2012) and in the transplant ineligible population (Palumbo A et al NEJM 2012, Benboubker L et al NEJM 2014). In the Myeloma XI study, the largest of its kind, we explored the use of oral lenalidomide continued to disease progression compared to no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations. Here we present the results of this maintenance randomization, which demonstrate the efficacy and safety of maintenance lenalidomide. Methods The Myeloma XI study is a Phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages and includes a maintenance comparison of lenalidomide versus no maintenance. Newly diagnosed symptomatic myeloma patients both TE and TNE were enrolled to the study. Induction treatment in both pathways was with thalidomide or lenalidomide plus cyclophosphamide and dexamethasone, with appropriate dose reductions for TNE patients. TE patients proceded to a standard melphalan 200mg/m2 transplant. Patients were randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide was administered at a dose of 10mg daily in 21/28 day cycles until disease progression. Dose adjustments for renal impairment and following AEs were permitted. The primary endpoints for the maintenance randomization were progression-free (PFS) and overall survival. Secondary endpoints included response, toxicity and PFS2. Time-to-event endpoints were measured from maintenance randomization. This abstract summarizes a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 26 months [IQR 12-41]. Results A total of 1550 patients, 828 TE and 722 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=857) and no maintenance (n=693). The arms were well-balanced for clinical features and response to induction therapy (e.g. ISS stage III: 27% vs 23%, VGPR/CR: 73% vs 73%). The maintenance randomization has met its primary endpoint demonstrating a 55% reduction in risk of progression or death for lenalidomide compared to no maintenance (HR 0.45 [95%CI 0.39-0.52], median PFS 37 vs 19 months, p<0.0001) This significant improvement was observed in each pathway TE: HR 0.46 [95%CI 0.36-0.58], median PFS 60 vs 28 months, p<0.0001. TNE: HR 0.44 [95%CI 0.36-0.53], median PFS 26 vs 12 months, p<0.0001. The benefit of lenalidomide maintenance on PFS persisted across risk subgroups and was independent of induction therapy and response. An exploratory analysis of 132 patients stopping lenalidomide treatment for reasons other than disease progression (91 toxicity, 28 patient choice and 13 clinician choice) shows that patients receiving greater than 12 months of treatment have an improved median PFS compared to those stopping earlier (HR 0.35 [95%CI 0.18-0.68], 49 vs 31 months, p<0.0015). At this time 445 patients continue to receive lenalidomide maintenance on study. Of patients who have stopped therapy, only 21.5% did so due to toxicity. Relevant grade 3/4 adverse events were: neutropenia 35%, thrombocytopenia 7.4%, anaemia 4.4%, peripheral neuropathy 1.4%. Venous thromboembolism occurred in 2.3%. Second primary malignancy (SPM) data was collected and the relationship with maintenance therapy reviewed. 72 SPM were observed (24 no maintenance, 48 lenalidomide). Haematologic malignancy crude incidence was 0.3% vs. 0.9%. While we found a slight excess of SPM in older patients these were mostly non-invasive and did not impact the outcome benefit demonstrated. Conclusion The use of maintenance lenalidomide treatment results in highly significant improvements in PFS for patients of all ages and should be standard of care. On behalf of the NCRI Haem-Onc CSG Disclosures Jackson: Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Davies:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Pawlyn:Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:Janssen: Consultancy; Novartis: Other: Travel support; Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Celgene: Honoraria, Other: Travel support. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Kaiser:BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Chugai: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Morgan:Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding.

Post‐transplant consolidation plus lenalidomide maintenance vs lenalidomide maintenance alone in multiple myeloma: A systematic review

“…Baseline characteristics of included studies are summarised in Table . Patients were stratified according to the myeloma International Staging System (ISS) in 7 studies; cytogenetic risk profile in 4; age in 3; response after transplant in 1; response after induction in 1; and 3 RCTs did not provide details on patients’ stratification criteria . Of note, 4 phase II studies included a single arm only …”

“…Overall, all studies used novel agents such as proteasome inhibitors and IMiDs for the induction phase: 3 studies used proteasome inhibitors; 5 used IMiDs; 5 used a combination of both; and 1 study did not state the induction therapy used . Of note, induction treatment consisted of LEN plus dexamethasone (RD) in 4 and RVD in 3 .…”

“…LEN dose used ranged between 10 and 15 mg daily in 4 studies, whereas the remaining 10 RCTs used a fixed 10 mg daily dose. In addition, LEN was given for 1 year in 3 studies and for 2 years in 1 study, while in the remaining 10 studies, patients received LEN maintenance until disease progression . Participants received post‐transplant consolidation therapy prior to LEN maintenance in 7 studies, including LEN 25 mg for 2 cycles in 2, LEN plus prednisolone for 4 cycles in 1, KRD for 4 cycles in 1 and RVD for 2 cycles in 2 studies; Stadtmauer et al study also used RVD consolidation, but the number of cycles was 4 …”

“…Of the 8 phase III RCTs, 5 were open label studies and 2 were double blinded RCTs, and no data were available for the remaining study . The intervention and comparator arms were related to transplant vs no transplant in 3 studies, LEN maintenance vs no maintenance in 3; and 1 study compared LEN maintenance vs no maintenance in both transplant and no transplant patients’ groups . The StaMINA trial was a phase III RCT that randomised NDMM patients following transplant into 3 arms: RVD consolidation (n = 254); or tandem ASCT consolidation (n = 247); or no consolidation (n = 257).…”

“…More importantly, data in some abstracts might not represent the final results of the analysis. In this respect, 3 of the included studies are yet to present their updated analysis . Moreover, non‐publication of ongoing studies of the same context may have affected our results, such as EMNO2/HO95 MM trial by Cavo et al ( J Clin Oncol 34, 2016 (suppl; abstr 8000) ).…”