Work

A phase I/II trial of the combination of lenalidomide, thalidomide and dexamethasone in relapsed and/or refractory multiple myeloma

Year: 2019

Type: article

Abstract: Lenalidomide is a second-generation immunomodulatory drug (IMiD) that now forms the backbone of myeloma treatment regimens in the frontline, maintenance, and relapsed and/or refractory settings. It has contributed, along with proteasome inhibitors (PIs), to a substantial improvement in outcomes in multiple myeloma patients over the last 10-15 years. However, disease eradication in myeloma patients remains elusive, and prognosis is poor in patients who develop resistance to novel agents. Therefore, developing strategies to overcome resistance to approved drugs such as lenalidomide remains an important focus in improving outcomes in patients with relapsed and/or refractory disease. Preclinical studies in lenalidomide-resistant myeloma models have suggested that lenalidomide treatment upregulates the canonical Wnt/β-catenin signaling pathway, and is an important mediator in the development of lenalidomide resistance.1 Because the first generation IMiD thalidomide inhibits Wnt/beta-catenin signaling,2 this provided the preclinical rationale of adding thalidomide to lenalidomide, to both enhance sensitivity to lenalidomide and overcome its resistance. Moreover, while thalidomide and lenalidomide are both IMiDs, they also have distinct properties which may be complementary. For instance, thalidomide may be a more potent inhibitor of angiogenesis, whereas lenalidomide is more potent in inhibiting pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and augmenting T-cell activation and proliferation.3 The dose-limiting toxicities of each drug are also relatively non-overlapping as thalidomide causes more peripheral neuropathy, whereas lenalidomide leads to greater myelosuppression. Based on this rationale, we conducted a phase 1/2 clinical trial of the combination of lenalidomide, thalidomide, and dexamethasone in relapsed and/or refractory multiple myeloma with ≥1 line of therapy, with the biologic and clinical hypothesis that the addition of thalidomide to lenalidomide will increase sensitivity and overcome resistance to the latter (NCT00966693). The phase 1 portion consisted of a Bayesian dose-finding design starting at dose level one of lenalidomide, thalidomide, and dexamethasone (Table S1), to determine the maximum tolerated dose (MTD) of the combination. In the phase two dose-expansion, patients were treated with lenalidomide, thalidomide, and dexamethasone at the MTD established in phase one of the study. The study sponsor was The University of Texas MD Anderson Cancer Center (UTMDACC), with study support provided by Celgene, Inc., and approved by the UTMDACC Institutional Review Board. All patients enrolled provided written informed consent. The data cut-off for this analysis was July 4, 2018. Patients were treated for up to eight cycles with the combination of thalidomide, lenalidomide, and dexamethasone on a 28-day cycle, after which patients would proceed with the maintenance phase. Dexamethasone dosing for cycles one to two was 40 mg orally on days 1-4, 9-12, and 17-20. For all subsequent cycles, dexamethasone was administered at 40 mg on days 1, 8, 15, and 22. If a complete response (CR) or very good partial response (VGPR) was achieved within the first eight cycles, then a patient could receive two additional cycles beyond best response, or up to eight cycles of treatment at the treating physician's discretion, and then proceed with the maintenance phase. The maintenance phase of the study consisted of lenalidomide, 21 out of 28 days, at the dose level tolerated at the completion of cycle 8, and thalidomide at 50 mg daily. Dexamethasone was continued in the maintenance phase at the treating physician's discretion. The primary objective of the phase one dose-finding was to determine the MTD of the combination of lenalidomide, thalidomide, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. The primary endpoint for the phase two dose-expansion part was the overall response rate (ORR, ≥PR), as assessed by International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints included progression free survival (PFS), time to best response, and overall survival (OS). For both parts one and two of the study, safety assessments were conducted each cycle, and toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. The Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) (see Supplementary Methods). Between October 21, 2009 and January 26, 2012, 64 patients enrolled and were treated in the study, and 13 patients failed screening. Of the 64 patients dosed, 15 patients were enrolled in the part one dose-finding phase, and 49 patients were enrolled in the part two dose-expansion. The baseline demographics of patients enrolled on study are summarized in Table S2. Patients had a median of four lines of prior therapy, including 11 patients (17%) refractory to thalidomide, 42 patients (66%) refractory to lenalidomide, 34 patients (53%) refractory to bortezomib, and 30 patients (47%) double refractory to lenalidomide and proteasome inhibitors (bortezomib and/or carfilzomib). High-risk cytogenetics defined as deletion 17p, t(4;14) and/or t(14;16), as per Revised International Staging System (R-ISS) criteria, were present in 11 of 60 patients (18%) with available cytogenetics/FISH data and present in 17 patients (28%) when expanding the definition of high-risk disease to include patients with +1q21, −1p, hypodiploidy, and/or deletion 13q by conventional cytogenetics. During the dose-finding phase of the study, no DLTs were observed at dose levels one and two. At dose level three (lenalidomide 25 mg, thalidomide 200 mg, dexamethasone 40 mg), three DLTs were observed in nine patients dosed. Based on the Bayesian dose-finding algorithm, dose level three had the smallest absolute value of (posterior mean of pi-pT) among all the tried doses i for which Ti = 0, and therefore would be selected as the MTD. However, five out of nine patients treated at dose level three required dose reductions to dose level two in subsequent cycles of treatment due to adverse events. Therefore, based on the safety data from the dose-finding phase, dose level two of lenalidomide 25 mg, thalidomide 100 mg, dexamethasone 40 mg was determined to be the MTD and selected for the phase two dose-expansion cohort. Among 52 patients dosed at the MTD with lenalidomide 25 mg, thalidomide 100 mg, dexamethasone 40 mg, the median number of cycles on therapy was four (range, 1-56), and the median time on therapy was 4.1 months (range, 0.2-57.2). The most common treatment-emergent hematologic grade 3/4 AEs included neutropenia (31%/4%), leukopenia (21%/2%), anemia (19%/2%), and thrombocytopenia (13%/8%) (Table S3). The most common treatment emergent non-hematologic grade 3/4 AEs included fatigue (35%/6%), pneumonia (23%/4%), and dyspnea (21%/0%). Treatment-emergent peripheral neuropathy occurred in 67% of patients, of which grade three and four events occurred in 13% and 2% of patients, respectively. Reasons for treatment dose-reduction and discontinuation are available in the Supplementary Material. A total of 49 of 52 (94%) patients were evaluable for response with at least one post-treatment myeloma disease assessment. The ORR was 52%, which included 27% PR, 17% VGPR, and 8% CR/sCR (Figure 1A). The median number of cycles until best response was two (range 1-21 cycles). The ORR in patients previously refractory to lenalidomide, refractory to bortezomib, and dual refractory to lenalidomide and PI therapy were 33%, 45%, and 30%, respectively. The ORR in patients previously with one line of prior therapy, two lines of prior therapy, and ≥3 lines of prior therapy were 100%, 67%, and 45%, respectively. Median duration of response was 6.1 months among the 27 patients who achieved ≥PR. Median progression free survival in patients treated at the MTD was 4.1 months (95% CI, 3.7-7.4 months, Figure 1B). In patients with one to two lines of prior therapy, ≥3 lines of prior therapy, and R-ISS high-risk Cg/FISH, median PFS was 7.6 months (95% CI, 4.2-NA months), 3.9 months (95% CI 2.8-6.4 months), and 4.0 months (95% CI 3.0-8.0 months), respectively (Figure 1C and D). Median overall survival was 20 months (95% CI, 12.5-37 months, Figure S1), with a median follow-up time of 81.2 months (range: 78.0-89.2 months) for the eight censored observations. In summary, we report the safety and efficacy of a phase 1/2 dose finding and expansion study of the combination of lenalidomide, thalidomide, and dexamethasone in relapsed and/or refractory multiple myeloma. The MTD and recommended phase two dose was thalidomide 100 mg on days 1-28, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg. Notably, a number of novel agents have gained regulatory approval for the treatment of relapsed and/or refractory myeloma since the study was initiated including pomalidomide, carfilzomib, panobinostat, ixazomib, elotuzumab, and daratumumab. While the ORR in lenalidomide-refractory patients in this study is comparable to pomalidomide and dexamethasone (30%) and single-agent daratumumab (28%),4 novel triplet combinations such as daratumumab, pomalidomide, and dexamethasone5; daratumumab, bortezomib, and dexamethasone6; and carfilzomib, pomalidomide,7 and dexamethasone have all demonstrated much higher ORRs of 78%, 81%, 50%, respectively in lenalidomide-refractory patients. The safety, tolerability, and efficacy of these novel triplet combinations have now established them among the current preferred regimens in treating lenalidomide-refractory patients. Therefore, the combination of lenalidomide, thalidomide, and dexamethasone may have more limited applicability in the context of newer drugs and combinations that are available today. However, in patients where access to novel agents is limited or when an all-oral regimen is preferred, the combination of lenalidomide, thalidomide, and dexamethasone represents a potential treatment option for lenalidomide-refractory myeloma patients in this setting. This work was supported in part by The MD Anderson Cancer Center Support Grant (P30 CA016672). H.C.L. would like to acknowledge support from the Baer Family Fund and Goff-Street Foundation. The authors would like to thank members of the MD Anderson Plasma Cell Dyscrasias Clinical Research Team including Marcus Austin, Brandon Crumpton, Maureen Daily, Claudia Morales de Partovi, Jasper Olsem, Kinishia Smith, Amishi Vora, and Kathleen Wall for providing study support with data collection and management. H.C.L. has received consulting fees from Amgen Inc, Celgene Inc., Janssen Pharmaceutical, and Takeda Pharmaceutical and research support from Amgen Inc, Celgene Inc., Daiichi Sankyo, Janssen Pharmaceutical, and Takeda Pharmaceutical. J.J.S. is an employee of Karyopharm Therapeutics. M.L.W. has received research support from Pharmacyclics LLC, an AbbVie Company, and Janssen and honorarium from Janssen Pharmaceutical. S.K.T. has received consulting fees from Amgen Inc. and research support from Acerta Pharma, Amgen Inc., Array BioPharma, Bristol-Myers-Squibb, Celgene Inc., and Idera Inc. R.Z.O. has received consulting fees from Amgen Inc, Bristol-Myers-Squibb, Celgene Inc, Janssen Pharmaceutical, Kite Pharma, Sanofi and Takeda Pharmaceutical and research support from Amgen Inc, BioTheryX and Spectrum Pharmaceuticals. L.F., A.M., R.J.J., E.T.W., R.A., and D.M.W. reports no conflicts of interest. H.C.L. treated patients, collected data, analyzed data, and wrote the manuscript. J.J.S. designed the study, analyzed data, and treated patients. L.F. designed the study and performed biostatistical analysis. M.L.W., R.A., S.K.T., R.Z.O. treated patients. A.M., R.J.J., and E.T.W. collected data. D.M.W. designed the study, treated patients, and analyzed data. All authors reviewed and approved the manuscript. Table S1. Treatment Dose Levels and Schedule (28-day cycle). Table S2. Baseline Patient and Disease Characteristics Table S3. Adverse Events at MTD Figure S1. Overall Survival. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Source: American Journal of Hematology

DOI: 10.1002/ajh.25633