Phase I/II Trial of Lenalidomide and High Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma
Authors: Shah Nina , Thall Peter F. , Fox Patricia S , Bashir Qaiser , Shah Jatin J. , Parmar Simrit , Kebriaei Partow , Nieto Yago , Popat Uday R. , Hosing Chitra M , Patel Krina K. , Lin Pei , Shpall Elizabeth J , Orlowski Robert Z. , Champlin Richard E. , Qazilbash Muzaffar H. 
Published: October 2019

Abstract
Introduction
While high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In the era of modern therapeutics, it is reasonable to consider that the advantages gained for relapsed patients in the conventional setting may also extend to auto-HCT. We thus hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control.
Methods
We conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier curves were used to estimate PFS and OS and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant.
Results
57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose limiting toxicities were seen, both at dose level 75mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 3%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). By day +90, 8 patients (14%) had achieved a CR, 25 (44%) a CR or very good partial response (VGPR), and 42 (74%) a CR, VGPR or partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. By day 180, 12 patients (21%) had achieved a CR. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 12.3 months (range 0.5-41), median PFS was 23.7 months and median OS had not yet been reached. The 1-year progression-free rate was 64% (95% CI: 49-75%). Multivariable Bayesian survival time models found both dose level and longer time between diagnosis and transplant to be significantly beneficial to both OS and PFS. In addition, high risk cytogenetics and LDH were significantly harmful to OS, and LDH was moderately harmful for PFS as well (Figures 1 and 2).
Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Our previous data has shown a median PFS of 12.3 months in a comparable population. Thus this treatment regimen yields an encouraging PFS, offering relapsed or refractory patients another option for disease control.
Figure 1. PFS by lenalidomide dose level (N=57, Events=24) Figure 1. PFS by lenalidomide dose level (N=57, Events=24)
Figure 2. OS by lenalidomide dose level (N=57, Deaths=12) Figure 2. OS by lenalidomide dose level (N=57, Deaths=12)

Disclosures
Shah: Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Off Label Use: This presentation discusses lenalidomide in a transplant preparative chemotherapy combination. . Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Champlin:Celgene: Consultancy, Research Funding.