Pomalidomide + Low-Dose Dexamethasone Following Second-Line Lenalidomide-Based Therapy in Relapsed or Refractory Multiple Myeloma: A Phase 2 Study Investigating Efficacy and Safety
Authors: Siegel David S. , Schiller Gary J. , Song Kevin W. , Agajanian Richy , Stockerl-Goldstein Keith , Kaya Hakan , Sebag Michael , Reu Fred J. , Malek Ehsan , Mouro Jorge L , Chung Weiyuan , Srinivasan Shankar , Qian Max , Rizvi Syed , Thakurta Anjan , Bahlis Nizar J. 
Published: October 2019

Abstract
Background: Pomalidomide (POM) in combination with low-dose dexamethasone (LoDEX) is approved for the treatment (Tx) of patients (pts) with multiple myeloma (MM) who have had ≥ 2 prior lines of therapy, including lenalidomide (LEN) and a proteasome inhibitor. Although LEN and POM are both IMiD® immunomodulatory agents, preclinical studies have shown that LEN is not cross-resistant with POM (Ocio et al, Leukemia, 2015) and that LEN-resistant myeloma cells remain sensitive to POM (Lopez-Girona et al, Leukemia, 2012). Furthermore, sub-analyses of the MM-002 and MM-003 trials demonstrated that POM + LoDEX had comparable efficacy in pts refractory to their last prior Tx with LEN as in the overall pt population (San Miguel et al, Lancet Oncol, 2013; Richardson et al, Blood, 2014). Here, we present an updated analysis of MM-014, a single-arm, phase 2 trial of POM + LoDEX in pts with MM relapsed or refractory to LEN-based second-line therapy.
Methods: Pts were ≥ 18 years old with a documented diagnosis of MM, measurable disease, 2 prior lines of Tx, and progressive disease after ≥ 2 cycles of second-line Tx with a LEN-based therapy. The Tx regimen was POM 4 mg/day on days 1-21 and LoDEX 40 mg/day (20 mg/day for pts > 75 years old) on days 1, 8, 15, and 22 of a 28-day cycle; thromboprophylaxis was mandatory. Responses were assessed using modified International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]). Secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Secondary primary malignancies (SPMs) were monitored and recorded as serious AEs regardless of relationship to Tx. Exploratory endpoints included measures to identify potential molecular, immune, and cellular biomarkers for POM + LoDEX response, resistance, or mechanism of action.
Results: Of 51 enrolled pts (N = 85 planned), 16 (31.4%) remain on Tx, and 35 (68.6%) discontinued from Tx (n = 20 due to PD, n = 7 due to withdrawal by pt, and n = 2 each due to adverse event [AE], death, lack of efficacy, and other reasons). The median age was 68.0 years, and most pts (92.2%) had an Eastern Cooperative Oncology Group performance status of ≤ 1; 34 pts (66.7%) were refractory to their last Tx with LEN, and 37 (72.5%), 2 (3.9%), and 1 (2.0%) pts had prior Tx with bortezomib, carfilzomib, or ixazomib, respectively. A total of 33 pts (64.7%) had prior stem cell transplant. The median duration of the most recent prior LEN-containing Tx was 24.6 months, and the median study follow-up time was 11.4 months.
The ORR was 31.4%, including 3.9% (n = 2) with complete response, 5.9% (n = 3) with very good PR, and 21.6% (n = 11) with PR. The clinical benefit rate (≥ minimal response) was 41.2%. Of the 16 pts who achieved ≥ PR, 12 (75.0%) have an ongoing response; median TTR in these pts was 1.9 months. The median DOR based on Kaplan-Meier estimates was not reached. The 1-year PFS, OS, and TTP rates were 60.2%, 87.4%, and 64.6%, respectively. Common (≥ 5%) grade 3/4 AEs included anemia (23.5%), neutropenia (13.7%), thrombocytopenia (9.8%), fatigue (7.8%), and infections (19.6%; including pneumonia [7.8%]). AEs of special interest (any grade) included pulmonary embolism (3.9%), deep vein thrombosis (2.0%), and peripheral sensory neuropathy (3.9%); no SPMs were observed.
The immune subset analysis showed a significantly elevated proportion of CD3+/CD8+ T cells after Tx (cycle 3, 5, day 1) compared with baseline (37.6% vs 30.5% of total lymphocytes; P < .01). A similar trend toward elevated proportions of CD3+ T cells (73.7% vs 66.6%) was observed; however, the difference was not significant. There was no significant change in CD3+/CD4+ T cells (35.9% vs 35.5%).
Conclusions: This updated analysis of the MM-014 trial demonstrates the safety and efficacy of POM + LoDEX in pts who were relapsed or refractory to their last prior Tx with LEN. Results suggest that POM + LoDEX can be used immediately following LEN-based therapy to treat pts with relapsed/refractory MM. The study has been amended to include a cohort of pts treated with POM + LoDEX + daratumumab. Investigations of additional biomarkers, high-risk genetic aberrations, clonal evolution, and minimal residual disease in MM-014 are currently underway.

Disclosures
Siegel: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Merck: Honoraria. Schiller:Incyte Corporation: Research Funding. Song:Otsuka: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria. Kaya:Celgene, Amgen, Takeda: Honoraria. Sebag:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reu:Celgene, Novartis and Takeda: Research Funding; Signal Genetics, Inc.: Consultancy. Mouro:Celgene: Employment, Equity Ownership. Chung:Celgene: Employment. Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Qian:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Bahlis:Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Onyx: Consultancy, Honoraria.