Final Results Of Phase II Study Of Pomalidomide (Pom) In GEP-Defined High Risk Relapsed and Refractory Multiple Myeloma (RRMM)
Authors: Usmani Saad Z , Stratton Kelly , Hansen Emily , Zhang Qing , Panozzo Susan B. , Petty Nathan M , Hoering Antje , Waheed Sarah , van Rhee Frits , Crowley John , Barlogie Bart 
Published: October 2019

Abstract

Background
Pom is an IMiD® immunomodulatory agent now FDA approved for treatment of patients who have received > 2 prior therapies, including lenalidomide (Len) and bortezomib (Bor), and have demonstrated disease progression on or within 60 days of completion of the last line of therapy. There is limited data evaluating efficacy of Pom in high risk RRMM. Herein, we are reporting the final report on a phase II clinical trial employing Pom in high risk RRMM with prior exposure and/or refractoriness to Len.

Methods
High risk RRMM was defined by having high risk on gene expression profiling (GEP70 or GEP80 signatures), elevated LDH, or having abnormal metaphase cytogenetics. Cycle #1 Pom was given at 4mg orally Days 1-21 q 4 weeks; in the absence of > PR by IMWG criteria after 2 cycles, dexamethasone (Dex, 4-20 mg orally q week) and/or Bor (1.3 mg/m2 IV days 1,4,8,11) and/or Vorinostat (Vor, 100-200 mg po days 1-21 q 4 weeks) could be added; in the absence of > PR by IMWG criteria after 4 cycles, cyclophosphamide (Cy, 300 mg/m2 q week) could be added. Primary endpoint was progression free survival (PFS) at 1 year, secondary endpoints included overall survival (OS), response rates and duration of response (DoR). Cox regression modeling was employed for univariate and multivariate analyses, Kaplan-Meier curves were used for OS and PFS. Best response was defined as the best response achieved while enrolled (regardless of prior progression, or relapse). Pharmacogenomic analyses using GEP were performed on 18 patients with paired baseline and 48hr post-Pom, using CD138-purified bone marrow plasma cells.

Results
71 patients with HRMM were enrolled between May 2010 and August 2012. Baseline patient characteristics included age > 65 years in 45%, cytogenetic abnormalities (CA) in 86%, GEP70 high risk in 14/34 (41%), GEP80 high risk in 28/34 (82%), extramedullary disease in 3/71 (4%) and secondary plasma cell leukemia in 2/71 (3%). 68/71 patients (96%) had a prior autologous stem cell transplant (ASCT), 30/71 (42%) had > 2 ASCT. Patients had received a median of 5 prior lines of therapy (range 1-10). There were 58 (82%) patients with Len-refractory (Len-R) MM, 64 (90%) with Bor-refractory (Bor-R) MM and 53 (75%) with dual-refractory (dual-R) MM prior to enrollment. 34 (48%) patients received > 6 cycles of treatment, 9(13%) received > 12 cycles. Patients who received > 6 cycles, had addition of Dex(67%), Bor+Dex(18%), Bor+Dex+Cy(12%), Bor+Dex+Cy+Vor(3%). As of July 2013, 45 patients (63%) discontinued therapy primarily due to progression or death. 20 (28%) patients achieved > PR as best response (1 Len-R, 2 Bor-R, 6 in dual-R), with median DoR for patients > PR of 1 month (range 0.5-18 months). 58 patients (5 Len-R, 8 Bor-R, 43 dual-R) had > stable disease, giving an overall disease control rate of 82%. Slight PFS benefit was observed in younger patients (HR=0.64, 95% CI: (0.39, 1.06), p=0.098). An increased risk for OS was observed among patients with LDH >= 190 U/L (HR=4.62, 95% CI: (2.28, 9.38), p<0.001), C-reactive protein >= 8 mg/L (HR=2.13, 95% CI: (1.03, 4.40), p= 0.041), hemogloblin < 10 g/dL (HR=3.47, 95% CI: (1.66, 7.27), p<0.001), and albumin < 3.5 g/dL (HR=2.83, 95% CI: (1.38, 5.79), p=0.005). The most common toxicities > grade 3 were leukopenia (75%), thrombocytopenia (60%), anemia (44%), infections (26%), dyspnea (19%), hypophosphatemia (20%) and hypocalcemia (19%). OS and PFS at 12 months were 63% and 13%, respectively. Pre/48hr-post POM GEP analyses showed that expression levels of 55 probe-sets (48 genes) were significantly changed in response to POM treatment (false discovery rate 0.01). These genes were related to cell adhesion, inflammatory and hypersensitivity response, such as GAS6, ITGB1, ITGB7, LYN, RAC1, PYCARD, CORO1B, F11R, and DKK1, all with higher expression values observed post POM. IRF4, one of the targets of cereblon (CRBN) previously reported to be critical for myeloma cell survival, was down-regulated post POM treatment (p=0.001,FDR=0.09), suggesting a unique CRBN-dependent anti-myeloma activity for POM

Conclusion
Pom demonstrates good anti-myeloma activity in a heavily pretreated, GEP-defined high risk RRMM in combination with other anti-myeloma drugs. Given the efficacy in patients with poor prognostic features, there is precedence to evaluate Pom as an IMiD of choice in combination with other novel agents in front line setting for GEP-defined high risk MM.

Disclosures:
Usmani: Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. van Rhee:Janssen Research & Development: Research Funding. Barlogie:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; MyelomaHealth: Patents & Royalties.