Patient Outcomes By Prior Therapies and Depth Of Response: Analysis Of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: San Miguel Jesús F. , Weisel Katja , Song Kevin W. , Delforge Michel , Karlin Lionel , Goldschmidt Hartmut , Moreau Philippe , Banos Anne , Oriol Albert , Garderet Laurent , Cavo Michele , Ivanova Valentina , Alegre Adrian , Martinez-Lopez Joaquin , Chen Christine I. , Renner Christoph , Bahlis Nizar J. , Yu Xin , Teasdale Terri , Sternas Lars , Jacques Christian , Zaki Mohamed H. , Dimopoulos Meletios A. 
Published: October 2019

Abstract

Background
Patient (pt) survival after becoming refractory/intolerant to novel agent treatment (Tx) is short (Kumar 2012). Depth of response has been shown to predict favorable outcomes (Harousseau, 2010). POM is a distinct oral IMiD® immunomodulatory agent with 3 primary activities: direct anti-myeloma activity, stromal cell-support inhibition, and immune modulation (Quach, 2010). POM has been approved by the US FDA for RRMM pts with ≥ 2 prior Tx, including lenalidomide (LEN) and bortezomib (BORT), and progressive disease (PD) on or within 60 days of completion of the last line of Tx. The randomized phase 3 trial MM-003 demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) with an acceptable tolerability profile for POM + LoDEX vs HiDEX in pts with RRMM (San Miguel, EHA 2013).

Methods
Pts must have been refractory to last prior Tx (PD during Tx or within 60 days) and exhausted BORT and LEN after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1-4, 9-12, and 17-20. HiDEX was chosen as the comparator to isolate the effects of POM as at the time of trial design it was the standard salvage Tx for heavily pretreated pts. Tx continued until PD or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS, time to progression (TTP), overall response rate (ORR; ≥ partial response [PR]), and safety. The current analysis describes pt outcomes by prior Tx history and depth of response.

Results
302 pts were randomized to POM + LoDEX and 153 pts to HiDEX. Pt characteristics were well balanced between Tx arms. The median number of prior Tx was 5 (range, 2-17). Most pts (75%) were refractory to both BORT and LEN. POM + LoDEX significantly prolonged PFS vs HiDEX regardless of type or number of prior Tx (Table). OS favored POM + LoDEX for all subgroups analyzed. Importantly, significant OS benefits were observed in pts with ≤ 3 prior Tx and in pts who were refractory to LEN as last prior Tx. The ORR was consistently and significantly higher for POM + LoDEX vs HiDEX. The TTP for POM + LoDEX pts was similar in this trial vs that seen with their last prior LEN-based line of Tx (4.8 vs 6.2 months; P =.11). Additionally, LEN as the last prior Tx did not negatively impact PFS, OS, or ORR when compared with the intent-to-treat (ITT) population. In the POM + LoDEX arm, a total of 17 pts (6%) achieved a very good partial response or better, and 78 pts (26%) achieved PR as best response. Baseline characteristics were generally similar regardless of the degree of M-protein reduction. Analyses of the correlation between M-protein reduction and PFS and OS are ongoing and will be presented at the meeting.

Conclusions
In this heavily pretreated population, POM + LoDEX provided consistent efficacy regardless of number of prior Tx or prior Tx type. Significant OS benefits were observed for pts who received POM + LoDEX earlier in Tx and immediately following the development of LEN-refractory disease. Importantly, LEN as last prior Tx did not impact response, PFS, or OS vs the overall ITT population. POM + LoDEX should be considered a standard Tx option in RRMM pts.

Disclosures:
San Miguel: Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: POM is approved in the US but not in Europe. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Song:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Delforge:Celgene: Honoraria. Karlin:Celgene: Export board committee Other, Honoraria; Janssen: Honoraria. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Moreau:Celgene: Honoraria, Speakers Bureau. Oriol:Celgene: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Alegre:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Martinez-Lopez:Celgene: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Renner:Celgene: Consultancy, Honoraria, Travel support Other. Bahlis:Celgene: Consultancy, Honoraria, Research Funding. Yu:Celgene: Employment, Equity Ownership. Teasdale:Celgene: Employment, Equity Ownership. Sternas:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Dimopoulos:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.