Clinical Cancer Stem Cell Targeting In Multiple Myeloma: An Early Phase Trial Of The Anti-Cd19 Monoclonal Antibody Medi-551 In Combination With Lenalidomide And Dexamethasone

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LABackground: Cancer stem cells (CSCs) have been identified in many diseases, but it is unclear how their frequencies change during treatment with either standard or CSC targeting agents. In multiple myeloma (MM) CSCs can express B cell surface antigens, including CD19. We studied anti-CD19 MoAb, MEDI-551, in combination with lenalidomide (Len) + dexamethasone (Dex) (Rd) in newly diagnosed pts.Methods: In this single arm trial, newly diagnosed MM pts received 28 day cycles of Rd (Len 25mg PO, days 1-21 and Dex 40mg PO, weekly). Following 2 initial cycles of Rd, MEDI-551 (4mg/kg IV) was administered in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding pts continued on Rd. MM CSCs were serially measured by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates prior to any therapy (baseline), at end of cycle 2 (Rd alone), and cycle 4 (Rd+ MEDI-551). Peripheral blood CSCs were quantified by flow cytometry (CD19+CD27+ALDH+) at baseline and end of cycles 2, 4, 5, and 7. Clinical response and toxicity were assessed according to IMWG and CTCAEv4.0 criteria, respectively.Results: 17 newly diagnosed MM pts were enrolled on this study with a median age of 65 (range 34 - 73) yrs and ISS stage I (n = 11), II (n = 2), and III (n = 4). 7pts had t(4;14). 2 pts did not receive MEDI-551 due to PD and noncompliance. Responses of 15 evaluable pts included VGPR (n = 3), PR (n = 10), MR (n = 1), SD (n = 1) after cycle 2 (Rd) and VGPR (n = 6), PR (n = 8), and MR (n = 1) after cycle 4 (Rd+MEDI-551). There were no serious adverse events. Two patients experienced grade 2 infusion reactions after first MEDI551 dose. Bone marrow derived CFU-MM increased by a median of 2.5 fold (range 0.4-7.4) after cycle 2 (Rd) then decreased in 14/15 pts after cycle 4 (Rd+Medi-551; 0.48 fold, range 0.14-0.85) relative to baseline levels. In contrast, MM-CFU in 5 newly diagnosed MM pts receiving standard treatment with Rd continually increased 9.3 fold (range 4-14) at a median of 4 months (range 2-4) despite clinical responses ? PR in all pts. Circulating MM CSCs increased in 14/15 pts after cycle 2 (Rd; 1.6 fold, range 0.4-8.6) then fell in 13/15 after cycle 4 (Rd+MEDI-551; 0.6 fold, range 0.01-7.4). 10 pts completing Rd+MEDI-551 remain on Rd, and responses at the end of cycle 7 include CR (n = 1), VGPR (n = 8), and PR (n = 1). At end of cycles 5 and 7 (approx.55 and 110 days, after the last dose of MEDI-551) MM CSCs subsequently increased in 4/10 and 8/10 pts, respectively. Circulating MM CSCs increased by end of cycle 4 in 2 pts, and both experienced PD by end of cycle 7.Conclusions: The frequency of MM CSCs uniformly increased in pts receiving Rd suggesting that CSCs are enriched by standard therapy. In contrast, MM CSCs decreased in most pts following 3 doses of MEDI-551. Follow up is ongoing to determine the impact of MEDI-551 on long-term outcomes, but notably the 2 pts with increasing MM CSCs after MEDI-551 experienced PD. MM CSCs rebounded following the completion of MEDI-551 treatment. Combination of Rd+MEDI-551 was well tolerated suggesting that prolonged treatment may be safe and clinically beneficial.Citation Format: Carol Ann Huff, Douglas Gladstone, Ivan Borrello, Qiuju Wang, Christian Gocke, Shannon Marshall, Parthiv Mahadevia, Boyd Mudenda, Ronald Herbst, William Matsui. Clinical cancer stem cell targeting in multiple myeloma: an early phase trial of the anti-CD19 monoclonal antibody Medi-551 in combination with lenalidomide and dexamethasone. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT102.