Novel Combination Therapy Targets Cancer Stem Cells in Multiple Myeloma

Cancer stem cells (CSCs) have been identified in many diseases, including multiple myeloma (MM), but it is unclear how their frequencies change during treatment with either standard or CSC-targeting treatments. According to a study of 17 patients with newly diagnosed MM presented at the AACR Annual Meeting, the novel anti-CD19 monoclonal antibody MEDI-551, in combination with standard lenalidomide and dexamethasone (Rd), was well tolerated and decreased the frequencies of CSCs. Results from the single-arm trials also suggested that prolonged treatment with MEDI-551 was safe and had clinically benefit.

MEDI-551 works by targeting CD19, and, the study authors, led by Carol Ann Huff, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, explained, “In multiple myeloma, CSCs can express B-cell surface antigens, including CD19.”

The patients had a median age of 65 years (range = 34-73 years). Two patients did not receive MEDI-551 due to progressive disease (PD) and non-compliance, leaving 15 evaluable patients.

Patients enrolled in the trial received two initial 28-day cycles of Rd: lenalidomide 25 mg administered orally twice daily on days one through 21 and dexamethasone 40 mg administered orally twice daily once per week. Following these two cycles, MEDI-551, at 4 mg/kg, was administered intravenously on days one through eight of cycle three and day one of cycle four. Patients who responded to this treatment then continued on Rd therapy.

The researchers serially measured myeloma CSCs by quantifying the growth of colony-forming units of MM (CFU-MM) from marrow aspirates at baseline, the end of cycle 2 (Rd alone), and the end of cycle 4 (Rd + MEDI-551).

Peripheral blood CSCs were quantified by flow cytometry at baseline and at the end of cycles two, four, five, and seven. Clinical response and toxicity were assessed according to the International Myeloma Working Group and the Common Terminology Criteria for Adverse Events v4.0 criteria, respectively.

At the end of cycle two, 10 patients had a partial response (PR), three had very good partial responses (VGPR), one had stable disease (SD), and one had a molecular response (MR). After cycle four, eight patients had PR, six had VGPR, and one had MR.

The authors observed no serious adverse events, but two patients experienced grade 2 infusion reactions after the first dose of MEDI-551.

Relative to baseline levels, bone marrow derived CFU-MM increased by a median of 2.5-fold (range = 0.01-7.4-fold) after cycle two, then decreased in 14 patients after cycle four, when MEDI-551 was administered (median = 4.8-fold; range = 0.14-0.85-fold). However, in five patients who received standard treatment with Rd, CFU-MM increased 9.3-fold (range = 4-14-fold) at a median of four months (range = 2-4 months), despite clinical responses of PR or better in all patients.

Similarly, following cycle two with Rd, circulating myeloma CSCs increased by 1.6-fold (range = 0.4-8.6-fold) in 14 patients, then decreased 0.6-fold (range = 0.01-7.4-fold) in 13 patients after cycle four.

Ten patients who completed the combination therapy regimen remained on Rd and, at the end of cycle seven, eight patients achieved VGPR, one a complete response, and one a PR. At the end of cycle five (approximately 55 days after the last dose of MEDI-551), myeloma CSCs subsequently increased in four of 10 patients; at the end of cycle seven (approximately 110 days after the last dose of MEDI-551), eight of 10 patients had increased myeloma CSCs.

Circulating myeloma CSCs increased by the end of cycle four in two patients, and both experienced PD by the end of cycle seven.

“The frequency of myeloma CSCs uniformly increased in patients receiving Rd, suggesting that CSCs are enriched by standard therapy,” the authors noted. Following three doses of MEDI-551, however, myeloma CSCs decreased in most patients. “Notably, the two patients with increasing myeloma CSCs after MEDI-551 experienced PD,” they added, suggesting that myeloma CSCs rebound following the completion of MEDI-551 treatment and prolonged treatment might be necessary. Follow-up to assess the long-term outcomes associated with MEDI-551 is ongoing.


Reference

Huff CA, Gladstone D, Borrello I, et al. 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 CT102. Presented at the AACR Annual Meeting, April 19, 2016; New Orleans, LA.

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