Ajay K. Nooka, MD, MPH, Associate Professor of Hematology and Medical Oncology at Emory University and Medical Director, Winship Research Informatics Shared Resource at Winship Cancer Institute, Atlanta, considered the presentations on bispecific T-cell–engaging antibodies in myeloma to be among the most exciting news at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition. It is particularly encouraging to see drug development outside of the B-cell maturation antigen (BCMA)-targeting domain, he said.
“Despite the stellar myeloma drug development over the past 2 decades, the majority of patients with myeloma still are not cured and eventually become resistant to therapies,” Dr. Nooka explained. BCMA-targeted therapies in myeloma have demonstrated significant clinical activity, leading to U.S. Food and Drug Administration approval of the antibody-drug conjugate belantamab mafodotin-blmf in August 2020. In addition, numerous ongoing clinical trials are showing “amazing activity” for antibody-drug conjugates, chimeric antigen receptor T cells, and bispecific T-cell–engaging antibodies aimed at this important target, he said.
Ajay K. Nooka, MD, MPH
“A dire unmet need exists, however, for understanding relapse on BCMA-targeted therapies, as well as identifying and leveraging newer myeloma targets, aimed at preventing relapse,” Dr. Nooka said. “A potential hypothesis for such relapse could be that low or no BCMA expression on myeloma cells may serve as a reservoir, and further expansion of this clone may lead to clinical relapse.”
Dual-Targeted Approach
A combination approach simultaneously targeting BCMA and a different antigen on the target cell might eliminate the residual low or negative expression of BCMA on the myeloma clone, according to Dr. Nooka. Two such novel agents were described in presentations at the 2020 ASH meeting.
G protein–coupled receptor family C group 5 member D (GPRC5D) is highly expressed on plasma cells across the spectrum of normal plasma cells, monoclonal gammopathy of unknown significance, smoldering myeloma, multiple myeloma, and plasma cell leukemia, but it is minimally expressed on other cells except hair follicles. Talquetamab is an IgG4 “duo body” that binds to GPRC5D and CD3, redirecting T cells to GPRC5D-expressing myeloma cells to mediate T-cell killing.
Similarly, another antigen, Fc receptor homolog 5 (FcRH5), is a type I membrane protein that is expressed on nearly 100% of myeloma cells. Cevostamab, a humanized IgG antibody, binds the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 and facilitates immunologic synapse formation, resulting in T-cell–mediated killing of myeloma cells.
This dual-targeted approach to enhancing the durability of responses to cellular therapy for myeloma has been demonstrated preclinically by targeting both BCMA and GPRC5D. However, clinical efficacy to prevent BCMA escape–mediated relapse has yet to be demonstrated. An early-phase trial combining talquetamab with teclistamab is currently underway, Dr. Nooka noted.
‘Enticing Approach’
The response rates of 69% with talquetamab and 53% with cevostamab given as monotherapy to heavily pretreated patients in the step-up dosing studies were presented at the 2020 ASH meeting (see full text discussion of both studies). Treatment was well tolerated, with little concern for severe cytokine-release syndrome.
In addition to their potentially greater antitumor activity, these off-the-shelf agents, Dr. Nooka said, “have an easy route of either subcutaneous administration or every-3-week dosing, with manageable cytokine-release syndrome (usually seen within the first cycle). Patients can be monitored at an academic center initially, with subsequent dosing given in the community setting, closer to patients’ homes. This seems to me to be a highly enticing approach,” he concluded.
DISCLOSURE: Dr. Nooka has received honoraria and served on advisory boards for Janssen, GlaxoSmithKline, Takeda, Oncopeptides, Sanofi Genzyme, Karyopharm, Bristol Myers Squibb, Adaptive Biotechnology, and Amgen.
