Immunotherapy Trials in High-Risk Smoldering Multiple Myeloma

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The major recent advances in multiple myeloma (MM) therapy have centered around immunotherapies targeting B cell maturation antigen (BCMA), utilizing either chimeric antigen receptor T-cell therapy (CAR T-cells) or bispecific antibodies. There are currently 2 CAR T-cell therapy products approved for relapsed and refractory MM patients who have had 4 or more lines of therapy. These include the CAR T products idecabtagene vicleucel (ide-cel, Abecma) and ciltacabtagene autoleucel (cilta-cel, Carvykti) and bispecific antibody (teclistamab). While these therapies have led to unprecedented outcomes in patients with heavily pretreated MM, they may have even greater potential benefit if utilized early when the patient’s immune system is healthier and less exposed to conventional therapy. Indeed, ongoing trials are currently evaluating the benefit of these immunotherapies in earlier lines of therapy, with some data already demonstrating improved efficacy without any new or concerning safety signals.  

The Center for Early Detection and Interception of Blood Cancers at Dana-Farber Cancer Institute is dedicated to patients with precursor hematologic malignancies. The goal of the Center is to increase early detection efforts, improve risk stratification, and prevent progression to symptomatic MM by offering early therapeutic intervention with innovative clinical trials. Thus, we have aimed to study these immunotherapies in patients with high-risk smoldering myeloma (SMM) at considerable risk of progression to symptomatic MM based on validated risk stratification models. 

Immuno-PRISM (NCT05469893) is a phase 2 randomized, platform study evaluating the effectiveness of various novel bispecific antibody treatments in preventing disease progression in patients with high-risk SMM. This trial will compare the standard lenalidomide and dexamethasone therapy to the highly effective bispecific antibodies teclistamab (targeting BCMA) and talquetamab (targeting GPRC5D). This is a fixed duration treatment that will be administered for 2 years. This is the first study to evaluate the role of bispecific antibodies in high risk SMM and is currently enrolling patients.

CAR-PRISM (NCT05767359) is a single-arm study of the highly effective CAR T-cell therapy, cilta-cel in patients with high-risk SMM. The patients will receive standard lymphodepletion chemotherapy followed by one-time cilta-cel infusion. This will be the first trial to study CAR T-cells in high-risk SMM, with the goal to eradicate the disease at an early stage and to demonstrate safety of this treatment in this at-risk population.

Our hope is that with these advances in MM therapy, patients at risk of developing symptomatic MM can be spared the morbidity that comes from this disease, by delivering highly effective immunotherapies earlier in the disease course.