Efficacy, Toxicity and Targets for Adoptive Cellular Therapy in Multiple Myeloma: A Systematic Review

Introduction Advancement in multiple myeloma (MM) has led to the development of adoptive cell transfer (ACT), an immunotherapeutic modality that utilizes body's own effector cells (T cells or Natural killer cells) to kill cancer cells. These include chimeric antigen receptor T cells (CAR-T cells), genetically modified T cell receptors (TCRs), activated Natural Killer (NK) cells and native T cells armed with bispecific antibodies. Potential antigen targets for TCRs in MM include B cell maturation antigen (BCMA), CD19, CD138, NKG2D, Ig kappa, LeY and SLMF7/CS-1, MAGE A3 and NY-ESO-1. The purpose of this review is to summarize various types of cellular therapies which are being tested in early phase clinical trials for treatment of MM. Methods We performed a comprehensive literature search (PubMed, EMBASE, AdisInsight and Clinicaltrials.gov) between January 2008 to December 2017, to identify early phase (I and I/II) trials of cellular therapy for the treatment of MM. We included studies involving cellular therapy, irrespective of the geo-location, age, sex or specific eligibility criteria. Results With initial search yielded 2537 phase I and phase I/II studies. After initial screening by two reviewers and categorization by mechanism of action, 37 clinical trials (CTs) that involved ACT were included. Out of the 37 trials, 18 are active or completed (Table 1) and 19 are recruiting subjects (Table 2). Most explored mechanism of action (21 CTs) in these trials is CAR T-cell therapy directed against B cell maturation antigen (BCMA). Anti-BCMA CART has shown promising efficacy of up to 100% objective response (OR) in a phase I trial (NCT03090659, n=22). In a phase I/II trial by Fan et al. (n=19), 6 (32%) patients showed complete response (CR), 12 (63%) developed near complete response (nCR), 1 (5%) achieved partial response (PR). In phase I trial by Ali et al. (2016, n=12), anti-BCMA CART cells led to stringent complete response (sCR) in 1 (8%) patient, very good partial response (VGPR) in 2 (16%), PR in 1 (8%) and stable disease (SD) in 8 (66%). Grade 3-4 cytokine release syndrome (CRS) was reported in 3 (25%) patients receiving high dose of CAR T cells (9 x 106 / kg in 2 patients and 3 x 106 /kg in 1 patient). Cohen et al., 2017 (n= 24) reported the objective response rate (ORR) defined as ≥PR in 11 (47%) patients. In 75% of patients with grade 3-4 CRS, tocilizumab/siltuximab was used to manage CRS. According to Garfall et al. (2018, n=10), administration of ant