1. Fuerst, Mark L.

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NEW YORK CITY-The future of multiple myeloma therapy lies with immunotherapy, according to an expert on cancer immunotherapy.

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"Immunotherapies are truly becoming the next-generation therapies for multiple myeloma," said Adam Cohen, MD, of the Abramson Cancer Center, and Assistant Professor of Medicine and Director of Myeloma Immunotherapy at the University of Pennsylvania, Philadelphia, at a session on immune-oncology at Lymphoma & Myeloma 2017: An International Congress on Hematologic Malignancies. He noted the immune microenvironment is immunosuppressive, which makes this disease susceptible to cellular therapy with chimeric antigen receptor (CAR) T-cell therapy, novel bispecific T-cell engagers (BiTES), and antibody drug conjugates.


CAR T-Cell Therapy for Myeloma

CAR T-cell therapy combines recognition of the domain of an antibody with the signaling domain of the T cell. Using gene transfer, for example, with lentiviral vector, researchers can stably express CARs on T cells and confer novel antigen specificity. The addition of co-stimulatory domains augments proliferation and survival.


CD19 targeted CAR T-cell therapy has shown activity in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The most promising target in multiple myeloma is B-cell maturation antigen (BCMA).


"BCMA is a good target because it is expressed primarily on plasma cells, as well as some mature B cell subsets and plasmacytoid dendritic cells," said Cohen. "It is highly expressed in myeloma cells and soluble in patient serum. We can measure it in patients and it has prognostic significance."


BCMA-specific CAR T cells have shown in vitro and in vivo activity in NIH studies. The first in-human trials of 12 patients induced a partial response for 2 weeks, very good partial response for 8 weeks, and strict complete response (CR) for 17 weeks. In this ongoing study, higher dose levels led to the best responses, he noted.


At the University of Pennsylvania, a BCMA CAR T-cell trial divided nine multiple myeloma patients into three cohorts, including the CAR alone with no lymphodepletion, with cyclophosphamide first, and with lower and higher doses of CAR cells. The patients, mean age 57 years, had a median of nine prior lines of therapy. All of them had high-risk genetics.


The researchers achieved an objective response of partial response or better in four of the nine patients (44%), with one patient achieving a strict CR for more than 1 year. "We saw potential for a long duration of response with no other therapy," stated Cohen. "We are still detecting CARs in all of the patients." He noted that the researchers even saw responses in extramedullary disease.


Two other multicenter trials of CAR T-cell therapy in multiple myeloma also show durable responses, with some approaching 1 year.


The four studies in different centers show the power of the CAR T-cell approach in multiple myeloma. "It is too early for head-to-head comparisons. All of the studies developed promising responses. We need longer follow-up to see how durable the responses will be," said Cohen.


CAR T-cell therapy has issues of toxicities and logistics that need to be addressed. "We need to mitigate toxicities before we can expand this therapy to other patients. We are in the early days for CAR T-cell therapy for multiple myeloma, but the future is bright," he said.



Blinatumomab, with a CD19 target, is the first FDA-approved BiTE for multiple myeloma. This drug has a short half-life and is continuously infused. "The next generation will include infusions once a week or every 2 weeks," he said.


In a comparison of BiTEs and CAR T-cell therapy, Cohen noted they both have similar activity in preclinical models. Other studies are opening with preliminary clinical data on BiTEs. Neurotoxicity is an issue with blinatumomab, and researchers will compare it to neurotoxicity in CAR T-cell therapy.


Checkpoint Inhibitors Plus IMiDs

Early studies of the checkpoint inhibitor pembrolizumab showed synergy with immunomodulary drugs (IMiDs) in relapsed/refractory multiple myeloma. This led to an explosion of clinical trials with PD-1 inhibitors in multiple myeloma. However, the FDA put a hold on trials with anti-PD-1 agents after reports of excess deaths due to autoimmune toxicities.


Antibody Drug Conjugates

An anti-BCMA immunoconjugate has shown promising early activity in relapsed/refractory multiple myeloma. In a phase I study, 30 patients who were dual refractory to IMiDs and proteasome inhibitors received an infusion for 1 hour every 3 weeks. No drug-limiting toxicities were reported at any dose level. The majority of adverse events were grade 1 or 2 and predicted. Ocular toxicity was noted in more than half of the patients, but this was low-grade and improved with reducing doses or lower the amount of drug, he said.


Importantly, "higher doses of this single agent led to some objective responses in a heavily pretreated population," said Cohen. Six of nine patients responded. All responses are ongoing and durable for more than 1 year. "High single-agent activity in multiple myeloma is another way to target BCMA," he said.


In conclusion, Cohen said that BCMA is the most promising target for immunotherapy. "CAR T-cell therapy and antibody-drug conjugates lead to high response rates. BiTEs are now entering trials," he said. On the other hand, the role of immunotherapy with PD-1 or PD-L1 blockers is still unclear.


"Many questions and challenges remain, including optimal patient populations, managing toxicities, and sequencing or combining immunotherapies with current therapies," Cohen concluded.


Mark L. Fuerst is a contributing writer.