Ajai Chari, MD, professor of medicine, director of clinical research, Icahn School of Medicine at Mount Sinai, explains the mechanism of action of talquetamab and what method of delivery patients may prefer.
Recently-published phase 1 results presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition show talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. Ajai Chari, MD, professor of medicine, director of clinical research, Icahn School of Medicine at Mount Sinai, explains why the bispecific antibody is a good choice for patients who have received multiple prior therapies.
Why does the mechanism of action for talquetamab make it a good choice for patients who have received multiple prior therapies, including CAR T-cell therapy?
The first monoclonal antibody for any human being was actually, the Nobel Prize was given in the 1980s, and it was thanks to a myeloma cell. So I always like to start everything about antibodies in general with that statement, because they fused a spleen cell to a myeloma cell, and every antibody in human beings today owes its legacy to myeloma. But it wasn't till 30 years later that we got naked antibodies, and then now, for the first time, we have bispecific antibody. The difference between a naked antibody and a bispecific antibody is the bispecific has 2 binding sites, if you will. Here, one site binds to the myeloma and the other site binds to the T cells. And by doing that, you can kind of think of cancers like myeloma as occurring due to a lazy immune system because if the T cells are able to generally monitor cancers and detect them early, they should be eradicating them, and if they don't, they're failing. We know one way of getting around that is to take them out and genetically modify them in CAR T. Here, the difference is this is an off the shelf product. You don't need this complicated collection, manufacturing, bridging—this is ready to go. ...The binding of both components, the tumor and the T cell, basically traffics the T cells to where the cancer is, the T cells release chemicals like perforin, granzymes, pokes holes in the cancer membrane, and you have cell death. So it's bringing your army to the enemy.
Based on the phase 1 results, will one dose or method of delivery be the preferred option?
In the phase 1 study, which just came out in the New England Journal [of Medicine], a variety of doses were studied both intravenously and subcutaneously. The decision was made to go more with subcutaneous, least of all because of physicians. Because what do we do? We just sign the orders. But for everybody else in the health care team, it makes a big difference. For the pharmacists, it's much easier to mix the drug. For the nurses who are administering the drug, it's a shot instead of a long drip. And finally, for the patient, you're decreasing the time they're spending in clinic. For us [physicians], we're just signing the orders. For the rest of the team, it makes a big difference. It does change the properties of the drug, because when you give a drug IV gets absorbed very quickly. Subcutaneous administration is has a delayed absorption, so when you think about things like cytokine release syndrome, which is one of the main side effects, that happens earlier with an IV drug compared to the subcutaneous drug of the same formulation. That was really important for the phase 1 study. The New England Journal [of Medicine] is showing that the drug works and the safety profile was characterized. But here at this year's ASH meeting, what's new is, for the first time, we're presenting the phase 2 part of the study where we're clarifying the efficacy and the safety as well.