David S. Siegel, MD, PhD

There has been a lot of excitement in multiple myeloma about B-cell maturation antigen as a target unique to plasma cells. Although there is a whole series of potential treatments targeting BCMA, CAR T-cell therapy seems to get most of the press.

This study by Topp and colleagues looks at a bispecific antibody construct that targets BCMA — one of two versions of an Amgen product currently being tested. Both are looking at ways to pull the cancer cell and the potential killer of a cancer cell into closer proximity.

The data about AMG 420 being presented at ASCO show that the treatment is certainly capable, at relatively low doses, of killing myeloma  with impacts even at the lowest doses administered. At higher dose levels, we are seeing very high levels of activity.

One of the issues with CAR T cells for myeloma is that it takes a long time to construct the cells, and it’s very, very expensive. AMG 420 may be a shortcut or alternative to the same type of benefit seen with CAR T-cell therapy, except using an off-the-shelf product.

There is already a commercially available product that uses the same approach — blinatumomab (Blincyto, Amgen), which is directed at killing lymphoma, chronic lymphocytic leukemia and acute leukemias — and it has been very successful in that space. AMG 420 is an application of the same approach to multiple myeloma and the view of it so far is that it works.

We are getting our first look at the toxicities associated with this treatment, and as one might expect, there are significant ones, such as infections. There are also short-term neurologic toxicities that resolve with discontinuation of the drug.

Nevertheless, we have every reason to be excited about these findings. The results we are seeing with AMG 420 are comparable to what we saw with CAR T-cell therapy, which is being held up as the gold standard of immunotherapy. I’m not sure that the depth of response for AMG 420 is comparable to CAR T, but AMG 420 is something that can be administered continuously.

If we can’t cure myeloma patients with one dose of CAR T cells, then AMG 420 may be a less complex and longer-term intervention that may end up controlling disease for longer periods of time than CAR T cells.

It’s hard to say where AMG 420 might be placed in the strategy to treat multiple myeloma, but if we can continue to push up the dose to higher levels and use it in combination with other therapies, this could be a very important asset in the treatment of this disease.

Jens Hillengass, MD

B-cell maturation antigen has been identified as a promising new target for treatment of multiple myeloma. CART cells have been manufactured to target this antigen.

However, this technology has several challenges. From a side-effect profile, cytokine release syndrome and central neurological symptoms most likely caused by an overactivation of these modified immune cells are significant. Further, because mostly heavily pretreated patients with advanced and often aggressive disease are enrolled in clinical trials with BCMA-directed CAR T cells, the manufacturing time of more than 3 weeks can become an issue. Therefore, an “off-the-shelf” product with a similar mechanism of action is desirable. Bispecific antibodies such as blinatumomab have already been established in other hematologic malignancies, but not yet in multiple myeloma.

This study reports on early results of using a bispecific antibody, or so-called T-cell engager. AMG420 is a construct that connects the myeloma cell via BCMA on one side with a T cell via CD3 on the other. The study objectives were to find the maximum tolerated dose, assess safety and tolerability, and to show first antimyeloma activity of the compound. Forty-two patients with relapsed or refractory myeloma after two or more lines of therapy were enrolled in this phase I study to receive up to 10 cycles of a 4-weeks-on, 2-weeks-off schedule of continuous infusion of the bispecific antibody.

This is a new treatment approach with some benefits over CAR T cells. However, the data are very limited and further studies are needed to evaluate the side-effect profile and efficacy using the maximum tolerated dose of 400 µg daily. An important challenge of this treatment is the constant infusion over 4 weeks. Further development of bispecific antibodies with longer half-lives is underway.