Novel Immunotherapy Approaches for Multiple Myeloma

Adam D. Cohen, MD, Director, Myeloma Immunotherapy, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, discusses a few promising immunotherapy approaches for patients with multiple myeloma.

Transcript

A second big theme at this year's ASH meeting for myeloma were a number of abstracts looking at novel immunotherapy approaches. We've heard about a few trials using CAR T cells in myeloma over the past couple of years.

These have generally targeted a molecule called BCMA, or B-cell maturation antigen, which is a protein expressed on the surface of myeloma cells and normal plasma cells, but not generally other normal cells of the body which makes it an attractive target.

Some prior studies have demonstrated proof of principle that you could use BCMA-directed CAR T-cells to get responses in heavily refractory patients who had really exhausted all other therapies. At this year's ASH, there were actually at least 12 different oral abstracts that looked at various CAR T-cell approaches in relapsed/refractory myeloma, all of which are targeted BCMA.

The general gist of all these was that they are active, that response rates can be seen anywhere from 60-100% of patients, again, usually very heavily pretreated. The toxicities generally include cytokine release syndrome and neurotoxicity, which is similar to the toxicities we see with CD-19 specific CAR T-cells and other B-cell malignancies.

What we are seeing also is that in many of these patients, the responses are not durable long-term. We're getting responses, but patients are ultimately starting to relapse. One thing I think that's going to be important is trying to understand the mechanisms of resistance to CAR T-cells and why some patients are getting durable remissions the last a year or 2, or even more.

In other patients, the disease starts to come back in three to six months. Certainly, we saw validation of this approach with all of these different CAR T-cell products going forward in various trials.

The one abstract I'll mention specifically is a study that we were participating in at Penn. This is Abstract 3012. The lead author was Tara Gregory. The data was presented by my colleague, Krina Patel, at MD Anderson. This is a BCMA-directed CAR T-cell product that is a little bit different in the way it's developed.

Rather than using a viral vector to infect the T-cell and transfer the CAR gene, this uses a transposon-based mechanism, which is thought to create a final CAR T-cell product that may have more favorable properties. The T-cells that are generated in the end with this method seem to have more what's called a central memory or stem cell memory phenotype.

Meaning they seem to be less terminally differentiated, perhaps less exhausted, have a greater ability to divide and persist in the patient once they're infused. Perhaps, also, the cells don't divide quite so rapidly when you put them in the patient. The thought would be that there might be less toxicity.

In this study, patients had to have relapsed/refractory multiple myeloma after at least 3 prior lines of therapy. All the patients had T-cells manufactured, which took up to four weeks. They could get additional therapy during CAR T-cell manufacturing.

They then received fludarabine and cyclophosphamide, which are standard chemotherapy drugs, and conditioning to help make room for the CAR T-cells, and then the CAR T-cells were given as a single infusion.

This study looked at escalating doses of the CAR T-cells, anywhere from 50 million up to a 1.2 billion CAR T-cells given so far in five different dose cohorts. 23 patients had been infused at the time of the presentation and data was available on 19 of them.

I think what was striking about this was that the rate of cytokine release syndrome, which is one of the most severe toxicities of CAR T-cell treatment, was only 9.5 percent. It was seen in only 2 out of the 23 patients treated so far and was mild in both cases. Only one patient required what's called tocilizumab, the anti-cytokine antibody that we use to treat this.

Additionally, 1 patient had neurotoxicity, which is another one of the feared complications of CAR T-cell therapy. Perhaps it's early, but this may be a better tolerated CAR T-cell product that allows for more widespread use, not just in specialty centers.

The efficacy data on the 19 available patients did show 12 out of 19 had a confirmed response, although several of those patients are early and are still undergoing response assessment. We're now just getting up to the higher dose levels where we're hoping to see higher response rate for more durable responses.

Again, I think this study just confirms the efficacy of BCMA-directed CAR T-cells, but take a little bit different approach that perhaps may improve the safety profile. We're certainly waiting to see longer follow-up data for that.

The other exciting immunotherapy abstract was Abstract 1010. This was by Max Topp and colleagues, looking at a different approach called a bispecific antibody, or a bispecific T-cell engager called a BiTE therapy.

In this approach, rather than taking the T-cells out, like you need to do for CAR T-cells and manufacturing a large number and then putting them back in the patient, in this case, there's actually an antibody that's infused into the patient where one end is specific for the target antigen on the myeloma cell. In this case, BCMA. The other part of the antibody hit CD3 which is on T-cells.

The idea is to bring the T-cells already in the patient to the tumor, activate them in the bone marrow, and have them try to kill the myeloma cells right there, without this need for taking the T-cells out and generating a CAR T-cell product. This approach has shown benefit in leukemia patients. There's an FDA-approved product called blinatumomab already out there.

This is the first publicly presented data of this approach in myeloma. The drug is called AMG-420. It's given as a continuous infusion. Patients have to wear a pump that infuses it into the patient. They get the infusion 4 weeks in a row continuously, and then they get 2 weeks off.

In this phase 1 dose escalation study, they ended up treating so far 42 patients starting at extremely low doses, and then moving up to doses now between 400 and 800 micrograms a day. Toxicities are similar to CAR T-cells. You can get cytokine release syndrome which were seen in 38% of patients. The most low-grade, you can get central nervous system or neurotoxicity. They saw 2 patients with a polyneuropathy.

However, what they also was some interesting efficacy. 11 patients overall had a response. Particularly at the higher doses of 400 micrograms per day, 5 out of 6 responded, and 3 out of 3at 800 micrograms per day, including several stringent complete remission. Some of which were ongoing as long as 10 months.

I think this also is very early data, but shows proof of principle that this approach with bispecific antibodies can also have efficacy in myeloma. It provides another option for immunotherapy that's more off the shelf and can be given right away, rather than CAR T-cells where you have to wait for manufacturing.

The study is going forward with an expansion cohort at the 400 microgram per day dose. We'll hopefully hear more about the true efficacy rate and toxicities in that population. There were some infection seen. That's something that we have to look out for.

I think another promising immunotherapy approach. There's a lot more of these bispecific antibodies going forward in the clinic at this time. We'll have more data hopefully by ASH next year.