New Targets on the Horizon for Multiple Myeloma Treatment

At the 2023 Lymphoma, Leukemia & Myeloma Congress in New York, New York, Kenneth C. Anderson, MD, Dana Farber Cancer Institute, Boston, Massachusetts discussed both existing and promising novel therapies on the horizon for patients with multiple myeloma (MM). 

Transcript:

I'm Ken Anderson from Dana-Farber Cancer Institute here at the Lymphoma, Leukemia, and Myeloma Meeting 2023. It's a very, very exciting meeting. I'm going to talk about how to exploit new targets in therapeutics in myeloma. We've been blessed with 16 new classes of agents and 32 FDA approvals. And myeloma is a chronic illness in many patients, but the future is brighter still.

I'm going to talk about how first to use some of the targets we know in a better way. For example, the venetoclax targeting BCL2 is very, very useful by itself, together with dexamethasone, together with bortezomib, and even together with antibodies, daratumumab. The trial that recently came out comparing venetoclax-dexamethasone with pomalidomide-dexamethasone, the CANOVA trial, was not a positive trial, [and] didn't meet its statistical end point, but it did show benefit. And so, I think we really need to be able to use venetoclax in the appropriate settings in myeloma. It really is our only precision medicine.

In terms of a second way of exploiting drugs we already know about [is] the concept of immunogenic cell death. We use proteasome inhibitors, for example, to kill by inhibiting the proteasome, but the dying myeloma cell triggers an immune response and we've shown that in high-risk myeloma there is no such immunogenic cell death. And we have strategies on how to restore immunogenic cell death and overcome high risk. 

And finally, we use daratumumab and isatuximab CD38 antibodies, but patient cells become resistant by down-regulating CD38, and we've shown that KDM-6A regulates CD38 expression. Not only that, [but] it [also] regulates natural killer cell activity. It turns out EZH2 inhibitors can be utilized to both restore CD38 expression and augment NK cell activity. So [it] could in fact overcome resistance to daratumumab or isatuximab.

I'm [also] going to talk about the exciting immune therapies which are palpably promising and very, very exciting here this year. I'm going to talk about CAR T-cells and how they're being used earlier and have even more efficacy, but really the practical issue of how we can make them more user-friendly. We have a protocol that I'll mention, PHE885, which is rapid production in 2 days of CAR T-cells, and giving small numbers back and allowing them to expand in the patient. There are several such protocols.

I'll also mention the soon, I believe to be, approved GPRC5D CAR T-cells, and then the concept of bispecific T-cell engagers, which is very exciting. We have teclistamab, elranatamab, targeting BCMA, approved, and we have talquetamab, targeting GPRC5D, approved.

The point I want to really emphasize is we need to both profile tumor as well as the immune repertoire of the host. It turns out that resistance based in the tumor can be [due to] downregulation of the antigen, or mutation, on the other side, exhaustion of T cells, expression of checkpoint inhibitors, can underlie relapse of therapy and increase infection risk. 

I think the future is bright in myeloma. We've had a transplant revolution since 1980 that keeps getting better. We've had novel targets since about 2000, proteasome inhibitors, IMiDs, antibodies; it keeps getting better. And then the immune revolution from 2020 on. 

All [of] this comes to say that many patients are really cured right now of their myeloma, if you think of cure meaning growing old and dying from something else. But I believe the future is brighter still.

Source:

Anderson K. Towards a Cure: How New Targets are being Exploited. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-21, 2023. New York, NY