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Treating Multiple Myeloma When T-Cell Redirection Is Not an Option
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Released: July 30, 2026

Joshua Richter
Joshua Richter, MD

Treating Multiple Myeloma When T-Cell Redirection Is Not an Option

[00:00:04] Joshua Richter, MD: Hi, welcome to Hematology Highlights, brought to you by Decera Clinical Insights. I'm your host, Dr. Joshua Richter from Mount Sinai.

For the next part of our multiple myeloma series, I wanna focus on patients who are ineligible for or decline T-cell redirection therapies such as CAR T-cell therapy or a bispecific antibody.

In the world of newly diagnosed myeloma, we've narrowed things down to a few core types of treatments, most of which utilize either daratumumab or isatuximab, both monoclonal antibodies targeting CD38.

CD38 is a target on all myeloma cells. We typically give this in combination with drugs like lenalidomide, bortezomib, and dexamethasone, and we give either 3- or 4-drug regimens in combination to people with newly diagnosed myeloma. We then discuss whether or not to proceed with autologous stem cell transplant for consolidation. But ultimately, most people then remain on long-term maintenance-based therapy.

The question is: what do we do at the time of relapse? Although, for many years, the standard of care in the relapse setting has been going back to that well of what we call novel agents—drugs like lenalidomide and pomalidomide, drugs like bortezomib and carfilzomib, and drugs like isatuximab or daratumumab—we now have the opportunity to give T-cell redirection therapy in the relapsed/refractory setting of myeloma.

At the time of this recording, we have two FDA-approved CAR T-cell therapies, Carvykti and Abecma, approved as early as the first relapse, and we have four FDA-approved bispecific antibodies: teclistamab, talquetamab, elranatamab, and linvoseltamab. Now, although these drugs are highly effective, some people may or may not want to proceed with these treatments for a variety of reasons.

Let me explain a little bit about CAR T cells and bispecifics to make it a little clearer.

CAR T-cell therapy is based on the notion that the best cancer fighter is our own immune system. So, what could we do to even the score? We perform apheresis, collect a patient's T cells.

We can engineer them to attack and target the myeloma cells and then reinfuse them to attack the myeloma, with some of the most impressive data to date seen with this type of therapy. Of note, this type of therapy takes time because we have to collect the cells and manufacture them, and we actually have what we call a brain-to-vein time, which may take several months. Additionally, patients need to be admitted to the hospital for monitoring, prevention, and mitigation of some acute toxicities, such as cytokine release syndrome, where the immune system gets very overactive, and ICANS, immune effector cell-associated neurotoxicity syndrome, where patients can have everything from confusion to even seizures.

Additionally, there have been reports of some delayed neurotoxicity with things such as Parkinson's disease. However, there are a number of patients who may have been cured by this protocol, so we're very excited about this type of therapy.

Bispecific antibodies are an off-the-shelf version of this type of T-cell redirection and what I like to call the Thunderdome of myeloma. For those of you who remember the movie Mad Max Beyond Thunderdome, Thunderdome had a motto, which was, "Two men enter, one man leaves." Bispecific antibodies have two arms: one that grabs onto the cancer cell and the other that grabs onto your own immune cell. Both cells enter Thunderdome, and only the T cell emerges victorious.

These treatments are highly effective, with some of the most impressive response rates we've seen to date. However, they have some similar toxicities, like CRS and ICANS, although they are typically more muted than what we see with CAR T-cell therapy. There is a higher rate of infection. As you remain on these drugs long term, they can suppress the immune system, so infection rates are a concern.

Additionally, they do require some type of hospitalization during the step-up period, and at the end of the day, despite the fact that both bispecifics and CAR T-cell therapies are highly effective, some patients have concerns about proceeding with them. One is that some patients don't wanna be admitted to the hospital at all, which is a very reasonable thing.

Additionally, some CAR T-cell therapies have been associated with delayed motor neurotoxicity, with things such as Parkinson's disease. This has given some people pause about proceeding with this type of therapy. Additionally, some patients have fought many infections throughout the years and are concerned about the immunosuppression that we see with both bispecific antibodies and CAR T-cell therapy.

Additionally, some people may simply not want to go on these therapies because they have been associated with a slightly increased risk of secondary cancers. So, overall, despite the fact that these therapies are highly effective, there are some notable toxicities that people may be concerned about. Additionally, patients who are older and frailer, with multiple comorbidities, may be worried about some of the acute side effects during that CRS step-up period.

Well, do we have options for patients who either progress beyond these therapies, are ineligible for these therapies, or simply decline going through a bispecific antibody or CAR T-cell therapy? And the answer is yes, we do. We have a number of them. First off, we have a drug called belantamab mafodotin. Belantamab is a BCMA-targeting antibody-drug conjugate.

So, just like three of our bispecifics and two of our CAR T-cell therapies target the BCMA antigen that's on all myeloma cells, belantamab mafodotin targets that BCMA as well. However, an antibody-drug conjugate takes the concept of a naked antibody and the concept of classical chemotherapy and merges them. Basically, the drug finds the cells and injects the chemotherapy directly into the cell.

Belantamab mafodotin is currently approved by the FDA in the third-line-plus setting in combination with bortezomib and dexamethasone. This is a highly effective agent. It's usually given with extended dosing every 3 to 4 weeks and, in some cases, every 6 to 8 weeks. However, the main toxicity is ocular toxicity, so you need to be monitored by an eye doctor throughout your treatment.

Selinexor is another drug that can be used for patients who decline T-cell redirection therapy. Selinexor is an oral selective inhibitor of nuclear export. The reality is that, as our bodies make cancer cells, we have mechanisms through which the body tries to kill cancer cells, and cancer cells have developed survival tactics.

Selinexor seeks to block this and, in reality, is active across a variety of tumor types above and beyond myeloma, including lymphomas, GYN malignancies, and myeloproliferative neoplasms. Selinexor is a highly active drug that can be combined with many of our classic agents, including bortezomib, daratumumab, and carfilzomib, although the drug does have some toxicity in terms of, uh, GI tox, which we can prophylax by giving antiemetics.

Venetoclax is another interesting drug.

Now, venetoclax is FDA-approved to treat a variety of tumors, such as lymphomas, myeloproliferative disorders, myelodysplastic syndromes, and AML. It is an oral BCL-2 inhibitor. Now, in general, myeloma is not BCL-2 dependent, so blocking BCL-2 does not work. However, in myeloma with a t(11;14) translocation, those myeloma cells are BCL-2 dependent and respond very quickly and very rapidly to venetoclax.

So, traditionally, patients with a t(11;14) translocation can be treated with venetoclax, either as a single agent or in combination with drugs like dexamethasone, bortezomib, and daratumumab.

Now, we always have the good old-fashioned cytotoxic chemotherapy: drugs like cyclophosphamide, bendamustine, and melphalan, and even some of our combination chemotherapies like DCEP, V-DCEP, and VD-PACE.

These drugs are highly effective and utilize classical chemotherapeutics to kill the myeloma cells. These tend to be a little more aggressive and can lower blood counts, so patients need to be monitored closely. And it's important to think about this in terms of sequencing because many of these drugs will kill lymphocytes along with plasma cells.

And because lymphocytes are needed for subsequent T-cell redirection therapies to work, you really wanna strategize: are we gonna give another T-cell redirection therapy down the road? 'Cause we may want to avoid classical chemotherapy to avoid impacting the T cells that we'll need to work later on.

Now, there are a number of upcoming therapies that will be at our advantage and at our use pretty soon, and the biggest ones are gonna be the CELMoDs. CELMoDs are a new class of agents that, in many ways, are like the super-IMiDs. So, we started off with thalidomide, then we went to lenalidomide and pomalidomide, and we have two upcoming CELMoDs: iberdomide and mezigdomide.

And these are two oral agents that are very similar to the IMiDs. You take them 3 weeks on and 1 week off. We can combine them with many of our classic therapies, and they have a role in helping our immune system work even better. So, these drugs will work great with some of our classic treatments, or there are some really great data looking at combining them with some of the T-cell redirection therapies to improve the response rates to those treatments in general.

Throughout what I like to call the chess game of myeloma, it doesn't just matter what your next move is; it also matters how your next move impacts the move after that, the move after that, and so on. So, we're really trying to strategize the long view.

And with that, I'm Dr. Joshua Richter. Thank you for spending time with me today on Hematology Highlights. I look forward to seeing you soon.

This transcript was generated by AI and lightly edited.