Immune Approaches Hold Great Promise in Myeloma, Expert Says

Alexander M. Lesokhin, MD

Alexander M. Lesokhin, MD

Over the past 5 years, several therapies have been developed that have proven to be effective for patients with multiple myeloma. The FDA has approved several 3-drug regimens, including the combination of immunomodulatory drugs (IMiDs), a proteasome inhibitor, and dexamethasone, which is now the standard of care in the first-line setting.

At this time, there are a variety of treatment options available for patients with multiple myeloma. While the availability of different treatment regimens has been a major advance in the field, more research is still necessary, as the majority of patients with multiple myeloma become refractory at some point and require alternative treatment options. Some of the latest research in the field revolves around CAR T cells, which are showing significant initial responses. More research is still necessary to determine the durability of these responses.

In an interview withTargeted Oncologyduring the2nd Annual Live Medical Crossfire: Hematologic Malignancies meeting, Alexander M. Lesokhin, MD, assistant attending physician in the Department of Medicine and Myeloma Service at Memorial Sloan Kettering Cancer Center, discussed the current treatment landscape of multiple myeloma and where he predicts the field will be in the next decade. He also shared his thoughts on the current research in CAR T-cell therapy.

TARGETED ONCOLOGY:Can you give us an overview of the current treatment landscape for multiple myeloma?

Lesokhin: The treatment landscape has evolved continuously over the last 4 to 5 years with ongoing development of monoclonal antibodies, second-generation proteasome inhibitors, and the combination of immunomodulatory drugs(IMiDs) and these monoclonal antibodies. Specifically, in the first-line setting, it is now standard of care to administer a 3-drug regimen — a combination of IMiDs, a proteasome inhibitor, and dexamethasone. Based on the response and patient characteristics, patients then go on to receive stem cell transplant and maintenance therapy.

For transplant-ineligible patients, they receive this initial induction therapy and then go on to maintenance therapy. Maintenance is typically lenalidomide. In the relapsed setting, there have now been a number of 3-drug combinations, including combinations of the second-generation proteasome inhibitor carfilzomib (Kyprolis), the immunomodulatory drug lenalidomide (Revlimid), and dexamethasone. The monoclonal antibody daratumumab, has [also] been very, very effective in combination with both lenalidomide and dexamethasone or the third-generation IMiD pomalidomide (Pomalyst), and dexamethasone. These are all options.

Also, the monoclonal antibody against SLAMF7, elotuzumab (Empliciti), in combination with either lenalidomide and dexamethasone [is an option]. Most recently, [there were] data presented at EHA for pomalidomide and dexamethasone. These are all options, and there are also orally available proteasome inhibitors, ixazomib(Ninlaro) with lenalidomide and dexamethasone.

Patients, at this point, have a pretty reasonably well-established standard of care as their frontline regimen, followed by maintenance, and a variety of treatment options in the relapsed setting that can be chosen based on patient factors, convenience [of either] oral or IV, and disease characteristics.

TARGETED ONCOLOGY:What is the appropriate rationale for selecting a targeted agent, checkpoint inhibitor, or a CAR T-cell treatment for a patient?

Lesokhin: There are multiple treatment options in the relapsed setting that I just reviewed. You decide which to use based on the patient’s other comorbid conditions. For example, carfilzomib has a potential for cardiac side effects. It’s relatively low and generally relatively manageable. However, patients with preexisting cardiac conditions may not be the ideal candidates for these drugs. In those patients, you might select a monoclonal antibody such as daratumumab, with an IMiD lenalidomide and dexamethasone, or pomalidomide and dexamethasone. Also, if patients have a very durable response to their initial therapy, then one could use that same combination initially as their induction therapy regimen in the relapsed setting.

[Looking at] the characteristics of the relapse itself, if one has a very rapid relapse following an initial therapy that is very aggressive and highly symptomatic, one might use a more intensive treatment program to elicit disease control or consider a clinical trial in that setting. With more indolent relapse, then, in a way, there are multiple options. Dealer’s choice.

TARGETED ONCOLOGY:What are some of the recent advances in the field that you’re particularly excited about?

Lesokhin: There’s a ton of excitement around CAR T cells. These are not yet available or FDA approved, but certainly these therapies do elicit significant initial responses. We still have some time to see if those responses are durable. I think also, some of the antibody drug conjugates, for example the BCMA conjugate with a drug has also shown efficacy in patients that are refractory to every other line of therapy. That drug, developed by GlaxoSmithKline, has shown a 60% response rate in that setting with manageable toxicities. I think this is also a very interesting approach.

Other approaches include bispecific drugs. These are drugs that target the tumor and also bring in T cells by a CD3 engager, which would activate the T cells. It brings T cells within close proximity, resulting in tumor cell killing. A similar drug to this, blinatumomab (Blincyto), was approved in acute lymphocytic leukemia, so this concept has shown feasibility and is now being evaluated in myeloma as well.

In terms of immune checkpoints, those have been unfortunately less promising, although these drugs can elicit very durable and meaningful responses and a whole host of solid tumor malignancies, as well in Hodgkin lymphoma. In myeloma, as single agents, they’ve had limited efficacy. In combination with immunomodulatory drugs, they have elicited more side effects than we would like to see when treating our patients without a clear efficacy signal, at least when evaluated by a response rate. Progression-free survival (PFS) times would probably be more meaningful in these immunotherapeutic types of settings, but the data has yet to be matured or reported.

TARGETED ONCOLOGY:What is a major unmet need that still needs to be addressed?

Lesokhin: It’s quite clear that we have made some really tremendous advances in the time that I have been a myeloma clinician and researcher. The outlook for myeloma patients has improved tremendously. Our therapies are less toxic and more effective. However, patients do ultimately become refractory. We have yet to develop a treatment that leads to a very durable PFS or survival signal. We are not inherently curing the majority of our patients. We still need additional drugs. I still think that the immune approaches hold a lot of promise because our bodies are built to resist infections and other things. In durable ways, we can elicit immunological memory, thus these types of immune approaches that can elicit immunological memory and more durable responses hold a great deal of promise. That promise has not yet been realized in multiple myeloma, but that, I think, is just a matter of figuring it out.

TARGETED ONCOLOGY:Where do you see the field heading in the next 5 to 10 years?

Lesokhin: I think the other major advance has been that with the advent of more effective therapies, we are able to elicit really deep responses, ones where residual disease is really not detectable using our most sensitive assays. Those patients that achieve minimal residual disease (MRD)-negativity tend to have the most durable responses. Our tools for assessing MRD negativity are also improving and right now, this requires bone marrow testing. There are a variety of other technologies being evaluated for blood-based or radiographic testing of MRD. Hopefully, in the next 3-5 years or so, or maybe a little longer than that, we will see clinical trials designed based on the achievement of MRD. Instead of having a predetermined treatment program, we would design your program around depth of response and achieving this MRD-negative endpoint where you could make decisions of whether or not to pursue an autologous stem cell transplant as your initial therapy based on MRD, or whether or not to reduce the intensity of your therapy once patients achieve an MRD endpoint and move on to a maintenance approach. I think these kind of modifications will lead to a much more tailored, personalized, and better-tolerated treatment approach for patients.

TARGETED ONCOLOGY:What do you hope physicians take away from this discussion?

Lesokhin