Leveraging Mechanisms of Action With Triplet Therapy in Multiple Myeloma

Joseph Mikhael, MD, is a professor in the Applied Cancer Research and Drug Discovery Division of the Translational Genomics Research Institute in Phoenix, Arizona, which is an affiliate of City of Hope. He spoke with The American Journal of Managed Care®about his work with patients with multiple myeloma and the increased use of triplet therapy to treat this disease.

This interview is lightly edited for clarity.

AJMC: Triple regimens have evolved as a standard of care treatment for patients with multiple myeloma in recent years. What has driven the change toward a 3-drug regimen?

Mikhael: We've had a significant move from doublets to triplets, and even potentially soon to quadruplets. This has been driven by multiple factors. It's been driven by biology, as we come to appreciate that myeloma is a complex disease with multiple facets—and overcoming it with a single or even a 2-drug combination is unlikely, much like our colleagues in infectious disease have overcome HIV by using the right combination of drugs as opposed to a single drug.

Secondly, we've had overwhelming evidence, from several phase III clinical trials, that in general triplets have been better than doublets in most of the trials that have been performed. And then thirdly, it's been a feasibility function; it's been a function of the fact that we've had more and more triplets that are easier or more convenient to deliver, instead of trying to combine some of the older agents. We’ve developed drugs that have fewer side effects or that are more easily administered subcutaneously or orally. All of this is built our platform of having moved from single to doublets now to triplets in multiple myeloma.

AJMC: Is there an understanding on the part of the patient and the payers that that you’re really leveraging multiple mechanisms of action?

Mikhael: Leveraging multiple mechanisms action is critical in multiple myeloma—and we have seen this again, both biologically and clinically. This is a disease that has multiple different manifestations. In fact, I often say it's called multiple myeloma for a reason and very appropriately, there is tremendous heterogeneity [in this disease]. So indeed, one of our principles of treatment is leveraging different mechanisms together, and when patients relapse on one, moving to a different mechanism of action. We have shown that, for example, giving drug A and B together is more effective than giving drug A for a period, followed by drug B—that synergy [of using the drugs] together provides a deeper and a more durable response than one would be able to achieve by administering them subsequently.

AJMC:What's been your experience with the anti-CD38 regimens in relapsed refractory multiple myeloma?

Mikhael: Anti-CD 38 regimens in relapsed myeloma have really become a centerpiece of what we do. For so long we had 2 major classes of drugs in the proteasome inhibitors and immunomodulatory drugs. With a desire to introduce a new mechanism of action, it’s been very attractive to us to now have a third major class of drugs in these monoclonal antibodies. Initially, we had tremendous evidence in using daratumumab, in combination with either bortezomib or lenalidomide. But now our portfolio has grown considerably, to also add carfilzomib and pomalidomide as options to partner with these medications. Similarly, we now have another anti-CD38 antibody, isatuximab, that can also partner it with pomalidomide and with carfilzomib. So, this now gives us more options to leverage a new mechanism of action in an anti-CD38 antibody with an appropriate partner for a patient, based on what they've previously been treated with, with what their preference may be, and with what we think will be the most effective triplet combination with that anti-CD38 antibody.

AJMC:Is there a best agent to pair with anti-CD38 therapy? Or is there really an individualized approach, based on what you’re saying about each patient?

Mikhael: It really is an individualized approach in selecting the right partner for the anti-CD38 combination. We're grateful that the anti-CD38 drugs are rather promiscuous in the sense that they can be partnered with just about every other agent in multiple myeloma; we partner them with proteasome inhibitors and immunomodulatory agents for now, and frankly, all of those drugs within those classes. There are 3 drugs in each of those 2 classes—so, they're 6 partners already. And now we're building other opportunities--antibodies with drugs like selinexor, which is an XPO1 inhibitor, or even at times, potentially other antibodies and other drugs have different mechanisms of action.

AJMC: So, we know that the time of remission tends to decrease with each subsequent line of therapy. Are learning why this happens?

Mikhael: We always learn from biology, and the biology and the science of myeloma teaches us this. We see this pragmatically, also for several reasons. Biologically, we know this disease becomes more resistant with time because of course, it becomes resistant to the chemotherapy it's been exposed to, but not only so it becomes more aggressive with time, because it has the opportunity to acquire new mutations and undergo changes that can make it more and more aggressive, almost like a fire that over time that can build and build and ultimately become like a bonfire. Pragmatically, at the same time, patients have been treated with more therapies. So, their bone marrow has less reserve to tolerate the kinds of treatments that we want to give them over time. And then lastly, unfortunately, patients do age over time, so they may become more frail or less able to tolerate the treatments that they've had. This is all an unfortunate recipe for seeing how the disease becomes more aggressive, and so fewer and fewer patients are eligible for treatment. And classically, patients have shorter times in remission.

AJMC: How does the length of time of the previous remission help the clinician decide what the next choice of therapy will be?

Mikhael: This really becomes the greater strategy in myeloma—and this is perhaps where we've seen the greatest shift. Over the last few years, there has always been this tension in myeloma—are you of the cure camp or of the control camp? Which is to say, do you think we can just throw everything at the disease up front and cure it? Or do you think we treat it like hypertension, you kind of give the minimum amount to keep the patient in remission, for as long as possible? And I think we all agree that those 2 extremes are not correct. But there has definitely been a tipping towards more of the cure-like approach or a more aggressive approach. We have been using more and more combinations—we’ve gone from doublets to triplets as we've discussed, and maybe even to quadruplets, to better control the disease early on. Because those first few remissions are going to be patients’ longest remissions, we want to do the best we can to get that deep and durable remission.

Early on, what I often say is the first 2 regimens you use are almost like the 1-2 punch—they are more prognostic in the life of a patient than perhaps anything else. And so, it's influencing our treatment strategies by using the best therapies, we have the ideal combinations that we have earlier in the disease course. Of course, in drug development, many of these great novel agents that are coming online have to prove themselves in the most resistant settings, but they will eventually make their way earlier [in the course of disease]. Saving the best for last is wonderful for a Hallmark movie, but it's really not appropriate for multiple myeloma. We want to not necessarily save those items for later—we want to use them in combination earlier in the disease course.

AJMC: I had time to read your recent article regarding renal function with patients in multiple myeloma.1What can be done in a more holistic way, perhaps in cooperation with the patient's primary care physician, to limit the loss of renal function?

Mikhael: Renal disease in multiple myeloma is a real burden. It's a burden, first, because myeloma itself induces renal disease, but also because myeloma is more common as we age and is more common in the African American population. And these 2 items bring us to see that there are more patients with myeloma who have underlying renal insufficiency, perhaps even before they're treated. So very often in clinical trials, these patients may be excluded. We sought to do a better real-world analysis of what is really happening in the community in patients who have pre-existing renal insufficiency, or have renal insufficiency that may be attributable to the multiple myeloma.

We learned various things through this. We learned, for example, that this is perhaps more common than we really thought. Often, these patients aren't captured in certain databases, or, of course, in clinical trials, and so we know the burden of renal disease is significant. Furthermore, the presence of renal insufficiency does indeed reduce patient's overall survival. And this is very unfortunate, of course. And so, this is what drives us to say, “What can I do to reduce that patient's renal disease, which of course involves the myeloma and non-myeloma management. We want patients’ renal disease to be managed, whether it's from vascular causes or diabetes or from whatever other cause it's critical that we have a multidisciplinary team evaluating that I as a myeloma doctor may not be the best one to guide their hypertension management of their diabetes manage, so that becomes important.

But what we particularly learned in this study was their myeloma management is key. And we don't want to withhold or reduce the efficacy of these combination strategies that we've been discussing in a renal patient just for fear of the potential toxicity or the renal clearance of some of these agents. And so, what we learned through this study was that although patients can have improvement in their renal function, if it is caused by the multiple myeloma, when we use treatment strategies, we still want to use the optimal treatment strategies. Many patients in the community are not receiving both a proteasome inhibitor and an immunomodulatory drug as guidelines would tell us, but they're receiving one or the other. And those patients that have the combinations with renal insufficiency did better than those who received only one or the other. So really, the take home message was that it's important to treat the patient's myeloma as effectively as possible. The best way to rescue a myeloma patient’s kidneys is to treat their myeloma most effectively. And that does require a combination of both proteasome inhibition and immunomodulatory drugs.

AJMC: So, you mentioned that not too many renal patients make it into clinical trials. Why is this?

Mikhael: There are some clinical trials that are specifically dedicated to renal sufficiency. I had the privilege of leading 1 several years ago where we helped demonstrate the benefit of lenalidomide in this population, with what the right dosing should be. There are more and more studies that are trying to be more inclusive of renal insufficiency. But because of the potential toxicity, many are excluded. We look at CAR T-cell therapy right now, which is really a revolution in myeloma. [Trials for] many of these therapies have had to exclude patients with significant renal insufficiency. And so, it's going to take us some time to determine how safely we could administer those therapies to patients with renal insufficiency. As that fraction is significant, it's important not to exclude the renal insufficiency patients from those kinds of studies.

AJMC: We've covered a lot of ground. Is there anything we didn't cover that you'd like to add?

Mikhael: I think there are very few malignancies that have undergone the change and the revolution that we've seen in multiple myeloma over the last 5 years—especially over the last 2 years. I've had the privilege of being involved in myeloma for over 20 years. I don't know if I've ever seen as exciting a year as this year in drug development for multiple myeloma. We have great drugs that have clearly improved [outcomes] for patients, in both progression-free and overall survival. But looking to the future, I think we're going to see another tremendous wave of CAR T-cell therapies, bispecific [antibody] therapies, and novel smaller molecules that will really change the face of myeloma and how we treat myeloma.

In the interim, it's critical that we do give the best therapies we have for our patients earlier in the disease course, so that we can extend progression-free, and even overall survival on patients early on. We've actually seen tremendous advances in frontline therapies, even for patients who are ineligible for transplant, where their average survival has so significantly improved. I see that there's a lot of hope in the future of multiple myeloma for our patients.

Lastly, we all still struggle with a subset of myeloma patients that have very high-risk disease. This remains the unmet medical need in myeloma, where we need very active investigation to help us understand why the myeloma is that aggressive, and how best we can control it.

Reference

1. Mikhael J, Singh E, Rice MS. Real-world renal function among patients with multiple myeloma in the United States. Blood Cancer J. 2021;11(5):99. doi: 10.1038/s41408-021-00492-6.