Melanie Cole, MS (Host): Welcome to the podcast series from the Specialists at Penn Medicine. I'm Melanie Cole. And we have a panel for you today highlighting the Multiple Myeloma Program at Penn Medicine. Joining me is Dr. Shivani Kapur, she's an Assistant Professor of Clinical Medicine in Hematology-Oncology at Penn Medicine; and Dr. Adam Cohen, he's an Associate Professor of Medicine in the Division of Hematology-Oncology, and the Director of the Myeloma Immunotherapy at Penn Medicine.

Thank you both for being with us today. Dr. Cohen. I'd like to start with you. If you would just speak a little bit about multiple myeloma, the clinical manifestations, and the scope of what we're discussing here today.

Dr. Adam Cohen: Of course, I'd be happy to. And thanks for having us on the podcast. So, multiple myeloma is a cancer of the bone marrow. It's the second most common hematologic malignancy with an incidence of about 35,000 new cases a year in the United States. The main manifestations clinically can be anemia, lytic bone lesions, high calcium levels, impaired renal function, and recurrent infections, although there are a subset of patients who can present without any symptoms and the diagnosis can be made just based on laboratory testing.

Host: Well, thank you Dr. Cohen. And Dr. Kapur, what main issues do you consider when you're deciding on first-line therapy for patients with multiple myeloma? Is this approach standardized at this point, or do patient-specific factors affect your choice of the initial therapy you're going to choose?

Dr. Shivani Kapur: So, with treatment with myeloma, there really isn't a one-size-fits-all approach that we can do when we are determining first-line therapy. There are certainly patient-specific factors as well as disease-specific factors that we take into account when we are deciding on first-line treatment options.

So, age is one consideration. But certainly, organ function, looking at the heart, lung, liver, kidney function, and the overall fitness is really important and, on top of that, looking at the cytogenetic risk of the cancer really helps determine the aggressiveness of the disease to tailor the approach to these patients.

So, yes, there are certain standard regimens that we now use for our patients when we first get them started out on treatment, which generally is a combination of a quadruplet regimen, four drugs for about four to six cycles; followed by, if candidates desire one, an autologous stem cell transplant, followed by maintenance, which all have, really been proven to be very effective. We still need to personalize the plan to make sure it's still the best fit for the individual.

Host: Well then Dr. Kapur, how can multiple myeloma specialists specifically be helpful at this early stage in a patient's journey? Tell us about the necessary procedures that have happened at this point.

Dr. Shivani Kapur: Myeloma being heterogeneous and complicated, and as our treatments are evolving, I think involving specialists early on in their treatment course can actually make a real difference. Early in their journey, we can help patients understand their diagnoses, navigate treatment options, make sure that their diseases are not associated with any other conditions such as amyloid, that can be associated with myeloma. Making sure that they respond appropriately to therapy, adjusting their treatments and, more importantly, just making informed decisions, especially about something like transplant and considering clinical trials when it's appropriate.

So summing this up, help make a roadmap for patients for their long-term care, and help them through, feeling supported from the very beginning.

Host: Well, Dr. Kapur, sticking with you for just a minute. I'd like you to speak about the options available to these patients after they respond to first-line therapy. How have these options evolved with all the new therapies developed in recent years for multiple myeloma? Tell us a little bit about the evolution and what comes next with these new therapies.

Dr. Shivani Kapur: Exactly. I think we are in the novel era with a lot of newer drugs that are coming out. So, the treatment therapeutic landscape for myeloma has really been changing. For the longest time, initially, in those patients who are transplant-eligible and who do respond to the initial four-drug regimen, we still think doing the autologous transplant, which remains a very safe and effective treatment option. As we know, it does help prolong their progression-free survival and help people live longer.

In general, we tend to prefer doing transplants in the upfront settings, especially for those patients who are at a higher risk. And in those patients who don't feel like they're ready for a transplant for some reason and choose to defer transplant for a later time, there's enough data and evidence to say that transplant can be done at the time of relapse. So, there certainly has been this evolution of doing transplants for all patients and now having this option to do it at the time of relapse as well, but still remains a very effective therapy for our patients and also helps get their disease response into a deeper remission.

Moving towards a relapse setting, there's just such amazing novel therapies that are now out there. There are targeted therapies, monoclonal antibodies, CAR T-cell therapy, all of these bispecific antibodies. So, there's a lot of new, exciting things that we can offer our patients, which are also very effective throughout their disease course, essentially at every stage, which is very exciting.

Dr. Adam Cohen: I certainly agree with everything Dr. Kapur is saying. We really do have all of these new exciting therapies, particularly the immunotherapies as Dr. Kapur has mentioned but we're actually starting to move some of these therapies up right into the consolidation-slash-maintenance setting after initial therapy.

And so, we're going to have a clinical trial opening up where we're looking at bispecific antibodies as a maintenance therapy, either alone or in combination with lenalidomide. And there's a number of other studies looking at combination maintenance therapies with more than one drug. So, this is, a really exciting time, and it's another reason why a referral to a myeloma specialty center can be helpful because we may be able to offer things to patients that may not be out there outside of the context of a clinical trial.

Host: Well, thank you to both of you. And Dr. Cohen, you mentioned CAR T. Tell us a little bit about where this fits in in the treatment of the disease. You mentioned, you know, at first adjuvant, but now more involved in maintenance. Speak about where this fits in in the treatment of disease, and tell other providers what you're doing at Penn Medicine with CAR T therapy.

Dr. Adam Cohen: Sure. CAR T-cells have been studied in myeloma for over 10 years now, and we actually have two FDA-approved products. One is called ide-cel, one is called cilta-cel. And we've been involved at Penn Medicine in some of the early trials of these that led to the approvals. And so, both of these were initially approved for very late line patients, patients with four or more prior therapies, where they showed remarkable activity response rates anywhere from 80 to 97%, including a high proportion of patients with complete responses. And many of these responses could be durable for several years without additional therapy. So, that's really the promise of CAR T-cells within the multiple myeloma space.

And more recently, these CAR T-cell therapies have been moved even earlier. We now have approvals to use one of them, cilta-cel, for patients in their first relapse. And  ide-cel is now approved after just two prior lines of therapy. So, it gives us a lot more flexibility as to when we want to use these powerful therapies within our myeloma patients. And then, as I alluded to earlier, there are trials ongoing now moving these up even a little bit earlier into the frontline and maintenance setting. So, there's really a lot of potential places to use these great therapies right now.

Host: Dr. Cohen, as we know, CAR T's been shown to produce improved survival and durable remissions in B-cell lymphomas. What are we seeing today in outcomes as far as multiple myeloma?

Dr. Adam Cohen: Sure. So, the initial studies, particularly with cilta-cel—which is the CAR product we tend to use more often here—had a medium progression-free survival of three years in a very heavily pretreated patient population median of six prior lines of therapy, mostly refractory to all of our standard agents. And there are a subset of those patients that continue to have durable remissions, even five years or more.

So while we are not convinced that CAR T-cell therapy is curative for multiple myeloma at this point, we see these prolonged remissions, and give patients a break from therapy sometimes for many years, which is appreciated because, in most cases, once you have relapsed from myeloma, you're just on continuous therapy and never get a break.

So, that's the initial data in the very late line setting. And then, once they're moved up a little earlier in the one to three prior line settings, that's where we're seeing even better outcomes. You have somewhat healthier T-cells at that point. The disease is less refractory. And in at least one large randomized trial comparing CAR T-cells to standard of care, there was not only a progression-free survival, but also an overall survival advantage, again, with the cilta-cel CAR product.

And so, that's what we're seeing today in terms of outcomes. And our experience in the real world is generally similar to what's been described in the trials. There've been a couple of real-world experiences published, and we're looking at our own experience and also seeing, very high response rates. There are toxicities with CAR T-cells, and we do have to monitor for those and counsel our patients about them. But for the most part, these treatments have really revolutionized the therapy of myeloma, particularly for relapsed refractory disease and, hopefully, soon in earlier lines than that as well.

Host: Do we know what contributes to these durable remissions and what can be done? What do you do to treat patients who relapse?

Dr. Adam Cohen: That's a great question. And one that's a really active area of investigation, both here at Penn and elsewhere. There are a few factors that have been identified. So, certainly, the health of the T-cells or what we call T-Cell fitness, I think, is important. And so, patients who have less exhausted T-cells, more naïve, early stem cell memory-like T-cells, seem to have better outcomes.

And so, one way we're trying to get a higher proportion of patients with those better qualities are to treat earlier, as we mentioned, also better disease control going into the CAR T therapy seems to be helpful. And so, we're using what we call more aggressive bridging therapy, the treatment that we use to keep the myeloma under control while we're waiting for the CAR T-cells to be manufactured.

In terms of relapse, there's actually a lot of options for patients, even if they relapse after CAR T-cells, and that's really important to get across to our patients that, even if this isn't curative and it does come back, the fact that they may have been off treatment for a year or two years or three years really allows their immune system to recover and then they have a better chance to respond to the next treatment.

And so, there are something Dr. Kapur alluded to called bi-specific antibodies. These are medications that are injected into the patient to activate the T-cells that are already in their bodies to try to attack the myeloma. And there are three of these now approved, and we use these commonly here at Penn. And then, sometimes you can even go back to some of the older drugs that you tried earlier if the patients haven't seen them in quite some time, and you can use them in a new combination.

  lastly, I think for patients who have relapsed after CAR T-cells or some of these other immune therapies, clinical trials can be really important. And this is where we're looking at a lot of newer immune therapies and other approaches to treat relapsed myeloma here at Penn and have a number of trials even for patients whose diseases come back after CAR T. So fortunately, there are still a lot of good options available.

Host: Dr. Kapur, how important is the multidisciplinary management for patients with multiple myeloma? Tell us a little bit about why a multidisciplinary team is so important for these patients.

Dr. Shivani Kapur: So, with myeloma therapy, especially during duration of the autologous stem cell transplant or while receiving cellular therapy, there are a lot of logistical considerations that really require a very large multidisciplinary team, including our expert physicians. We've got nurses, we've got APPs, pharmacists and social workers who help patients navigate and work very closely together and support them through this journey, and requires a team effort.

And I wanted to also highlight that our nurse coordinators for the transplant and cellular therapy do an excellent job in making sure the patients get the insurance approvals they need, that they know where they're showing up. They are supported towards understanding every step of the process of going through with these really good treatment options that are out there, but they're relatively new, and educating our patients to understand this a little bit better.

Host: I would love to give you each a chance for a final thought here, because this is really such an enlightening discussion we're having. Dr. Cohen, what does the future hold for CAR T in multiple myeloma? I'd like you to speak about the advent of T-cell redirecting therapy, for example, and how might someone who wishes to contact you about this, reach out for more information.

Dr. Adam Cohen: To answer the first question, the future of CAR T I think is really bright. We have two products approved, as I mentioned, but they're just the first-generation CAR T products that are out on the market. And there are newer ones, some of which hitting the same target on multiple myeloma cells called BCMA.

But some of the newer products are hitting a different target on the myeloma cell, and therefore may work even when the prior CAR T-cells have stopped working.

So, I think the immediate future is taking the existing products and moving them up earlier. And using them perhaps even in the frontline. And there are several trials that are ongoing exploring that. But then, coming shortly after that are some of the newer CAR T products that either may have better toxicity profiles or overcome resistance to the original products.

And then, as you mentioned, T-cell redirecting therapies, which can include CAR T, but also include these bi-specific antibodies. These are, I think, really nice off-the-shelf medications that can be given in the outpatient clinic and can be started here, but then can be given with the primary oncologist. And these can work maybe not quite as well as CAR T, but can salvage patients who have relapsed after CAR T, can get durable remissions that also can last in some cases for many years.

And so, I do think the future is bright. And one thing we're looking at Penn is figuring out ways to maybe combine these two approaches. So, we have a couple clinical trials now where patients get CAR T-cells and then are followed by a bi-specific antibody hitting a different target, trying to maybe eradicate any residual disease that might have lost or down-regulated the original antigen target. And so, we're hopefully having the tools now to try to really treat myeloma and maybe start to increase that cure fraction, and we just have to figure out the right way to put them all together.

Host: Thank you for that. And Dr. Kapur, last word to you. What makes the myeloma program at Penn Medicine so unique in your region? And what's your vision for this program? How will this care model improve the way patients receive their care? Tell us a little bit about what you would like to see happen, any blueprint for future research and what makes this program so unique.

Dr. Shivani Kapur: At Penn Medicine, again, we love combining the latest science and providing individualized care to our patients. We are able to offer access to clinical trials that are not available elsewhere in the region, which also means that our patients can get access to breakthrough treatments before they're widely available. We are looking forward to working with a lot of our partners out in the community to make a comprehensive care plan for our patients so that they're able to get some of these treatments locally, and close to home, where they feel more comfortable and not have to make many rides.

So, hoping that we can provide our patients ongoing care in terms of science as well as the latest treatments available.

Host: Thank you both so much for joining us today and sharing your expertise for other providers. To refer your patient to Dr. Kapur or Dr. Cohen at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole.

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