Recent Advances in Multiple Myeloma: Insights from Experts at Dana Farber Cancer Institute and Massachusetts General Hospital - Episode 8

Patient Profile 3: A 57-Year-Old Woman With Triple-Class Refractory MM

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Moving to the last patient profile, expert panelists discuss a patient with triple-class refractory multiple myeloma managed with BCMA-targeting bispecific therapy.

Noopur Raje, MD:
With that, we’re going to move into the relapsed/refractory setting where we have an interesting case, and Andrew you’re going to be presenting this next case for us.

Andrew J. Yee, MD: Thank you, Noopur. I wanted to talk to you about a patient in our practice who is illustrative of where the field has gone in relapsed/refractory multiple myeloma. This is a 57-year-old woman who presented with right pathologic hip fracture. She had high-risk FISH [fluorescence in situ

hybridization] with translocation (14;20). She received initial therapy with lenalidomide, bortezomib, dexamethasone followed by lenalidomide maintenance. However, she developed relapsed disease and has been through multiple lines of therapy. She had daratumumab, bortezomib, dexamethasone then she had daratumumab, RVd [lenalidomide, bortezomib, dexamethasone], and then she had 2 additional lines with carfilzomib, lenalidomide, dexamethasone, and carfilzomib, pomalidomide, dexamethasone. You can see here that she has developed what we would call triple-class refractory, penta–drug exposed disease. We all have patients like this in our practice, and these patients are some of the most challenging patients to treat. She was able to participate in the clinical trial with anti-BCMA bispecific antibody for triple-class refractory disease, which occurred 3 years after her diagnosis, which illustrates how high risk she was; the fact that she has gone through all these lines of treatment within 3 years. In this clinical trial, she received step up dosing anti-BCMA antibody and a week later received the full dose, however, 2 days after the full dose she develops a fever of 101 °F as well as some mild grade confusion. With these clinical trials and anti-BCMA bispecific antibodies, they are generally hospitalized to monitor for risk of CRS [cytokine release syndrome] as well as neurotoxicity, so in the hospital she received tocilizumab as well as dexamethasone given that she had elements of both. Fortunately, the CRS and ICANS [immune effector cell-associated neurotoxicity syndrome] responded nicely to the tocilizumab and dexamethasone. The key thing is that this patient can see that she went through all those lines of therapy and continues this anti-BCMA bispecific antibody over a year later with excellent quality of life and continued complete response.

Noopur Raje, MD: This is a great case Andrew, thank you for sharing. This speaks to the evolution of where we are with myeloma. She has been through multiple lines of treatment and seems at least up until what she got in terms of the bispecific was refractory patient. She never achieved any kind of remission, was never able to collect her stem cells, or get transplanted. In this younger patient you are having access to a bispecific T-cell engager, which was absolutely critical, but before we talk about what’s available in terms of immunotherapies I think it’s important to recognize relapse is common in all myeloma patients and generally when we think about relapse we think about late relapse; early relapse would be patients who have had one line. The typical patients which you both described GRIFFIN trial [NCT02874742], we don’t know what the PFS [progression-free survival] will be, but the MAIA trial, we know on average these patients are going to relapse at least close to four years out. That’s quite remarkable and at that first relapse most of our patients who relapse, as you both have pointed out, continue treatment pretty much up until progress, until most of them are on lenalidomide maintenance. Maybe going forward they would be on daratumumab as well but if they are on lenalidomide maintenance most of them are lenalidomide refractory. When you think about that first relapse before we talk about this specific patient, Andrew, what would be the kinds of combinations that you would think of in a lenalidomide-refractory patient?

Andrew J. Yee, MD: In this current scenario, and in this current time, nearly all patients have had lenalidomide upfront and are on lenalidomide maintenance. When I think about patients who have developed refractory disease I think about, as Jacob pointed, the factors that influence treatment decision. Was this an early relapse? was it1 to 2 years of their initial diagnosis, or was this later on, 5, 6, or 7 years? is it asymptomatic biochemical relapse or is it relapse that has some clinical feel to it; as in the patient noticed the relapse like the patient had a painful lytic bony disease, more fatigue, or the patient is becoming increasingly anemic or developing renal dysfunction? Those are things I think about in terms of the ideal therapy. Typically when I think of a patient who has not had NTCD30 antibody, if they have not had in the beginning, now there is opportunity to receive it at this point, because as you mentioned there’s an ongoing theme here, which is that you want to give your best treatments upfront not just save them for later because there is this continued attrition over time. When they relapse that is an indicator that the disease is acting up and that should be a time to think about intensifying their therapy. At first relapse, I typically think of using anti-CD38 antibody, either daratumumab or isatuximab, and there is a growing bench of clinical data using triplet-based combinations with either daratumumab or isatuximab, and then we think about the partner and again that’s a whole other debate. We could speak all afternoon or evening talking about which [] in terms of pomalidomide or carfilzomib. I think both have their advantages as well as considerations. From the emerging data from the CANDOR [NCT03158688] data and IKEMA [NCT03275285] data, if you look at the lenalidomide, one of the criticisms with CANDOR and IKEMA was that half the patients were lenalidomide, but if you look at the lenalidomide refractory cohort of CANDOR or IKEMA, those patients did well with the triplet-based combination. I also realize you must think about the patient in front of you, for some patients carfilzomib can be tougher to manage, but as we have gotten more used to itwe have been able to better manage and reduce the risk of some of the cardiac adverse events. Pomalidomide is also a great agent. For patients where it maybe more of a biochemical relapse, some of the convenience of having the oral pomalidomide, can be convenient, for example when married daratumumab subcutaneously. For that patient that could be an ideal triplet combination. Again, it depends on the type, not all relapses are the same. You must tailor the regimen to the type of the relapse.

Noopur Raje, MD: I couldn’t agree with you more Andrew. It speaks to the heterogeneity that we see in our patient population, and having a good understanding of what’s available. You mentioned pomalidomide based combinations and carfilzomib-based combinations. If you haven’t had a CD38 upfront this would be the time to consider it. We tend to use a lot of carfilzomib and pomalidomide combinations because our patients have seen the CD38 monoclonal antibodies, so lots of interesting exciting data in that early relapse.