What Advanced Practitioners Need to Know About the Administration of Multiple Myeloma Agents: A Case-Based Approach

TIFFANY RICHARDS: We're going to move now into our second case, which is a patient with relapsed myeloma. So, this is a 56-year-old who was diagnosed in 2005, and we can see that their M-protein was 5.3 at the time of initial diagnosis. They were placed on a clinical trial, which randomized patients to an IMiD with dexamethasone versus placebo/dexamethasone, and they were randomized to the steroid only. At the time when the study was unblinded, they were then placed on an IMiD with dexamethasone followed by an autologous stem cell transplant, and, at that time, we weren't placing patients on maintenance therapy, and so they were followed in observation.

And so, for monitoring for these patients when they're in remission, making sure that we're getting routine myeloma staging studies, that we're monitoring imaging at least yearly, or, if they're having any new symptoms of bone pain, making sure that we're monitoring that because we can see progression of bone disease even when they don't have reoccurrence of their monoclonal protein. It's really important that we're following that. And then assessing for relapse, making sure that we're doing the serum protein electrophoresis and the free light chains, because there can be patients who while at the time of diagnosis had a monoclonal protein, at the time of relapse, they may just have progression of their light chains, and they may not have reappearance of their monoclonal protein, so it's really important that we're monitoring both of those.

If we look at the criteria for relapsed disease that was developed by the International Myeloma Working Group, we can see that it's a 25% increase from nadir, so in the patient, his nadir was zero. And it has to be an absolute increase of 0.5 in the serum, or 200 mg of their Bence-Jones. So, this person had a nadir of zero, and in order to be considered for relapsed disease, the M-protein would be 0.5, or their Bence-Jones would go to 200 mg. If they're having a rapid rise in their light chains, then it would be a difference between their involved and their uninvolved free light chains with an absolute increase of 100 mg/L.

If they have non-secretory disease and let's say they just had marrow plasma cytosis, and while those patients are very few, we do have patients who present that way, it would be an absolute increase by 10%. Or if they have development of a new bone lesion such as an increase in the size of their lesion or reappearance or appearance of a brand-new lesion. Or if they have circulating plasma cells, it would be an increase of 50%.

So, if we look at treatment regimens for patients in the relapsed setting, Donna and Beth talked about front-line therapies and all the different options for them. For maintenance therapy, we have the option of lenalidomide and/or proteasome inhibitor, and if we look at the relapsed setting, we have so many different options, and we generally use different combinations of all these regimens together. And so, I think it's really an exciting time for patients, particularly those who have gone through a lot of treatment and have been living with this disease for a long time, all the new treatments that have been approved in myeloma.

So, when we're selecting a second or subsequent line treatment, what are the characteristics in the patient and the regimen or in their disease, how their disease is relapsing, would you want to consider? And I'll start with you, Beth.

BETH FAIMAN: There are, you know, certain things that I'd like to consider, you know, in the relapsed setting again. What did they have before, how did they tolerate it? We highlighted the importance of neuropathy assessment, and so did they have neuropathy? And then I would try to avoid proteasome inhibitors. Are they refractory to IMiDs or refractory to other drugs? And so again, those are all important, but also important are, you know, what are their preferences? Does this person have to work full-time, and maybe they want an all-oral regimen or an intravenous or subQ regimen that can get them in and out of the clinic in a timely manner, and possibly be administered after hours, before hours, or on the weekend. So, again, finding out what's really important to them, what worked before, what didn't, and the disease characteristics as well are important to consider. Donna, what do you think?

DONNA CATAMERO: I agree with you. I would also add that what type of relapse is this? Is this something like a biochemical progression, or is this a symptomatic progression? Is the patient going into renal failure because of their disease? And again, that would reflect how I want to manage the patient.

RICHARDS: And I think those are all really important considerations, and we have so many different combinations, and, so given their prior regimen, we could consider daratumumab in combination with lenalidomide or dexamethasone, or potentially daratumumab with bortezomib/dexamethasone. Both of these regimens are approved after one prior therapy based on the results from the Phase III POLLUX and CASTOR studies. If they've never seen a PI before, do we save that for later? Do we use that now? And so we could use a proteasome inhibitor such as carfilzomib in combination with lenalidomide and dexamethasone based on the SPIRE trial. The patient previously had responded very well to an IMiD with dexamethasone, and so the potential to add a proteasome inhibitor to that regimen. And then for patients who've had more than two prior lines of therapy, we also can consider daratumumab in combination with pomalidomide and dexamethasone. This regimen was approved in 2017 for patients who have had more than two prior lines of therapy that include lenalidomide and a proteasome inhibitor, and this is based on the phase I EQUULEUS study.

And there's a phase III that's currently ongoing that's looking at daratumumab/pomalidomide/dexamethasone versus pomalidomide and dexamethasone alone. And so, if we look at the SPIRE trial, patients were randomized either to carfilzomib in combination with lenalidomide/dexamethasone or to lenalidomide/dexamethasone. We can see there is an improvement in progression-free survival. The PFS for carfilzomib/len-dex was 26.1 months versus 16.6 months with lenalidomide/dexamethasone. Additionally, there was an improvement in median overall survival by about 8 months with carfilzomib. And we saw not only a very high response rate, but a deeper level of response with the triplet regimen compared to the doublet.

As far as AEs, we can see that in the carfilzomib arm, there was more hypertension that occurred. There was about 4% of patients who had cardiac failure, an increase in ischemic heart disease. The acute renal failure was equivalent in both arms, which I think that's a very important point to make, that there wasn't an increased risk of acute renal failure in the carfilzomib arm. And dyspnea was a little bit more common in the carfilzomib arm.

If we move to the POLLUX trial, where patients were randomized to daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone, again, we saw a more than doubling of the median progression-free survival with the daratumumab arm of 44.5 months versus 17.5 months. Again, we saw an improvement in the level of the depth of response. So, the MRD negativity rate in the daratumumab arm was 30.4% compared to only 5.3%, and I think that's a really, really important point to take note of.

If we look at the adverse events, we can see that cytopenias were more common in the daratumumab arm with neutropenia. Anemia was about equivalent in both arms, and same with thrombocytopenia. Pneumonia was more common in the daratumumab arm, which we have seen in prior studies.

If we look at daratumumab/pomalidomide/dexamethasone in the phase I study, there are three different cohorts. There was patients who received daratumumab with pomalidomide, and those patients had never seen pomalidomide before. There was Cohort 2, and these were patients who were daratumumab- and/or pomalidomide-naïve. And then there was Cohort 3, and these patients were daratumumab- and pomalidomide-refractory. And I think the important point to note with this group is the Cohort 3, because a lot of times I think—we think that because patients have progressed on a prior regimen or a prior drug that we can't use that drug in combination anymore, and that's just not the case. So, if we look at Cohort 3, we can see the overall response rate was 33.3%, and even though it's a third of patients, their median overall survival was 13 months, which is an improvement. And the same with Cohort 2, patients were daratumumab- and/or pomalidomide-naïve. Again, the response rate was 40.9% with a median overall survival of 15.2 months.

So, if we look at differences in adverse event frequencies between the first-line and subsequent-line treatments, I think we all can relate that patients, the more treatment that they’ve had, the more AEs they tend to experience. So, Beth, what would be your watch-outs?

FAIMAN: So, I think one of the things I just want to circle back and highlight, you did mention, Tiffany, about MRD negativity, and I don't know if we highlighted it enough. The MRD negativity, the 10x10^-5, 10x10^-6, that's detecting about 1 in a million myeloma cells in the bone marrow, and I think if we could achieve that at relapse, I think that is just phenomenal. It's a major goal at diagnosis, but at relapse it's also possible. We have clinical studies ongoing in my institution and others that are looking at it in relapsed population as well. But, again, making sure that they're responding to treatment is very important, as well as monitoring for side effects. Infection-related reactions about 50% of the time can occur with some of these monoclonals. In the ICARIA study, it was so nice to see a lower incidence. And then it's even further lower in the subQ daratumumab trials. So, I think looking for infusion reactions, infection, and DVT prevention are all these similar recurring themes that I'll look for in my patient population. Donna?

CATAMERO: Yes. So, again, with infection—so as we know, as with each relapse, the bone marrow fatigue as I call it, these patients will have baseline cytopenias. So, I'm always hypervigilant of infection, and we know in this day and age, with COVID-19, that we are worried about infection for our patients. So, those are my watch-outs again. I get very concerned about the cytopenias.

RICHARDS: And I think both of you are bringing some very good points. Other regimens that we can consider in this patient group are PI-based regimens, such as carfilzomib in combination with either lenalidomide, pomalidomide, or cyclophosphamide. We also have elotuzumab in combination with either pomalidomide or lenalidomide.

And then as of March 2, 2020, we have isatuximab in combination with pomalidomide/dexamethasone in patients who have had more than two prior lines of therapy, including lenalidomide and a proteasome inhibitor. And this is based on the phase III ICARIA trial. In this trial, patients were randomized to either isatuximab/pomalidomide/dexamethasone versus pomalidomide and dexamethasone. We saw almost a doubling of the progression-free survival in the isatuximab arm. The response rates were higher with the isatuximab. And as Beth had previously noted about the MRD negativity rate in our relapsed population, this is a patient who had received many prior lines of therapy, were refractory to a proteasome inhibitor as well as an IMiD, and still 5% of those patients were able to achieve MRD negativity.

As far as the adverse events that we saw, it was relatively similar. There was slightly more cytopenias in the isatuximab arm, but infection risk was about the same between the two arms.

So, when we consider treatment sequencing, what factors are most important to you? Is it the depth of response, disease control? How do you go about making that determination? Beth?

FAIMAN: I think it's different per patient. We really try to personalize the recommendations for therapy in our patients with myeloma, because it's one diagnosis but you have the light chain myeloma that has primarily serum free light chains, some people have more bony disease, and everybody's just different, in terms of the age as well. So, similar characteristics of the first and second, I think what's more challenging is they go along. The first relapse, second relapse even, it's kind of easy, what worked, what didn't work, what are their side effects and morbidities. But, as they get along in it, I think it's more challenging. Now we have isatuximab and daratumumab in a very similar space in first, second relapse especially, and they're both anti-CD38. So, I think it's going to be interesting to see if people didn't get daratumumab up front, are they going to now get isatuximab and then daratumumab, or is it gonna be back and forth? So, again, looking at the disease and the patient characteristics and preference is this overwhelming thing.

Donna, what were your thoughts now that isatuximab is available and also being an anti-CD38? Has that changed your practice at all?

CATAMERO: Well, I think now we feel more comfortable using daratumumab in the front-line setting, because we do have another effective monoclonal anti-CD38 for the relapse setting. So, and I think, you know, it's the year 2020, we have so many options for patients where we couldn't have said this, you know, a few years ago. I think in this day and age, given the options we can offer patients, I think that I would want both like depth and durability of my treatment regimens. And I think we can now do that, whereas a few years ago, we couldn't. So, someone on their fifth- or sixth-line of therapy, we can get into very deep remissions and durable remissions. I think that's my goal, given that we have now a new menu, a larger menu of agents that we can use.