The Current Treatment Landscape for Relapsed/Refractory Multiple Myeloma: A Case-Based Approach

Rhonda Hewitt: Welcome to this virtual Roundtable on management of relapse/refractory multiple myeloma. My name is Rhonda Hewitt, and I'm a nurse practitioner at Stanford Health Care in Palo Alto, California. And joining me today are two of my colleagues, Kevin and Ann. Kevin and Ann, if you would please introduce yourselves.

Kevin Brigle: Hi, I'm Kevin Brigle. I'm a nurse practitioner in the heme-malignancy clinic in Virginia Commonwealth University, Massey Cancer Center.

Ann McNeill: Hi, my name is Ann McNeill and I'm a nurse practitioner in the myeloma division at the John Theurer Cancer Center in Hackensack, New Jersey.

Rhonda Hewitt: Thank you. Today we'll be discussing steroids in the relapsed refractory multiple myeloma patient, and really the management of that. And how we'll discuss that is through a case study. Sergio is a 62-year-old male who presents to his primary care doctor complaining of bone pain and fatigue. His hemoglobin is 9.4. He has multiple lytic bone lesions with vertebral compression fractures at T4 and T7. His creatinine is elevated at 1.8, and he is referred to hematology, where he is diagnosed with IgA kappa multiple myeloma with a translocation 11;14, consistent with standard-risk multiple myeloma. Would you guys classify him as a standard risk? And with that translocation, how would that affect the therapy choices for Sergio?

Kevin Brigle: Well, I think upfront, if I can speak here first, I don't know that it impacts his treatment too much right up front. The 11;14 is a little bit more important down the line. I think the therapy up front is going to be fairly standard for a lot of patients.

Rhonda Hewitt: Yeah. I agree with you, but it does jump out at me that translocation and it makes me think, okay, well, what options do I have in the future for him? Sergio has a past medical history significant for diabetes, renal insufficiency, and now the myeloma. His family and social history, he's married, he lives with his wife. They have one grown daughter. He's actually a pharmacist and he founded two biotech companies here in the Bay Area. His medications, he's on metformin, 500 milligrams daily. And as you alluded to, Kevin, in May of 2015, he begins therapy with a pretty standard induction therapy with lenalidomide, bortezomib, and dexamethasone. Unfortunately, he had to have multiple dose adjustments due to toxicity. With the lenalidomide, he developed cytopenias, and with the bortezomib, he had peripheral neuropathy as well as cytopenias.

Possibly his diabetes contributed to that peripheral neuropathy, but as you are aware, that's a known side effect of bortezomib therapy. And then with his dexamethasone, he actually had steroid intolerance due to emotional liability, energy swings, and poorly controlled diabetes. Ultimately his dexamethasone was completely discontinued as his diabetes was out of control, necessitating endocrinology consult, sliding scale insulin, and actually hospitalization for an episode of hypoglycemia. In August of 2015, Sergio underwent a cyclophosphamide mobilization and autologous stem cell collection after receiving four cycles of the lenalidomide, bortezomib, and dexamethasone.

He had his autologous stem cell transplant in December of 2015 with a melphalan 200 mg/m² preparative regimen. And he went into a complete remission and he was started on post-transplant maintenance therapy with lenalidomide. Unfortunately, with the lenalidomide, he, again, developed cytopenias. I think we see this more after transplant when the marrow was a little bit more fragile as it’s recovering. But because of those cytopenias, he required multiple dose reductions. In August of 2017, his free light chains started to rise a little bit, and the patient preferred at that time to just try adding a little bit of steroids back.

We added 20 of dexamethasone weekly. With that steroid, he was followed very closely by endocrinology, and they were adjusting a sliding scale insulin pretty tightly. Overall, his diabetes though was very poorly controlled, and he generally would be hyperglycemic almost every single time that he came into the infusion area. In December of 2017, his free light chains were rising again. And he started therapy with daratumumab, bortezomib and dexamethasone. After his third dose of daratumumab, the dexamethasone was tapered.

It actually was tapered every week until it was completely discontinued because we could never get his diabetes back under control. And he continues to follow with endocrinology for that diabetes. And after several weeks of being off of the steroids, the sugars finally stabilized. He remains on insulin, and his myeloma is in remission on monthly daratumumab and bortezomib, which he's receiving both of those subcutaneously. Have either of you had patients like Sergio who have struggled with diabetes management?

Ann McNeill: Yes, absolutely. Unfortunately, dexamethasone is one of our most challenging drugs, and it's not a benign drug at all. And we've had to do the same situations with dose reducing the steroids. Unfortunately, we all know that when you start dose reducing and eliminating the steroids, you do risk having a reduced efficacy. It's a give-and-take relationship. But, of course, uncontrolled diabetes is harmful, it's not pleasant, it's something we have to deal with as well. But we have definitely in our clinic dose reduced the steroids and totally eliminated them in a couple of patients. We actually tried to go to prednisone in a few patients as opposed to dexamethasone to see if there was any benefit. Sometimes there is, and sometimes there isn't. So another possibility to try prednisone instead of dexamethasone.

Rhonda Hewitt: Yeah. That's an interesting thought. I don't know if we've done that. You also bring up another point where you say dexamethasone, it's in almost all of the myeloma regiments. And historically, before we move to this era where we're using less chemotherapy, more targeted therapies in myeloma, before we moved to that, many of the regimens for myeloma, the only active ingredient in them was probably the dexamethasone. I think those of us who have practiced in myeloma for a long time, it's really hard for us to give up the dexamethasone, but hopefully the agents that we're using today don't require as much dexamethasone.

Kevin Brigle: Right. And I would add in there too, that I think when patients first relapse when they're first diagnosed and their plasma cell burden's really high, that's really when the steroids have their most impact. When their disease level's very low, let's say a person's MRD negative but really the steroids don't have much impact at all. It's really more targeted therapies that we'd be talking about the dara, the lenalidomides that are really the most important part of them as well. And along the lines of what Ann said, yes we've used prednisone as well and even methylprednisolone which is a very [inaudible] drug as well. So that's another option for patients.

Some of the key takeaways from Sergio's case are the ones that we're talking about, how do we manage steroids, and how do we manage diabetes? But I think that in our institution and from talking to you guys, I understand that you work very closely with your consult services, the other departments, endocrinology maybe. We have a diabetes educator that works with our patients. Because some of our patients, maybe they were managed with oral medications and then once we give them steroids, they need to be put on sliding scale insulin and stuff.

And maybe they only need a sliding scale insulin temporarily, and then they can get back off of that. But I also wanted to ask when you're considering the next line of therapy for patients. For Sergio, we went to daratumumab, bortezomib and dexamethasone. And at the time, he had been induced with RVd, had an autologous stem cell transplant, and then was on lenalidomide maintenance. What would maybe be some of the other things? I think Kevin, you alluded to this a little bit. When you're thinking of the next line of therapy if Sergio was to relapse, what would maybe be something else that you might think of for him?

Kevin Brigle: Well, I thought in his case too, this was an interesting choice. Obviously he responded to the bortezomib regimen up front, but I noted he also had peripheral neuropathy, which I think we have to consider what's left over? What are the sequelae from your previous therapies that might be problematic? And sometimes it's those side effects that are going to guide your treatment even though the drug may be working, that the side effects are going to be the thing which tips you one direction or another. And I think originally, if we're going to go a little bit further when we look at his original cytogenetics, he had that 11;14 translocation, which we know is a reasonable marker. And there are clinical trials ongoing for drugs and specific for patients who have that marker as well. Something down the line as Ann alluded to.

Rhonda Hewitt: I think looking back on Sergio, he started on the daratumumab, bortezomib, dexamethasone in 2017. And I think today we probably wouldn't have given him the bortezomib. I can't recall when daratumumab, carfilzomib,, dexamethasone was approved, but maybe we would've done a different regimen had that been approved and we were able to give it with insurance authorization.

The last thing that I wanted to discuss when we are talking about Sergio is the use of minimal residual disease testing in multiple myeloma. When Sergio was going through therapy and he started on the daratumumab, bortezomib, dexamethasone, we were not routinely testing for MRD in our myeloma patient population. But it's interesting to me when I see that now he's been in remission for about 5 years, I wonder if he actually achieved a minimal residual disease status at that point in time. Can you guys tell me, when did you routinely start checking for MRD and myeloma, and how do you use it in myeloma? Do you use it more as prognosis or are you using it to guide your therapy?

Ann McNeill: That's a very good question, Rhonda. I mean, I can't remember exactly when we first started doing MRD testing. I just can't remember, but we do it in-house. A lot of the big academic centers do it in-house. A lot of places don't have that luxury of doing it in-house, but it's a very interesting tool. We all have patients who have a little bit of an M spike, and they stay like that for decades. And then you have somebody who is MRD negative, and you can see a full minute relapse 6 months later. So we are using it. I mean, there are studies that show that MRD negativity is associated with a better outcome, but we are using it very judiciously. So I think that we still need more studies, but we are using it. And it does guide our therapy where we would like to achieve that. We think it's a good goal but again, it's just a challenging topic right now.

Rhonda Hewitt: Kevin, did you want to add to that?

Kevin Brigle: Yeah, I'd agree. So we always get the MRD analysis on initial bone marrow biopsies on patients. And we do a gene testing as opposed to flow cytometry. I think Ann brings up a good point though. We don't really know what to do with it. And all of our clinical trials, of course, are looking at MRD. And so I think that's where we're going to get our guidance down the line. So if someone's MRD negative, we don't decrease therapy. And if they're MRD positive, we don't [inaudible] therapy, and patients are always big on this MRD. We have a lot of patients who are very savvy, and they talk about MRD, and we try to explain it to them, this is just the next step. We always like people to be in a stringent complete response as opposed to a complete response, but we didn't make therapy any tougher to get you there.

Ann McNeill: You bring up a great point about the clinical trials. I think that we're going to get a lot more information in the future. Because even though it's not an FDA requirement for a lot of these trials, a lot of the companies or the sponsors of trials are gathering this data, which is really going to be beneficial for the patients as a whole in the future. But what does this really mean? So I think it's going to be an excellent data point in the future.

Kevin Brigle: Absolutely. And I think what it'll end up being or at least the hope is that it'll end up being, we can no longer use for all survival because patients are living so much longer. But I think that might be a primary endpoint for a lot of the clinical trials as a surrogate marker than for efficacy.

Ann McNeill: Yeah.

Rhonda Hewitt: I think what I would say when I talk to my patients, when I say about MRD is in some of our malignancies that we treat, it really does guide our therapy. For myeloma, it certainly seems to be associated with prognosis, but we're not quite there on how to use it to guide our therapy yet. So those clinical trials, they'll come hopefully in our lifetime. So I think that brings us to the end of Sergio's case. Please see our other segments for further discussion about relapse/refractory multiple myeloma, or visit advancedpractitioner.com. Thank you for joining us today.