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

BETH FAIMAN: At this time, we'd like to start a discussion on what's new in the treatment of multiple myeloma and take a deeper dive into the newer regimens for multiple myeloma. Donna?

DONNA CATAMERO: Yes. So, our first patient is a 76-year-old woman who we've been monitoring two to four times a year for the past 7 years, given her history of MGUS. So, we follow this patient by her serum kappa free light chain, and as you can see on the slide, her kappa free light chain has steadily been increasing over time with various degrees of fluctuation in her numbers. But, since this patient was otherwise asymptomatic without CRAB symptoms, we continued to monitor her off treatment.

On her last routine visit, this patient complained to me about an acute history of lower back pain. So, I obtained an MRI of her spine, and it revealed that she had a compression fracture in her lumbar spine at L5, and on the slide here we can see that she has lost about 80% of the height of the vertebrae. We did a further workup with a bone marrow biopsy, which revealed 40% kappa-restricted plasma cells, with standard risk or normal cytogenetics. Her blood count revealed that she did have anemia with some degree of thrombocytopenia, as well as renal insufficiency.

When considering treatment options for newly diagnosed myeloma patients, we have to consider several factors. The first question that we need to ask is, is this patient transplant eligible? So, we know that age is an important factor, but it's not a limiting factor. We use the Myeloma Comorbidity Index, and this takes into account comorbidities, performance status, age, frailty, as well as cytogenetics. And some other considerations that we do take into account are caregiver support system, patient logistics, how far does the patient live from the center, can they come in for multiple visits, etc.

We determined that this patient was transplant-ineligible, given her age and some comorbidities. So, we do have several options we can choose from when starting treatment for this patient. We can either choose a daratumumab-based regimen in combination with either lenalidomide or dex, or in combination with bortezomib, melphalan, and prednisone. We can also consider a reduced intensity of RVd, which is lenalidomide and bortezomib/dexamethasone.

So, this brings us to our first question of the day. Given that we have multiple options for our patients, how do we approach the discussion with the patient so that we involve this patient in a shared decision-making model? Tiffany, I'm going to go to you first. How do you approach the patient?

TIFFANY RICHARDS: I think the good thing in myeloma now is we do have multiple options for our patients, even in the front-line setting. And so generally how I approach it with the patients is I give them their options. Go through each of the different regimens that are available, go over the side effects, go over the schedule, how often they're going to have to come to an infusion therapy center. I also look at do they have any pre-existing comorbid conditions that may preclude them from one option; particularly if, do they have peripheral neuropathy from, let's say, diabetes or other factors that could cause that. If they would, then I may want to avoid a bortezomib-based regimen. Additionally, I look at how active they are; are they able to get up and walk around, are they at risk for falls? And so those are all important considerations that I take into when discussing these regimens with our patients.

CATAMERO: And what about you? What are your thoughts, Beth?

FAIMAN: I think this is a really important discussion to have with the patients, in terms of, you know, what their desires are. Many patients are also afraid to say, “I don't really have a support system.” Maybe their daughter, son, significant other works full-time, and so they don't want to burden them with responsibilities. So, similar to what Tiffany shared, I like to look at the cytogenetics, what's the risk of the disease, do you have high-risk or standard-risk disease, what kind of side effects are you willing to accept in order to get treatment for your myeloma? And, again, setting the stage that this is a long-term therapy. It's a marathon, not a sprint. Sure, we want to achieve a deeper response to hopefully keep you in remission longer, but there are many different ways we can do that.

CATAMERO: So, you know, I did speak with this patient. However, she still wanted to pursue transplant as an option. depending on institution, there may be age limitations, but for—I know, Tiffany, you're at MD Anderson, which is a big transplant center. So how would you have this discussion with this patient? She is generally fit, but would she be an appropriate candidate? How would you lead that discussion?

RICHARDS: At our center, age really isn't considered an adverse feature. I think for us it's more important what their performance status is, and, if they have limited mobility, is it because of the disease process? So, let's say they've got a compression fracture, and maybe that's what's limiting their mobility. Or is there another factor due to a comorbid condition that's limiting their ability?

Sometimes if we're on a fence with a patient on whether they would be a good candidate, we tell them, “let's see how you do with induction therapy.” If they don't tolerate their induction therapy, then that would definitely tell us that this patient is probably not a good candidate for a stem cell transplant. And so that's generally how we approach it.

FAIMAN: And I would agree with Tiffany. I think that if patients are sick, they're in a wheelchair, they have compression fractures when they are diagnosed, we can actually improve their performance status with therapy. So, that's one of the ideas behind that induction regimen and starting that first 4 to 6 months. And so, again, age is not necessarily a factor, but you want to try to get the longer life available. Honestly, if she has normal cytogenetics, and she doesn't have high risk, I might just choose a standard therapy with ongoing therapy, and that might like help her live longer than complications from a transplant.

CATAMERO: Right. And as we discussed, this patient did have standard risk cytogenetics, which brings me to our next slide, which is the mSMART criteria. And this is a consensus opinion developed by the Mayo Clinic, and it takes into consideration cytogenetics. For example, if a patient does have high-risk cytogenetics, that would tell me that maybe their disease is a little more aggressive, that they are at higher risk for relapse, and that they probably have poorer outcomes. So, this might change how I'm thinking about how I want to treat my patient.

Then our next question is, you know, selecting that first-line treatment, given that we have so many options. Do we approach a daratumumab-based option or another option? So, how I approach this is, again, I have this conversation with the patient, and I review the results from recent phase III data, as well as the patient journey for myeloma, and the various options that this patient may have throughout the course of disease. Tiffany, how would you approach this patient?

RICHARDS: I would say that we generally don't use a BMP-based regimen. We would offer them either daratumumab, lenalidomide/dexamethasone, or bortezomib/lenalidomide/dexamethasone. And depending on the patient, and while we don't want to consider cost into our decision-making process, I think it's important for patients to be aware of the cost of the oral regimens. So, if I have a patient who maybe I don't think will qualify for a copay assistance program, but they tell me they still can't afford the price of lenalidomide, then that might be somebody that I would opt to do bortezomib/cyclophosphamide/dexamethasone, because I can always give cyclophosphamide IV if I need to. And so that's also, I think, an important discussion point when we're having these conversations, particularly with our Medicare patients, that I do talk with them about that.

CATAMERO: What are your thoughts, Beth?

FAIMAN: I totally agree. There are so many—it's almost an embarrassment of riches, right? We have oral, we have IV, we have subQ therapies, and they can be given in different ways. Daratumumab was just recently FDA approved for subcutaneous administration, which is so attractive for our patients. So, maybe it used to be a long infusion and you're in the clinic for hours and hours the first time, and then you're at risk for infusion reaction, and as we'll hear later on, I think it's not as much of an issue with the subQ formation. And so, when patients hear it's just a subQ shot, maybe oral or IV, that will impact their decision making in terms of transportation back and forth. If transportation is an issue, we do have programs within my cancer center, as many others do, where you can get like Uber and Lyft services, not only through the manufacturer but through the cancer center, and we can help facilitate their coming back and forth to therapy for free in many cases.

CATAMERO: Great. So, you know, speaking of daratumumab, it's a fully humanized IgG kappa monoclonal antibody that targets CD38. And what's attractive about the CD38 is that we know that it's overexpressed in myeloma cells. So, daratumumab actually has several indications in the front-line setting. First, in the non–transplant-eligible patient population, it's approved in combination with bortezomib, melphalan, and prednisone, and this approval was based on the phase III ALCYONE data. Next, it's also approved in combination with lenalidomide and dexamethasone, and this was approved based on the phase III MAIA trial. And then, for our patients who are transplant-eligible, daratumumab is approved in combination with bortezomib, thalidomide, and dexamethasone, and this was approved based on the phase III CASSIOPEIA trial.

So, let's dive a little bit deeper into the phase III trials which led to FDA approval of daratumumab in the non–transplant-eligible setting. So, ALCYON is a randomized phase III trial with bortezomib, melphalan, and prednisone plus or minus daratumumab. And, as we can see, the results on the slide that the addition of daratumumab improved outcomes. We had improvement in overall survival and progression-free survival at 36 months. Our overall response rate was 90%, and we saw an almost doubling of the CR rate at 46%. So, when we look at safety and tolerability, we see that the groups are fairly equal in regard to cytopenias, but we do see a higher incidence of infections as well as infusion-related reactions, which is the known safety profile of daratumumab.

Our next trial is the MAIA trial, which is, again, a phase III trial of lenalidomide and dexamethasone plus or minus daratumumab. And, again, we do see improved outcomes with the addition of daratumumab in progression-free survival at 30 months, and overall response rate at 92%. So, again, we see a doubling of that CR rate, and then we see even deeper responses with an over 3-fold improvement in the MRD negativity. So, again when we look at safety and tolerability, we do see higher rates of neutropenia as well as a higher incidence of pneumonia, but otherwise we don't really see any new safety signals in either this trial or the ALCYON trial.

Next, is RVd-lite. This is an alternate schedule of lenalidomide, bortezomib, and dexamethasone, and this was based on a single institution phase II study with a reduced intensity, and each cycle now is 35 days with bortezomib given on a weekly schedule of 4 out of 5 weeks. Lenalidomide is dose reduced at 15 mg, and is given on a 21 out of 35 day schedule. And then dexamethasone is reduced to 20 mg, and it's given on the day of and after bortezomib. So, really what this trial demonstrates, that the benefits of these more effective combinations that we observe in our fitter, younger patient population, we can modify them without compromising the efficacy for our older, more frail patient population.

So, this brings to me to my last question. When starting a patient on treatment, my AEs that I watch out for. So, as discussed in the trials, we did see that we had higher incidences of neutropenia. Cytopenias always concern me, so I'm always monitoring my patients quite frequently with their lab work. And then Tiffany had mentioned neuropathy, so I worry a lot about neuropathy, because in some cases, it's irreversible. If a patient has a pre-existing condition of diabetes, might be more prone to neuropathy, it might adjust what I’m thinking about how I start that patient and how I'm monitoring that patient, because I want to dose-reduce my regimen. So, Tiffany, I'll throw this question out to you. What are your watch-outs?

RICHARDS: The other thing I think is important is that patients are educated on the signs and symptoms of DVT and pulmonary embolisms, and that they're aware of those symptoms, so that they can promptly report it and go to the emergency room, and I think that, for me, is the biggest thing with our patients. And, also, what other symptoms that they need to know and making sure they know how to report those side effects. Generally speaking, if it's a patient that we're starting on treatment who’s more frail, I'll actually see them in clinic prior to each of their treatments or their injections. If it's a patient I feel pretty confident that they're going to do okay, then they'll just go to the infusion therapy center, and the nurses in infusion therapy will be monitoring them. So, it really depends on how concerned I am about their frailty and their other comorbid conditions. But, just making sure that they're aware what to report and when to report.

FAIMAN: Yeah, absolutely. I totally agree, Tiffany. I think infection is a big risk now. Right now, we are in an area of time where we're really worried about infection, so there's a heightened awareness of the need to report temperature elevations and wash hands and avoid people with colds, infection prophylaxis for monoclonal antibodies and proteasome inhibitors really includes that shingles prevention. I just want to ask the two of you—there was a paper out of the UK which used levofloxacin for the first 3 months of therapy to minimize the risk of early death from myeloma-related infectious complication. Does anybody in your center use levofloxacin for 3 months?

RICHARDS: At our center, we have not implemented that. You know, if we have like a patient who's maybe relapsed-refractory who's been having frequent infections, that might be somebody who frequently becomes neutropenic with therapy, we may put them on something, but we don't routinely put anybody on prophylactic antibiotics with levofloxacin.

CATAMERO: I agree with Tiffany. We haven't started implementing that, and, again, we know with refractory patients, relapsed-refractory patients, they have baseline cytopenias, so if I see a patient who has a baseline low ANC, we may prophylax, but routinely we don't start patients off on therapy.