What Advanced Practitioners Need to Know About the Administration of Multiple Myeloma Agents: A Case-Based Approach
In addition to choosing the right combination of agents for patients with multiple myeloma (MM), it's important to consider the best method of administration for each patient.
In this video roundtable discussion, moderator Beth Faiman and her colleagues weigh in on what APs need to know about the available administration options in the MM landscape. Learn from the panel members as they share their experience and expertise through cases illustrating the nuances of the advanced practice role.
Beth Faiman, PhD, MSN, APRN-BC, AOCN®, FAAN
Taussig Cancer Institute Cleveland Clinic
Donna Catamero, ANP-BC, OCN®, CCRC
Mount Sinai Hospital
Tiffany Richards, PhD, MS, ANP, AOCNP®
MD Anderson Cancer Center
BETH FAIMAN: Welcome to this virtual roundtable about what's new in the administration of multiple myeloma agents, a case-based approach. My name is Beth Faiman, and I'm a nurse practitioner in the department of hematology and medical oncology at the Cleveland Clinic Taussig Cancer Institute. Joining me today for this discussion are two of my colleagues. Donna?
DONNA CATAMERO: Hi, I'm Donna Catamero. I'm the associate director for myeloma translational research, as well as a nurse practitioner at Mount Sinai Hospital in New York City.
TIFFANY RICHARDS: I'm Tiffany Richards. I'm a nurse practitioner at MD Anderson Cancer Center in the department of lymphoma-myeloma.
FAIMAN: In this virtual discussion, we'll review several different new therapeutic therapies with different routes of administration for patients with multiple myeloma. Our discussion will begin with an overview of the current treatment recommendations for multiple myeloma. Then, we will explore together the treatment selection of three different patients, including a patient with newly diagnosed disease, and two patients with relapsed disease.
Here on this slide, we have the faculty—Beth Faiman, Tiffany Richards, and Donna Catamero.
Here, I'd like to start with the introduction to the treatment of multiple myeloma. So, multiple myeloma, as you are well aware, is a cancer of the bone marrow plasma cells. There are various stages of multiple myeloma and many tests that are required to accurately diagnose and appropriately monitor disease. Basically, any patient with an abnormal overproduction of one clonal protein or a monoclonal protein can be classified as having at least MGUS. Smoldering and symptomatic myeloma require more monitoring and more laboratory studies to accurately monitor the disease. In terms of the treatment for multiple myeloma, we'll go over that in a few minutes. In terms of the primary treatment, maintenance therapy, and supportive therapies such as bisphosphonates, denosumab, and other supportive care.
As I mentioned on the previous slide, patients with multiple myeloma can be categorized as having MGUS, which occurs when patients have a low M-protein of less than 3 g/dL, clonal plasma cells greater than 10% in the bone marrow, or sometimes less than 10%, but no end-organ damage or amyloidosis attributed to an underlying disorder.
The second phase is smoldering myeloma. These patients are considered smoldering when they have a higher M-protein concentration in the serum or urine, and the clonal bone marrow plasma cells tend to be between 10% and 60%. But these patients still lack myeloma-defining events. Now we have updated criteria for high-risk smoldering myeloma, called the 22-20 staging system, which takes into account a higher M-protein percentage, a higher serum-free light chain percentage, and a higher bone marrow biopsy percentage. These patients are more likely to progress to requiring treatment for myeloma and should be monitored even closer.
Finally, patients are catapulted into the diagnosis of multiple myeloma if they have a high percentage of clonal bone marrow plasma cells or extramedullary plasma cytoma, and if they have SLiM CRAB criteria. So, again, the SLiM is a bone marrow biopsy of 60% or higher, an elevated light chain kappa-to-lambda ratio greater than 100, and an MRI with greater than one focal lesion. As you recall, the CRAB mnemonic with hypercalcemia, renal insufficiency, anemia, and bone disease, those patients will require emergent therapy and need to be treated ASAP.
In terms of the staging, we first had the Durie Salmon Staging System in the 1970s, and this was revised in the early 2000s for the ISS Staging System. This staging system took into account a serum albumin and a serum beta-2 microglobulin which were thought to be markers of high-risk or low-risk disease. The earlier staging system failed to capture the cytogenetic risk, which is sometimes right now very heavily relied on, and by adding the LDH and adverse FISH genetics, such as translocation 4;14, 14;16, or deletion 17p, those patients confer a particularly poor prognosis if they have single-, double-, or triple-hit disease, meaning they have more adverse genetic abnormalities.
So who is a transplant candidate in myeloma? Well, in many centers, everybody is considered a transplant candidate unless you have lots and lots of comorbid conditions, which might place you at risk for not doing well with that transplant in terms of physical, psychological, or functional status. So, the first step when patients are newly diagnosed is to say, are they fit or are they frail? Do they have sufficient organ function? Advanced age used to be a reason to rule out; however, I know there are patients in my institution well into their 70s who might really want to have that transplant as an option. It's important to refer to a stem cell transplant center to assess for the candidacy and have that discussion, because we know many studies that are ongoing show that transplant will lead to deeper remissions, which is a surrogate marker for overall survival.
When we look at the guidelines from the National Comprehensive Cancer Network, there are differences between the transplant-eligible patients, in whom we like to avoid melphalan that could be toxic to the stem cells, and patients that are transplant-ineligible, in whom those therapies often contain melphalan. We will discuss therapies throughout, so I'll save this discussion for later, but as you can see on this slide, there are so many different options available.
Basically, Category 1 recommendations with the strongest evidence in randomized phase III clinical trials for transplant-eligible patients include bortezomib/len-dex, and then bortezomib/thal-dex, which is used in Europe. We will learn that there are new daratumumab-containing formulations for transplant-eligible patients that are FDA approved in the United States, which we will be hearing about. The transplant-ineligible patients can receive VRd, daratumumab, or any number of combination therapies with the goal to eradicate the plasma cell clone.
So, in terms of follow-up and surveillance, I think it is super important for the practitioner to have the discussion with the patients upfront, that treatment should continue indefinitely. As long as patients are responding to therapy, we will continue therapy to eradicate that stem cell clone in many different situations.
Maintenance therapy in transplant-eligible patients will occur after that stem cell transplant, and it is important to monitor CBC, blood glucose, electrolytes, renal function, liver function, etc., and assess for relapse disease, which is a serial increase of 25% from the lowest absolute measurement of the monoclonal cell. It will also include imaging with CAT scans, MRI, etc.
In terms of treatment for relapsed refractory multiple myeloma, relapsed or progressive disease includes treatment with systemic second-line therapy, perhaps a second stem cell transplant or a stem cell transplant if they have never had one, or participation in a clinical trial.
This next slide highlights current second-line treatments, and as you'll hear from our panelists today, there are different mixing and matching of classes of drugs, which is how we treat myeloma in 2020 and beyond, by using proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies to successfully control the disease.
Category I recommendations in relapsed disease include carfilzomib-based regimens, daratumumab-based regimens, elotuzumab-based regimens, and all oral regimens, including ixazomib, lenalidomide, and dexamethasone.
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?
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?
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.
FAIMAN: Got it.
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.
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?
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.
RICHARDS: Yeah, I think those are really good points.
FAIMAN: I think we should go on with another case. This is so much fun, I want to keep it going, right? But let's do another case.
So, we have a 62-year-old male who had first been diagnosed in 1997 with a monoclonal protein MGUS and was watched for several years with every 6-month blood and urine studies. Remember, we didn't have serum free light chains available until 2004. A lot of people that are younger might not be aware of that fact, but the Bence-Jones protein was assessed, as well as the M spike. And eventually this patient progressed to multiple myeloma needing treatment. And that patient started on a clinical trial with thalidomide and dexamethasone, and after the induction they got a tandem stem cell transplant. And then they went on thal-pred maintenance, which was a very common clinical trial that was available in the early 2000s. And so, after a period of remission, that patient progressed, had developed some pretty significant peripheral neuropathy from thalidomide, but the disease was in control, so that was good, right? Back then, we know more about pushing people with neuropathy, but anyhow, then they had lenalidomide/dexamethasone, then bortezomib/Cytoxan/dexamethasone. SubQ became in favor of the bortezomib, which led to that therapy. And again, a 10-year history of treatment.
So, now at this point, this poor 62-year-old is kind of beaten down by therapy, it's not that first or second relapse where we really have a plethora of options we can discuss as we've talked about before. Now, we're in a place where we really need to, as providers, really share our knowledge on clinical studies and what we think is best for the patient. Because now this patient's refractory to bortezomib, carfilzomib, they've had thal, lenalidomide and pomalidomide, enoblituzumab, and even a clinical trial with panobinostat and ixazomib. So, now what do you do after all these different therapies? The patient does not like the idea of an implanted Mediport and they have bad veins. So, a subcutaneous therapy would be ideal, but unfortunately, that individual has some significant neuropathy from thal and bortezomib earlier.
So, again, we've discussed the use of daratumumab in the newly diagnosed relapsed and refractory setting. Daratumumab can be given in combination with bortezomib, melpha, and prednisone. It can be given in combination with thal and dex and bortezomib, and len-dex, and all these different opportunities for giving that. But based on the data from the COLUMBUS study and the PLEIADES study, there were 263 patients actually in one of the studies which were given this daratumumab with the hyaluronidase, which I can't ever pronounce, in combination with bortezomib, melphalan, and prednisone. And, again, it's also been studied subcu dara in combination with lenalidomide and dexamethasone as well. So, in various combination therapies.
So, how is it given? It's given subcutaneously, and it was non-inferior to the IV study. In the major trial, the phase III trial, there were 522 patients with a median follow-up of 7.5 months, and you can see in this table highlighted on the slide that the subQ had median progression-free survival of 5.6 months versus 6.1 months, and that was not statistically significantly different. Looking at the pharmacokinetics, how it runs through the body, it was pretty much similar in the intravenous and the subcutaneous groups, and it tended to be again effective with very few side effects.
What's so nice about the daratumumab is that the median duration of administration is like 5 minutes, compared to the infusion time of 7 hours for the first dose. So, all these years we've been telling people, “come to the clinic at 7 AM, you might be here 'til 7 PM, pack a lunch, and then you're gonna get this long therapy, but then wait, you got to get a driver because you might be sedated because of the corticosteroids and the diphenhydramine we're going to be giving you to prevent a reaction.” So, you go from this long infusion time, and when this becomes readily available in clinics, I think it's a much different discussion as to the therapy. I don't know about you, Donna and Tiffany. I'll ask Donna first what your thoughts are. Whenever I say daratumumab equals 12 hours in the clinic, what's your feedback?
CATAMERO: it's the same, and it's more on an operational standpoint. Patients are in that chair for, like you said, could be up to 12 hours, and some clinics are not open, they're more of a 9 to 5. So, I think this will give us more of a chair availability for patients. And I think too that we saw fewer adverse events, the infusion reactions. So, it's very well tolerated. I think this is a game-changer in the way we give daratumumab. The only downside I would see is that, you know, we all have those frail patients with no subcutaneous fat that might not be the best candidate for a subq injection. That's the only downside I can see.
RICHARDS: I would agree. I think this is really definitely going to be such a huge improvement for our patients. I know at our center, like our patients right now can't go to any of the satellite centers around Houston, because that first infusion time is so long. So, they have to come down to our main campus. And so now we'll be able to give this their first injection right out at our regional care centers, and I think that's going to be very appealing for patients, and I think this is going be huge for patients as far as the amount of chair time that they have to spend at the clinics.
FAIMAN: Absolutely. And for our case study, who's had multiple prior therapies and doesn't really want to get an implanted Mediport at this stage in the game, I think it's a nice option for them.
There are other therapies such as selinexor, which is not easily tolerated, but it is still an excellent option for some people. That therapy is given orally, but as Donna and Tiffany are very well aware, patients need to be monitored. They can get hyponatremia, so, you know, we worry about telling them to eat salty snacks and they can have a lot of weight loss and GI issues. We have put a paper out with recommendations on side effects for that, but maybe the patient doesn't want to accept all of these side effects. There's not a good clinical trial.
The subQ dara incidence of infusion reaction was 7.5% in the clinical trial, and it's about 50% in patients that get the infusional daratumumab. In my experience, we do the best we can to premedicate them in the office. If they have a lot of breathing problems, I do recommend loratidine 10 mg, and I also recommend on top of that montelukast 10 mg, just for the first couple of weeks. I think everybody has their own. But I've not done this in any of the clinical trials with the subcutaneous. Do you ladies have any experience with additional pre-meds for that first IV dose or any experience with those same pre-meds with the subQ formulation?
CATAMERO: Beth, we actually use the same regimen, and we've seen a decrease in the incidence of more respiratory issues with patients, so I think with the addition of those two medications, the daratumumab was better tolerated.
RICHARDS: Yeah, I do too. We do the same thing, and I think we haven't seen a lot of the breathing-related infusion-related reactions, and I usually tell patients that, you know, make sure to report the initial symptoms of infusion-related reaction, rather than waiting until they can't breathe, and, I think, you know, our patients are very savvy, and I think generally speaking, a lot of our patients do what we tell them to do.
FAIMAN: Excellent. Are there any other concluding remarks that you'd like to share? Donna and Tiffany, you have lots of years of cumulative experience in managing myeloma, and you're on the nurse leadership board of the IMF, and you've done a lot of research. Any clinical pearls you'd like to share with the audience about, let's say, Donna, newly diagnosed. And then maybe Tiffany, you can share some clinical pearls about relapsed myeloma perhaps?
CATAMERO: For newly diagnosed patients, I think we've come a long way. We have several options now that we can offer our patients, and I think that goes for the whole journey for myeloma patients, that we now have more options for patients. And the fact that we can get patients into very, very deep responses, and a deep response tends to correlate with a longer time in remission, so I think that with these advents of novel therapies, we can get patients into very durable remissions and have an overall well quality of life that we're giving, offering patients.
RICHARDS: I would say for the relapse setting that patients need to know that, particularly, I think patients have a hard time with their first relapse, because I think no matter how long they've been in remission for, they always expect that it would have been longer. And so, I think it's really, really important that patients know that they have so many different treatment options, and that this relapse doesn't mean that it's the end of the road for them. And making sure that they really understand that.
Also, I think that for the relapsed-refractory patients, it's really important that you pay attention to their blood counts and bringing them in maybe more frequently for count checks if they're going to need blood and platelet transfusions, but also to take into consideration if you have a patient who has a platelet count of 25, but they have a completely packed marrow, that's not somebody that you're going to hold treatment on. That you have to support them through treatment, and get them through the first one or two cycles, until their marrow starts producing again. And so, I think that's really important that people understand that if a patient has a packed marrow, that we just need to push through the chemo and then support them, just like we would a patient with leukemia.
FAIMAN: Absolutely. And I'd just like to add on—those are excellent points—the valuable role that the tertiary centers such as Donna has at Mount Sinai, MD Anderson with Tiffany, and Cleveland Clinic with myself, the valuable partnership that we can form. You know, have your patients, encourage them to go back and forth through the community. They might come to you for an opinion. But then you can kind of share that patient base. Educating the local providers, forming that network, and then you can kind of comanage the patients. Then those local providers are more comfortable with myeloma. You can kind of set up a base to enhance patient care. Communication is so important. Nowadays, we do a lot of telehealth visits, and I always say, you know, you don't have to drive to see me, we can do a virtual visit over the phone, and we can still connect that way, and so making as many people on that treatment team to form those collaborations are super important.
So, anyhow, this has been a great discussion. I'd just like to conclude by saying that there are multiple first- and second-line treatments available for myeloma. Lots of category 1. That means that the NCCN guidelines have said that there's definite positive evidence in randomized, well-developed trials that show there's lots of therapies available. Deep response can happen at the beginning. We saw in the POLLUX and other studies that you can get deep response throughout relapse. And really building that relationship, having them take a journal, write down side effects, knowing when to call and what to look for, because they are really their own primary providers. Consider transplant eligibility before you give them melphalan, and definitely referral to a tertiary center is very important, as well as making that communication back and forth from the referral center.
Thanks again for joining us. I'd like to thank my colleagues, Tiffany Richards, Donna Catamero. Thank you for taking time out of your busy days. And also, for more information, please visit JADPRO online at AdvancedPractitioner.com.
Thank you so much, have a great day.