The AP's Role In Managing Patients With Early-Stage Multiple Myeloma

Patricia Mangan: It's great to continue our discussion on the approach to that newly diagnosed myeloma patient. Now that we have a good sense of that first-line treatment and our thoughts on choice of therapies, a very important aspect to many of our patients are the other end organ issues that they deal with or comorbid issues. What are the supportive measures that are so helpful? There’s a great amount of patients now are living longer. We want to ensure great quality of their life. How do we manage these other issues? I was thinking of a case that we just had discussed where this elderly woman with lytic bone lesions, clearly compression fractures in her low spine, really difficulty moving, actually required admission for pain management at diagnosis. I would love to hear your thoughts on your approach to patients with bone disease, Oxana. Any thoughts that come to mind in this particular patient?

Oxana Megherea: Of course. For any newly diagnosed myeloma patient, we would want to start an antiresorptive therapy. We have a couple of different options we can employ. We have bisphosphonate, so either zoledronic acid or pamidronate are options that we can utilize. We mostly use zoledronic acid in practice based on some overall survival data that was reported with this agent. We have denosumab that we typically reserve for patients that have a creatinine clearance lower than 30, where both of those agents, zoledronic acid and pamidronate, may not be the best options. Depending on the patient's renal function, these are the options that we can do.

I think that some of the things to keep in mind is that for all of these options, patients would have to get a dental exam and baseline. They would have to really have any invasive dental work done before initiating this agents due to the risk of osteonecrosis of the jaw. Then educating the patients to inform the team, that if after they start these therapies, they need any dental work done, they may have to interrupt this agent if the situation allows for it.

With zoledronic acid and pamidronate, we have to keep an eye on the creatinine as dose adjustments may be needed for both of them during therapy. With denosumab, we do see a little more hypocalcemia in this setting. For any of these therapies, we would want to make sure that patients are on calcium and vitamin D supplementation. Those are some of the things that come to mind when I think about bone health. With some of the interventions, perhaps you both have more insight than I do in terms of some of the surgical radiation therapy in this setting.

Patricia Mangan: Right. In this case that we're talking about, she even had a soft tissue mass surrounding this lesion in her L-spine. That is a great point that getting hold of that radiation oncologist and giving some radiation therapy can very quickly treat that particular impending fracture or impending cord compression. Utilizing radiation is a great multidisciplinary group that we deal with all the time in our bone lesion patients and things. Of the procedures that we can give often in that early compression fracture at diagnosis, starting treatment may be very helpful to rid that patient of that pain. For some people that pain persists and you can use medications to manage that, but we do refer also for kyphoplasty, real procedures that can lift the collapsed vertebral body to relieve the pressure on that nerve that's causing that pain. With that approach, I don't know, Amy, but our sense of that is it can be very helpful for some although we usually give the patient it's about a 50/50 chance of that working. What're your thoughts?

Amy Pierre: I would have to agree. For some patients, it works beautifully. For others, they get minimal relief. So, then you need to think about a multifactorial approach in controlling their pain. Things like the bisphosphonates and the RANK-ligand inhibitor, that's really to help prevent further down-the-line skeletal events. Maximizing pain control with either opiates or even using tricyclic antidepressants or gabapentin or Lyrica, those can be helpful. Utilizing your supportive care palliative care team to help manage the pain control can be really important too. Like you said, radiation for that extramedullary component. There're various ways we can attack that pain. If kyphoplasty is not 100% we're trying to solve patients aren't getting relief that way.

Patricia Mangan: My experience over the years in this, the use of bisphosphonates and other bone-strengthening medications, you know, we don't see the, the loss of height and the kyphosis that we have seen in the past. It's great to see the supportive measures utilized from the beginning and better treatment options that keep people in remission even deeper. The other consideration with, particularly in this case, elderly, that renal insufficiency and any thoughts that you have, Oxana, on how you would approach a patient with renal insufficiency who is on an immunomodulating agent like lenalidomide?

Oxana Megherea: We have data now that guides us on how to adjust the dose of lenalidomide depending on the patient's creatinine clearance. As we said with zoledronic acids, making sure that we periodically check the creatinine clearance and adjust the dose of lenalidomide because really about 82% of the drug is excreted via the urine. It's something we have to make sure that we keep an eye on. Another consideration with the IMiDs is the risk of VTE (venous thromboembolism) in this population. So again, depending on the risks for thrombosis that the patients may have, again, utilizing either an antiplatelet agent or an anticoagulant to reduce the risk of VTE, especially this patient comes to mind that she's older, perhaps she's not moving as much. Perhaps she has other additional comorbid conditions that may further predispose her to a risk of thrombosis.

Patricia Mangan: When I think of the clot risks that you're mentioning, it always brings to mind steroids and the use of steroids that we are giving and that combination can increase the risk in that population or in any patient population. Amy, what are your thoughts on steroids?

Amy Pierre: Steroids are the drug that our patients love to hate, but they're so important, right? They make all our drugs and myeloma work better. There's a synergistic response with steroids and our anti-myeloma therapy. It’s really important to be a part of the backbone of the regimen. But I do see patients get the most side effects from steroids. If we think about steroids, they affect pretty much every organ system in your body. Long-term usage can cause cataracts. We can see weight changes like bloating and fluid retention, we can see muscle wasting in those proximal muscle groups. One thing I see is patients have trouble getting up off an exam table without using their hands. That's how that can manifest very quickly. And blood sugars, right? We can see hyperglycemia happen. I always worry about my pre-diabetic patients, pushing them into diabetes with steroids. Our diabetic patients, we really need the endocrinologist on board to help manage those blood sugars accordingly. They may need adjustments in their insulin around the dosing of steroids. We can see an increased risk of infections with steroids as well. Our poor patients have trouble with insomnia too. We always say be cognizant of how you're dosing the steroids. They can irritate the stomach, make sure you take them with food. I have patients who take it first thing in the morning and so they're able to sleep at night. I have some patients that take it at bedtime because that sort of, you know, pep happens maybe six hours after they take it when they have to get up early in the morning. Whatever schedule works best for patients, but we do need to be cognizant of the slew of side effects that can happen with these agents. They're not benign agents. They can really cause a lot of side effects.

Patricia Mangan: To your point, I think working with the patient, really keeping a close eye, getting a sense of them, and learning from them what works best for them is always helpful. In terms of steroids, as you mentioned, infection, and I think that's a big issue that we are always trying to prevent infection and educating our patients about what to watch out for at this early stage in their treatment or throughout their treatment. Oxana, I know you have probably some insight about some uses of maybe prophylactic antibiotics and any thoughts that you might want to share.

Oxana Megherea: Of course. The treatments themselves as we discussed, for example, using a four-drug or a three-drug regimen compared to two or three may increase that risk. Newly diagnosed multiple myeloma (MM) patients are also more likely to have infections even in the absence of neutropenia due to their disease state. I think that utilizing antimicrobial prophylaxis is certainly one of the strategies that we can use to further reduce that risk of infection. And we have the International Myeloma Working Group that published recommendations at the beginning of last year on what strategies to implement in this patient population. One of the things they mentioned is the use of levofloxacin based on the TEAMM trial that showed the reduction of the incidence of febrile episodes, especially when utilized in the first 3 months of therapy because of that higher risk upfront. That's certainly one of the strategies that can be employed in patients at higher risk of developing an infection. And then of course, with the use of proteasome inhibitors with the use of anti-CD38 monoclonal antibodies in this case would really be daratumumab upfront use. It's making sure that we initiate an antiviral agent to account for that risk of reactivation of varicella-zoster virus. Effective immunization where making sure that our patients are immunized is very important. There're so many different factors that can impact the response to both of those vaccines. If we have the luxury of immunizing before initiating therapy, we're trying to immunize them when they have a lower disease burden so that we can maximize the benefit from immunizations is what we want to do. Making sure we immunize against pneumococcal disease, making sure that we're up to date with whatever COVID vaccination recommendation is at that time.

Patricia Mangan: Right. That's changing.

Oxana Megherea: Then of course the annual influenza vaccine, the Shingrix vaccine, and Tdap every 10 years is what we want to make sure that our patients are immunized and they’re up to date to further reduce those risks.

Patricia Mangan: One of the questions that come up a lot in practice is, “I've been vaccinated against shingles. Can I stop my antiviral prophylaxis?” Any thoughts on that?

Amy Pierre: It's a good question and we do get that a lot. For some patients, if they're adequately immunized, you know, we'll check titers and give them a break. Particularly if they're for some reason not tolerating their antiviral and they have adequate immunity, we will hold off on their antiviral. But you know, there's always that worry, right? A myeloma patient is seven times more likely to get an infection compared to the general population. Their immune system really is never normal and there're other factors at play, right? We have a lot of our patients who become hypogammaglobulin anemic. We have to support them with IVIG to get out of those sort of chronic serious infections. And then also supporting them with even Neulasta support or Neupogen support, growth factor support if they're neutropenic. Anytime we peel back supporting infection prevention, we're always a little bit nervous, but if the data is there, then we're happy to do so.

Patricia Mangan: It's an interesting point. The other questions that arise a lot are the, I know we talked about maybe an uptick in infection with daratumumab upfront in combination, and I guess any other management strategies or thoughts on dara administration in terms of the route of administration, potential toxicities, or administrative issues?

Oxana Megherea: We've primarily, and probably most centers, have switched to daratumumab Sub-Q since the results of the COLUMBA trial that showed us that it's non-inferior to the intravenous formulation. It showed the reduced risk of those hypersensitivity reactions. The big thing is also the chair time. That made really a big difference for practical considerations. Primarily we've switched this formulation and it's really that the risk of an injection-related reaction is much lower with the subcutaneous formulation. In fact, that low that we have new data coming out that's saying that we can actually stop medications sooner rather than having them on long-term per medications or per medication before each dose of daratumumab, and now new data saying that maybe we don't need to observe patients at all, or maybe for not that long. It certainly made things a little bit easier for us from that perspective.

Patricia Mangan: I agree. In my mind, walking down the classes of drugs, the other one that comes to mind are proteasome inhibitors. And Amy, I know you know, you certainly have your experience with using them in terms of potential toxicities, things that you would watch for in patients.

Amy Pierre: As a class as a whole, they do share some side-effect profiles. For example, the myelosuppression particularly affecting the platelets in a sort of a cyclical fashion. But then each one of them has a unique side effect profile. So, for example, like bortezomib, we do worry about peripheral neuropathy. We can really mitigate that with dose adjustments and frequency of giving that drug en route. Instead of giving bortezomib twice a week, we can give it weekly, it’s just as efficacious. Instead of giving it intravenously, we can give it subcutaneously, which is just as efficacious. Both strategies really minimize the risk for peripheral neuropathy, but be on top of it of course. If a patient's starting to feel that numbness, tingling, God forbid pain, we need to dose-reduce our holds.

Some GI upset that we see with some of those proteasome inhibitors as well. Carfilzomib is unique in the fact that it does carry some cardiovascular effects. Our patients who have comorbid conditions, either uncontrolled hypertension, you really worry about those types of patients to be on carfilzomib. And we always get a baseline echocardiogram and all of our patients before we start carfilzomib to assess their ejection fraction if there's any underlying pulmonary hypertension because we don't want to exacerbate that with that drug. For ixazomib a, it's the oral proteasome inhibitor, so we do worry about the GI toxicity that can happen. But it's really nice that it's a pill that you take, you know, once a week. Three weeks on, one week off, and all those drugs you really need to think about, you know, shingles prophylaxis. It's very important because the proteosome inhibitors can increase your risk of developing zoster.

Patricia Mangan: With prophylaxis, we don't really see much of the reactivation. That's a helpful thing. Just one other thing that in a patient that I actually saw yesterday, we were discussing this gentleman is in a nice remission now, on maintenance of daratumumab for I think it's 32 months. We were discussing how a lot of people get treatment fatigue, I think they call it. We have people we are expecting them to remain on treatment and things. That is an emerging issue that we're seeing now. I asked him, there's a lot of patients that feel very strongly like, no this is helping me. There's no way I want to stop therapy. But then we have other patients who are maybe not as compliant as we wish they were because they were just tired. It's like, “I'm tired of this, I got, you know, I got through so much and now I just kind of want to get back to baseline.” That's where managing toxicities, lowering the drugs, doses, and schedule, as you mentioned, can be so helpful in that to maintain treatment and maintain response. He was funny. I always try to find out what they're thinking, and he was like, “No, the data isn't there to stop. So, I'm happy with keeping it, but I hate driving over the bridge to come to the office.” It can be as simple as, as you know, just the aggravation of coming to the office. Amy, as you mentioned about the IV versus sub-Q preparation of things, patients sometimes love to be in the office, they love the nurses and things, but getting to the office can be difficult. And just the financial burden of all those things. I think one thing that I have found through the years is allowing some give, allowing for that vacation. You know, take a break. But not maybe stopping is our philosophy, but allowing for some flexibility and negotiation of those things I think can be very helpful.

Amy Pierre: It's really important because we're treating patients to bring down their level of myeloma so they can enjoy their life. Quality of life is just important to us as to the patient. Participating in that sort of shared decision-making and compromising is, particularly when their disease is under control, let them go on that vacation, let them attend that important wedding because we're treating them so they can feel good and do those things. I think it's important to have those conversations for sure.

Patricia Mangan: I thank you so much for a very wonderful discussion and really eye-opening about all the things that we deal with and just the great benefit that it has provided our patients. Thank you, Oxana and Amy. Thank you.

Amy Pierre: Thank you so much.

Oxana Megherea: Thank you.

Patricia Mangan: This brings us to the end of our discussion. Please see our other segments for further discussion on early-stage multiple myeloma, or visit JADPRO.com. Thank you for joining us today.