Tanya Wildes, MD
Siteman Cancer Center 
Interview Date: November 6, 2019

How does treatment for multiple myeloma change with age? Hear Dr. Tanya Wildes describe how care for elder myeloma patients can be modified and even optimized. She stresses that age is less of a factor when compared to an individual's fitness status and many fit elderly patients can receive the same treatment that younger patients receive. As an expert in geriatric hematology, Dr. Wildes shares how she considers modifying treatment in her elderly, more frail patients. There are key tips and tricks to keeping patients on optimal therapy while still making sure she is sensitive to her patient's other needs - like emotional or lifestyle requirements. There is much to learn in this valuable show. 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology for their support of Myeloma Crowd Radio and this program.

Now, before we get started with today's show, I'd like to share an update on a new program that we have called Myeloma Coach. If you are newly diagnosed or are looking for others who have traveled the same myeloma journey that you have, I highly recommend that you use this program, the Coach program. We have over 95 (now over 100) Myeloma Coaches who are willing to help you on your myeloma journey. They can connect you with many types of resources for myeloma patients including help with the HealthTree online tool. This is a program where you can find one or more Coaches to help answer questions you might have like, “What can I expect during a stem cell transplant,” or what to expect on certain treatments or how to join a clinical trial or even how to navigate the emotional aspects of having myeloma? You can use one or more Coaches. You can have a short or long term relationship with them . And you can find a Coach on myelomacoach.org. There are many Coaches just waiting to help you, so I strongly encourage you to find a Coach today if you're looking for help. These Coaches are myeloma patients or caregivers themselves. And they're anxious to help others on this really difficult road with multiple myeloma.

Now, on to today's show. As you know, the average age of diagnosis for multiple myeloma is 69. So as you might expect, there are many patients who are elderly or more frail than the general population. Dr. Tanya Wildes of the Siteman Cancer Center at Washington University joins us today to discuss specific issues for an older or more frail patients. Dr. Wildes, thank you so much for joining us.

Dr. Wildes: It's a pleasure. Thanks for the opportunity.

Jenny: Let me introduce you before we get started. Dr. Tanya Wildes is a Myeloma Specialist at the Siteman Cancer Center, an Associate Professor of Medicine at the Washington University School of Medicine. She's on the Siteman Cancer Center Protocol Review and Monitoring Committee in the Behavioral Science section. She's a member of both ASH and ASCO and additionally, the International Society of Geriatric Oncology, the American Geriatrics Society and the Cancer and Aging Research Group. She's Chair of the International Society of Geriatric Oncology Science and Educational Committee. She's also a member of the National Comprehensive Cancer Center Senior Adult Oncology Panel and Alliance for Clinical Trials in Oncology on the Multiple Myeloma Committee. She is Associate Editor of the Journal of Geriatric Oncology. Her awards include the Alene and Meyer Kopolow Award for Excellence in Geriatrics from the Barnes-Jewish Hospital Foundation and is also on the Best Doctors list in St. Louis Magazine from 2015 to the present. She’s also considered in the Top Ten Faculty and Patient Satisfaction at Washington University School of Medicine. Dr. Wildes, we are so excited that you are joining our program today.

Dr. Wildes: Well, thanks again for the opportunity. It’s my pleasure.

Jenny: Just as an interest, how did you come to specialize in elderly or geriatric care in general and then in myeloma specifically?

Dr. Wildes: Great question. It was a triangulation of a few things that led me there. First, when we complete our internal medicine residency, we do rotate through geriatrics. I remember really enjoying working with that population and learning how to assess an older person through a slightly different lens than the traditional medical model of looking at each individual organ system, but really rather looking at the whole individual and how all those complex health issues are woven together. Even though I enjoyed that rotation, I knew I was committed to a career in hematology and oncology. But then as I was moving towards my hematology oncology fellowship, I was looking for a research project. One of my mentors, Steve Devine, who is a bone marrow transplant physician suggested that I study transplant for lymphoma in older patients. And he said, quite curtly, “It seems like older patients do bad. You should study that.”

So I started looking at the outcomes in our older patients versus younger. He had tossed in, “Well, look at co-morbidities,” meaning the other medical issues the patient has in addition to their cancer. And low and behold, what we found was that it was not the patient's age that impacted the outcomes of transplant in the population, but whether they had other medical conditions. So that really got me thinking, “Well, what other aspects of a person's health impact how their cancer treatment goes?”

Then that brings us forward to during my hematology fellowship. Again, I was treating lymphoma at that point under the guidance of one of my attending physicians. I was about to see an 86-year-old woman with a very aggressive lymphoma. By her scans, I was sure that based on the location of her tumor, she would be paralyzed. So I walked in and rather condescendingly said, “Honey, can you pick your leg up? Can you move your leg at all?” She kicked her leg off the bed with leg strength that I don't know that I had. She, at 86, had very few other medical issues. She was living independently. She was still running a farm. She tolerated treatment for that disease that I had seen patients 30 years younger than her have serious toxicity from. So at some point, just all of those different threads wove together in my mind and I said, “This is where I'm going to make my career. I'm going to use the tools of a geriatrician and apply them in the care of older adults.”

Then fast forward to my early faculty career when I got interested in multiple myeloma and with all the amazing advances, seeing how it's turning into a chronic condition where the other medical issues, the patient's overall fitness plays such an important component in balancing the side effects and then considering our approach to treatment and especially as the models of care became more and more aggressive. We'll talk, I think, later about different approaches, whether it's a doublet or a triplet and how would we pick for an older patient, what was their risk of vulnerability to toxicities and that sort of thing.

Jenny: Well, I think you bring up a really, really important point that I want you to expand on a little bit because it's not age. It's fitness status. And you're right. I mean the longer now that patients are living, the more where you have to think about these other issues because you are on treatment long-term typically. Sometimes, it's just what the other side effects might be or longer term issues. Can you explain in general how a myeloma specialist might tailor treatment for somebody who's older? And when I say older, I don't mean highly fit like you're saying because I've had some of the doctors say, “I can have a 50-year-old walk into my office with congestive heart failure. And I'm going to treat them a lot differently than I'm going to treat this 75-year-old who's walking every day or still running marathons or something.” Can you just talk about how and why myeloma specialists do that with myeloma care?

Dr. Wildes: Yes, absolutely. First point would be just like you said -- it's really not age. One of the first questions I'm often asked when I say that I'm a geriatric oncologist is, “Well, what age is elderly?” I think that my plan is to spend my whole career pushing back on the notion that we could ever draw a line based on in age. Age is just -- as one of my colleagues said, it's the number of times we've traveled around the sun. And to think that that predicts or should tell us how which treatment we should use is really doing a disservice to that individuality that you described and captured here.

When we use age, we're just using that as a marker for these aging associated vulnerabilities, which tend to on average accumulate over time. But just like you've said, you can have a patient who is below what would be a traditional age cutoff of 65 or 70 and have significant comorbid medical conditions that will impact their ability to tolerate different treatments and approaches. And you may have a person who chronologically is much older but physiologically is very fit that they're going to have resilience to these side effects. So if a myeloma specialist is taking into account these vulnerabilities, the rationale behind wanting to tailor our treatment is to make sure we're hitting the sweet spot of using the treatment that is the most effective but at a crossroads with, at a level of anticipated toxicity that's acceptable.

We do know that with increasing aging associated vulnerabilities that an older patient will be at greater risk for toxicities and that not only may they be at greater risk for more severe toxicities, but also a side effect that is a level that would be tolerable for a younger patient may not be as tolerable for an older patient. Let me explain what I mean. Peripheral neuropathy is one of the most common side effects of bortezomib or Velcade. In a younger patient who has a lot of physiologic reserve, a grade two peripheral neuropathy which is just the amount of enough neuropathy that it's there all the time and maybe impacting day-to-day, if they have that physiologic resilience, they're still going to be able to do their day-to-day life. Whereas in older patient who may have that grade two neuropathy but then they also have some muscle weakness or they may have some slightly low blood pressure when they stand up, that same grade two neuropathy may increase the older patients’ risk for falls, for example. So it’s a combination of those things, wanting to decrease the total severity of the side effects and then be attentive to the impact of what typically would be considered a more moderate side effect, maybe actually greater in older patient.

Jenny: That makes a lot of sense. I'm glad you explained it like that. I had a doctor at one of our recent round tables just joke that 80 is the new 60. And maybe that's the case for certain patients. Let me ask you this. Let me go backwards a little bit and ask why is the older population more likely to get myeloma? We didn't really even address that, but it's a disease that has an average age of 69 or something like that?

Dr. Wildes: Yes. It depends on exactly which population we're estimating from. Sixty-nine is what we usually see in the SEER data. Some populations, it’s as old as 71. But yes, right around there. It’s the most common age. I don't think we know the whole story. As a whole, most cancers increase in prevalence across the lifespan. And that's probably a combination of things. One, we know there's genetic changes in the cells that become the cancerous cells. Those tend to accumulate over the lifespan.

But what's interesting and tells us that that doesn't explain the whole story in patients with myeloma is that when we look at the individual chromosome abnormalities across the lifespan or I should say across patients with myeloma who are diagnosed with myeloma or across patients -- I’m sorry. Let me start that again. Across different age groups who are diagnosed with myeloma, the percentage that have those chromosome changes tends to be pretty similar across the age. In fact, even translocation 4;14 decreases in prevalence in the oldest subgroup. So we know it's not just accumulation of genetic changes. There is likely what we call a seed and soil interaction, meaning that when those malignant cells develop in an older patient, it may be that the surrounding environment is more permissive to the myeloma taking root, so to speak.

There is a phenomenon of aging that occurs. There's an inflammation that increases across age. They call it inflammaging where there's increasing inflammatory cytokines present within the body as we age. So that's another potential hypothesis about what it is about aging that increases the prevalence of myeloma with age.

Jenny: Additionally, when you're talking about this seed-soil interaction, you're thinking about what's happening in the bone marrow microenvironment or the ability of your immune system to just keep it down and not allow it to grow, whether there's one or a million cells in your bone marrow. I know a lot of work is being done right now in myeloma to create an immune system panel. What factors are we looking at here? When you say an older patient might have a more weak immune system as well, what does that mean? What things are you looking at? Does that impact myeloma as you see it as you're working with this older population?

Dr. Wildes: I don't think any of these approaches are ready for clinical primetime at all. They're still at the research level. Among the factors that you pointed out, one would be these inflammatory chemicals called cytokines. For example, Interleukin-6 is a well known inflammatory cytokine that has direct pro-myeloma effects. In fact, back in the ‘80s, I remember digging up papers from Dr. Anderson where he was looking IL-6 in myeloma.

And really interestingly, if you look at the straight geriatrics literature, IL-6 is called the aging cytokine. It increases with age. So a natural product of the aging process results in increase in a cytokine that has direct pro-myeloma effects. Then as you pointed out, there's changes in the immune system related to the lymphocytes, some of the natural anti-cancer cells that are present in the body. It's an attractive hypothesis that those are involved, that as those immune changes are happening, that they're not as active at recognizing and controlling the myeloma. But again, that's really at the hypothesis in early laboratory testing, nothing ready for clinical primetime unfortunately.

Jenny: When you're studying these cytokines, you're looking at these inflammatory markers. Are you looking at them in the blood or are you looking at them in the bone marrow? Is there a difference?

Dr. Wildes: Oh, wonderful question, very, very early on that. I have data waiting for me to look at. Actually, because that area is not my expertise, this is one of these areas where we need the crosstalk between people like myself who really think clinically and then people who think about the laboratory medicine. Actually, hot off the presses, in the next month or so, I'm going to be trying to develop some more of those collaborations to speak with people who think like laboratory scientists about the mechanism of each of these cytokines. In answer to your question, we definitely have just the smallest amount of data. I'm not sure if others have looked at it as well. We do see some differences in the levels of those inflammatory markers in blood versus bone marrow. That'll be something important for us to keep in mind as we move forward. If a study does not find a relationship with the blood levels, we should think about, “Well, is the local bone marrow level of that cytokine different?”

Jenny: Yes, interesting. I think this whole area is just a huge area. That's so interesting that IL-6 is the aging inflammatory marker. I think that's just so fascinating because it is related to IL-17, and now we're working on this study that we talked about in prior shows to look at that. So that's so interesting.  

Dr. Wildes: Oh, and how fabulous that these conversations give us these insights, right?

Jenny: I know. It's so amazing. Let's talk a little bit about different therapies or therapy approaches. You referred to it a little bit earlier in the show when you were talking about triple combinations or double combinations. So maybe you just want to give us an overview of, in general, what do you adjust when you're treating a myeloma patient who might have additional health-related issues, especially in the elderly population?

Dr. Wildes: There are currently some guidelines that are available. Basically, they're currently expert opinion, just saying let's try and hone in to personalize these treatments. We don't yet have the whole right formula for which patients exactly need adjustment to which treatments. But some previously published guidelines can guide us in that way. As I think through each drug and what indication we have for dose reduction, some of them are really easy low-hanging fruit. For example, lenalidomide has very clear indications for dose reduction based on renal impairment. Those are on the package insert. So all physicians will be aware of those.

But further from there, we commonly see published recommendations to dose reduce lenalidomide to 15 milligrams even without reduction in renal function a priori just to improve tolerability. I'll commonly do that in a patient who's over their mid-70s and maybe a little bit more vulnerable. I should mention, I have not yet mentioned. How do we categorize these patients beyond the eyeball test?

Jenny: Oh, yes, let's talk about that.

Dr. Wildes: It is so evolving. One of the most widely cited ways right now is the International Myeloma Working Group Frailty Index, which is a relatively simplified approach using basically just patient age and what we call the “functional status”. So in geriatrics, we dive into the patient's daily functional and a little bit different way than a typical oncologist would. An oncologists will use a measure called performance status, either the ECOG scale, which is just zero to five. Zero is perfect, no impact to their disease on their daily function. Five is actually no longer with us, deceased. So that's not a number that's helpful in talking about a patients’ function. You can see that they're pretty crude tool. Most patients fall as a one or a two. One means they have some symptoms but otherwise really able to do normal day-to-day life. An ECOG performance status of two is up and about more than half the day, but maybe need to rest some. Three is in resting more than half the day. You can see a very crude tool.

The IMWG Frailty Index uses what we call functional status. That's more of a tool of a geriatrician. That's divided into the activities of daily living and instrumental activities of daily living. The activities of daily living are those things one needs to be able to do to stay independent in the home. One needs to be able to bathe themselves, dress, toilet, feed themselves and so forth. The Instrumental Activities of Daily Living, the IADLs are those activities someone needs to be able to do to maintain their independence within a community. So those include using the telephone, managing their finances, grocery shopping, meal preparation, handling their own medications, arranging transportation and so forth. And we know that with each one of those activities that a person needs assistance with, that is an indication of an underlying aging associated vulnerability.

So the IMWG incorporates age, those functional status measures that I mentioned and then comorbidities, meaning the other medical issues that a person has. And using that scale, patients are categorized as either fit, intermediate fit or frail. Then when we apply those to dose reductions on the drug -- I was talking about lenalidomide. So if a patient is intermediate or frail, we would likely start with a lower dose of the lenalidomide.

Other considerations when thinking about adjusting the dose of the different drugs are, number one, are we using them in combination with the increasing number of drugs put together? Overall, there'll be an increasing risk of side effects as we use more drugs together, a triplet over a doublet and so forth. Although I'll put an asterisk on that and say with the newest combination regimens adding in very well tolerated treatments like daratumumab, that mantra that more drugs means more toxicity has started to fall apart, so to speak.

Other drugs that I particularly have an aging-associated lens when I think about my dosing on them are bortezomib. As we talked about earlier, the peripheral neuropathy is a particular importance in older adults. Ways we can decrease the likelihood of that include using, number, one subcutaneous formulation (a shot under the skin). I don't know of any indication anymore for intravenous (IV) formulation because it so significantly increases the peripheral neuropathy burden. And it's been shown to be equivalent in efficacy. So subQ, meaning the injection under the skin, absolutely. And then once weekly as opposed to twice weekly.

Palumbo did work coming up on ten years ago where they were using a combination of bortezomib, melphalan, prednisone and thalidomide. And they found very quickly that when they were using the bortezomib twice weekly that the rates of peripheral neuropathy were just way too high. They had to stop the drug. Basically, the patient didn't get as optimal treatment as possible because of that significant side effect. They actually did an amendment after the first hundred or so patients and switched over to once weekly subcutaneous bortezomib and found that they basically dramatically reduced the rates of that peripheral neuropathy, that nerve damage from the chemotherapy. So that's going to be a much better tolerated treatment approach for older patients allowing them to remain on the drug longer than they would be. They would if we use the more aggressive twice weekly formulation.

I think steroids, the corticosteroids are another underappreciated source of significant morbidity in our older patients for a number of reasons.

Jenny: Right. They are hated by patients.

Dr. Wildes: Yes. So the high blood sugars in a patient who has diabetes or in a patient who was previously prediabetic or didn't even know they were prediabetic, we can precipitate diabetes, which is a life-changing complication to need to then be thinking about one more thing - monitoring blood sugars and so forth in patients who have underlying cognitive changes that may precipitate delirium, which is acute changes in memory confusion. An “acute confusional state” is another name for that. In the patients who are intermediate fit or frail, we’re certainly going to want to look at reducing, minimizing the doses of the corticosteroids of the dexamethasone or prednisone in those patients.

I'll pause for just a second. I didn't know if you wanted to talk about more drugs.

Jenny: I mean what you referred to earlier too -- so these are some of those specific drugs. These are great tips. So you can reduce the Revlimid dose. You can definitely do subQ Velcade and do it once weekly versus twice weekly. You can reduce your steroid doses. Then you can also look at -- I know a lot of the doctors are talking about, “Well, for induction, you should do think about triplet combinations or maybe quad combinations.” You mentioned adding a monoclonal antibody like daratumumab or something like that. It might not give you more toxicity. But for this elderly or more frail patient population, do you use three, triplet combinations when you start somebody on treatment right off the bat and then dose reduce? Or do you just start with a doublet instead? How do you make that decision about what you do? Because to me, this says, “You need to ask your doctor if you need to adjust therapy during the course of your care and not be afraid to do that. If you're seeing different side effects that -- and you need to share those with your doctors so the doctor can help you adjust accordingly as needed.”

Dr. Wildes: Yes. I love that point. It's such an important one. I'll take you on a little aside if you'll indulge me. I had an older patient that I had on bortezomib. Every week, I would ask him, “Have you had any numbness or tingling in your fingers or toes, numbness or tingling in your fingers or toes?” And he always said “no”. Then fast forward four cycles of a bortezomib-based initial therapy and my nurse calls me and says, “Mr. Smith, he can't stand up. He's fallen three times today.” This was a patient I would categorize as fit. I said, “We have to get him in clinic. I can't fathom what's going on. Is he dehydrated? What's going on?” It turns out I had given this poor man grade three peripheral neuropathy because the way I was asking the question, numbness or tingling was not how he experienced his peripheral neuropathy. He said, “My feet felt gritty.” So his experience didn't line up with how I was asking the question. I so regret that for whatever barrier I put up, he didn't feel empowered to tell me,, “Something is wrong with my feet.” So we had powered on with standard dosing of the bortezomib leading to the point where he was having difficulty walking and even falling recurrently, which is really not the outcome that we would want. So I really want to highlight your point of the patient feeling empowered to talk to the doctor if something feels wrong, even if the doctor doesn't specifically ask that way.

Jenny: Right. And I think as a patient, I mean I did this. I went on for six months with really bad side effects on something not knowing what was causing it because I was on a combination therapy. Then finally, I brought it up to my doctor six months in just because I'm thinking, “Well, this is what the treatment is like. I just have to put up with it and suffer through it and finish my treatment or whatever.” But in myeloma, you're playing the long game. So you really do that in myeloma.

Dr. Wildes: Right. Back to your question about then, how do you plan that for an older patient? How do you take the long game into account? How do you pick the regimen? This is certainly where some of the art comes in. We can lay out that we need to have a triplet in this situation and that sort of thing. But we're all born as clones. We age as individuals. And for my different individual patients, there may be different parts of their geriatric profile that make me weight different side effects more heavily than others. For example, a patient with a lot of known underlying cardiac disease, we may have greater concerns about the potential risks of blood clots. Or that individual patient may have such a high priority or level of concern about an individual toxicity that for them, that drug's not an option. And that may not be how I would want to proceed. I’m telling my patients, “I'm not the captain of this ship. You are. I'm the navigator. I can lay out our map. I can show us our different paths that we can take, but ultimately, we need to pick the path that's right for you.”

I've had patients who had TIA, transient ischemic attacks, which are mini strokes after a couple of days on Revlimid. I thought there were likely other reasons that we could blame other than the Revlimid, but knowing that that was one of the potential side effects of that drug, it was not worth the risk of a stroke to that patient. And he to this day has never had another dose of that category of drugs. They're really good drugs. I always have this regret that we aren't able to use those, but that's not that patient's priority, that the idea of having a stroke and the dependence that that might cause him was not worth that risk for him.

Another approach that we can use is what geriatricians have called Start Low and Go Slow. I think oncologists unfortunately sometimes get tied into, “I need to go on record right at the moment of diagnosis with what this patient's treatment is going to be.” And I think a geriatrician approaches it more from, “Okay, let's start and see how things go. Let's see what toxicities or if one drug or a doublet is well-tolerated. Let's see about adding in a third drug and see how it goes.” Outside of a clinical trial where it's really protocolized exactly what patients -- the treatment gets on which day, in routine practice, we have that flexibility. So I may start a patient just on lenalidomide and then if we do okay, add the bortezomib or vice versa. More often, we can start the bortezomib rapidly. And the lenalidomide takes more time to add in.

Now here, more recently, we have the option of adding in the daratumumab. We have FDA approval for the combination of daratumumab and first line therapy in older patients who are transplant ineligible in the combination with bortezomib, melphalan and prednisone. Interestingly, that regimen, the bortezomib, melphalan, prednisone backbone is much more widely used in Europe and really doesn't have as much traction here in the US where that's really -- the combination of the proteasome inhibitor and the immunomodulatory agent, Velcade and Revlimid is certainly more favored. That's not a regimen that I've utilized all too frequently.

Then most recently, we now have FDA approval based on the MAIA trial for daratumumab with lenalidomide and dexamethasone. Again, I just haven't had the right patient that that's been the right combination for, but it appears to be very effective. And that combination appears to get around the dogma I've said that more drugs is more toxicity, really well tolerated regimen aside from the potential reaction during the very first or first and second infusions and certainly more effectiveness of the combination without that cost of increased toxicity. So kind of an exciting time, things are rapidly, rapidly moving.

Jenny: Those are both situations (dara, melphalan, prednisone) or (dara, rev, dex) - those are triplet combinations that you could successfully use without a lot of extra toxicity. I mean our momentum is growing. And it sounds like you're going to have a lot of different options.

Dr. Wildes: Yes. And lots of opportunities to really individualize things. I sometimes need to remind myself that the things that -- the treatments that I see as relatively low burden from a side-effect standpoint, it still may be a significant burden on a patient. I've offered patients the triplets of dara with an immunomodulatory agent and a steroid and the weekly infusions for some patients were not something that was in line with their perception of good quality of life. I always say, “As long as I've given you the information, make your choice with…” If they choose just the doublet, that's fine with me. We need to find the pathway that's right for them. And if weekly trips to the doctor for a 90-minute infusion are too burdensome, I respect that. 

Jenny: Well, with dara, that phases out over time, right? So that might not be a long-term concern but, yes, everybody's different, right?

Dr. Wildes: Exactly. Right.

Jenny: Let's talk about stem cell transplant a little bit because I know sometimes patients think, “Well, if I'm over 65 or something, I'm not going to even consider a transplant.” In your opinion, how fit do you need to be and what are disqualifying factors or should transplant be considered by everybody?

Dr. Wildes: Really great questions and certainly not well-defined in the literature. It's interesting when you look at the trials that say these patients are either transplant eligible or transplant ineligible. There's actually not a definition of what that means. It's basically in the eye of the beholder. The Center for Medicare Services that provides the approval for transplant for patients with myeloma until about 15 years ago actually said it was only approved up to age 78. But I'm very delighted to report that they removed that age as criteria out of there. They said, “Basically, let's leave it to the doctors and the patients.” And they only stipulated the patient has kind of adequate organ function to tolerate it.

Most institutions have their own guidelines to some degree. For example, patients before transplant will undergo some breathing tests. There are some certain measurements that may demonstrate impaired lung function, which we know that if the patient has impairment in that type of lung function, if they were to develop say a pneumonia, they would be at dramatically increased risk of very serious side effects of the transplant. So the transplant teams will typically look at that performance status that we talked about earlier, basically how much of the day is the person up and about and how active are they in combination with their other medical issues. So significantly impaired heart function, lung function are probably two of the biggest reasons we would exclude a patient from transplant.

If we were to take the myeloma out of the equation, if their life expectancy is limited by those other conditions, then that's when we would not want a patient to go through a transplant because we do know the recovery is substantial. So kind of taking away that -- putting them at that increased risk of side effects of the transplant, without the longer game to look at because their life expectancy may be limited by these other issues, kind of part of the equation.

Now, those of us who are interested in geriatrics are really interested to say, “Can we use our tools of a geriatrician to describe the patients who are considered transplant eligible?” We can define this so that we can go beyond just what people like to call the eyeball test to say that these are our patients who are considered transplant eligible. I published a study a year ago in the Journal of the American Geriatric Society. Then there was another study that was at ASH last year that had very similar findings that basically that even though the oncologists were probably typically not using these geriatric tools, they were picking up on some of the vulnerabilities that we can categorize using the geriatric assessment. For example, I'll do a brief walking test called the Timed Up and Gowhere a patient will rise from seated, walk ten feet and then return to the chair.

We found that the patients who are considered transplant eligible walked faster than those that were considered transplant ineligible. So slowing is a well-known component of frailty. The clinicians were picking up on that. It just would be nice to rather than using the thumbnail estimation, if we could do that in a more rigorous type of way. Even though the oncologists were not measuring the daily activities, these instrumental activities of daily living I mentioned earlier, the patients who had limitations in those were less likely to undergo transplant as well. So I'd love to move beyond the eyeball test to using these geriatrics principles.

In the US, I would say it's pretty common for up to the age of 70 for patients to be by and large candidates for transplant. Between 70 and 75, as those aging associated vulnerabilities are starting to accumulate, there's a bit more variability in whether a patient would be considered a transplant candidate. But I'll hear in the myeloma community of people who are approaching 80 or even into their early 80s being considered candidates for transplant. I think taking into account these aging associated vulnerabilities and what the patient's life expectancy independent of the myeloma is to help guide those decisions rather than any of these age cutoffs.

Jenny: Wow, that's so fascinating. You mentioned the lung function and the heart function. Is kidney function part of that as well or no, not necessarily?

Dr. Wildes: No. In fact, even patients who are on dialysis are commonly considered candidates barring that they have any of the other significant comorbidities. They do need to have dose reduction in the dosing of the chemotherapy that's used with the transplant, but it's not an exclusion.

Jenny: Really? That's very interesting. I know there's a debate about should people do early transplant versus late transplant. Can you speak to that in terms of effectiveness of the therapy? Is there any data on that that shows that it is or it’s not more effective in the elderly population? And then just the practical issues, like if you wait too long to get a transplant, maybe it's not an option for you anymore.

Dr. Wildes: Yes. You hit the nail on the head. When we have looked at older patients versus patients who get transplant and we compare their outcomes, older patients get the same benefit as younger patients. So that's reassuring for it. When we compare older patients who get transplants to older patients who do not get transplant, even when we can control for all the factors that go into the decision about whether they do or do not get transplant, we still see a substantial benefit to undergoing transplant. So I recommend for all my older patients who are potential candidates that they consider it.

The early versus late question is a wonderful one and for exactly the reason that you said. I tell my patients, “We have a lot of cards we can play. The question is if we’ll wait with you, what is the likelihood that a new medical issue may have come up in the interval that would then take the transplant out of the running as a possibility?” I certainly have had my fair share of patients who they're doing well from the myeloma standpoint and then lo and behold, they ended up having a heart attack or needing a bypass surgery or ending up with heart damage that would then subsequently make them not a candidate for transplant and that their greatest likelihood of having the physical resilience that one needs to go through transplant is the younger that they are. So I encourage them to consider it rather than -- in the early setting as opposed to holding that card for a rainy day.

Jenny: I know some patients are like, “Oh, I don't want to do transplant.” But in my opinion in myeloma, you either get your therapy all at once or you get it over a long period of time or you get it -- like you're going to get it. If transplant can get you out further and you're on lower doses of maintenance therapy versus staying on a triplet combination for the same time period, it's -- I don't know. You're down for the count for a few weeks more but that's maybe just a personal preference.

Dr. Wildes: Jenny, it’s so funny. I think you and I have a very similar views on things. That's exactly what I'll tell my patients. It’s that this is just packing nine months' worth of treatment into a very concentrated period. When patients who physiologically, I think, are fit for it and that they described for me that their goals of care are really about quality of life and time and family and they want to have the mobility to go travel and not have to be tied to coming in for treatments, those are factors that are going to make me really want to make sure that they have an accurate perception of what the transplant period is like. I'll encourage them to talk to other transplant recipients to hear about what their experience was like, just so that they're making the decision that's best for them. Because as you said, ongoing therapy, like you said, daratumumab does decrease in frequency, so there's some flexibility in there. I have a dear, dear patient who absolutely wants to spend most of his life in his motor home and traveling and not spending a whole lot of time here in St. Louis, which is not really compatible with whatever schedule of injectable type therapy for him.

Jenny: Right. Well, there are a lot of things to consider as a patient. That's why patients have to come to you and talk about their preferences too.

Let’s say a patient comes into your office. They're older or more unfit. What would you choose if there are standard risk? Then how would you change that if they were more considered high risk, a high-risk patient?

Dr. Wildes: I think our understanding of this is rapidly shifting as we're adding the monoclonal antibodies into frontline therapy. Some of the challenges we have was looking at the risk groups. It’s how small those subgroups are within each of the clinical trials. And the fact that in those large trials are designed with what we call power, which is basically whether the study can answer the question of, “Is this treatment more effective in this subgroup?” When you break out a small group of those patients, from a statistics standpoint, our degree of certainty about the benefit of that treatment in that subgroup starts to get a bit more hazy, if that makes sense. So as we're incorporating things like dara plus lenalidomide and dexamethasone into our war chest, it starts to get a bit hazier what we do in that higher risk group.

In my standard risk myeloma patients, overall, my approach has been the combination of lenalidomide, bortezomib and dexamethasone in a modified regimen we call RVD-lite. Now, I will still occasionally use just lenalidomide and dexamethasone based on patient's individual preference. But based on the overall, if effectiveness is the primary concern and they're okay with the frequency of visits, then I'll head towards the RVD-lite. I haven't had as many opportunities to incorporate the Dara-RD regimen yet just because we got approval left for that so recently, but looking forward to adding that into the combination. As far as higher risk patients, I think my comfort level based on the available data is highest with the RVD-lite regimen having the proteasome inhibitor and the lenalidomide at this point, but we'll be anxious to be seeing more data about the Dara-RD combo in that high risk subset upcoming.

Jenny: Right. There is a ton of stuff coming out in clinical trials. When you look at all the development that's being done for myeloma patients, -- and the pipelines are huge -- what looks the most interesting to you from when you're looking at it with that lens of geriatric or elderly patients?

Dr. Wildes: Great question. For me, the question that I think needs to be answered most rapidly is less about the individual drugs and their side effects as opposed to what approach should we be using. So the trial that I cannot wait to see results on but unfortunately, I'm going to have to be patient and wait a few years because they just started enrolling this year, it's coming out of the United Kingdom. It's called the FiTNEss trial. I think it's MRC XIV. It has an acronym. That's the FiTNEss trial where they're randomizing patients to either the standard approach to dosing anti-myeloma therapy or a proactively dose reduced approach based on geriatric assessment. So categorizing the patients as fit, intermediate. I think it may be just intermediate and frail. I apologize. I need to look at the details again. But basically doing what we do in clinical practice, but doing it proactive dose reductions as opposed to reacting, waiting until the patients had a significant side-effect before reducing that dose.

It's a combination I believe of ixazomib and either cyclophosphamide or lenalidomide and dexamethasone. But basically just testing the approach of, “Is our standard way the most effective or is this a priori dose reduction based on stratifying the patient, based on vulnerability the way to go?” So that's one of the studies I'm most excited about. I also participate in the Alliance. And very, very shortly, we will be opening a trial of the combination that includes both the monoclonal antibody, immunomodulatory agent and proteasome inhibitor. It will be a combination of dara, lenalidomide and ixazomib in newly diagnosed transplant ineligible patients.

I think other approaches that are going to be really important too are categorizing the patients using these principles of geriatrics. One of the deficits that we have right now is when we look at that trial of patients, even if the average age is over 70, we don't know very much about those patients because we're just categorizing them based on an age range. Maybe the performance status and that's about it. We know very little about the spectrum of aging associated vulnerabilities present in that population.

So if we start to plan from the beginning when we conduct these trials to gather the data about the aging associated vulnerabilities using these frailty scales, I'm going to be able to look at a trial and say, “Sixty percent of the patients in this trial are frail. That's like the patient sitting in front of me. This is data I can apply to this patient.” We do know that the way clinical trials have traditionally been designed tends to discourage or even exclude patients as they age, whether it's the burden of extra treatment visits on the clinical trial or the way the dosing is done that either the patient or the clinician think is not appropriate for a more vulnerable patient. So if we start to design our trials more intentionally, making sure we're characterizing the vulnerabilities in the patients and then dosing in a way that is appropriate for these patients, I think it's going to give us just so much information to better tailor the treatment to a patient based on their current health status.

Jenny: Well, that's fascinating. When you look at the new stuff like the CAR T or the BiTEs or the antibody drug conjugates -- many of them seem to be going after this BCMA target, but now other targets are in the works too. When you look at that in the context of this older population, what do you think? I know CAR T, they're trying to figure out, “Well, why do some patients respond or not respond? Is it the age or the function basically of their immune system?” How do you look at that? Do you suggest, “Hey, get on that CAR T clinical trial list for an elderly patient,” or should you consider some of the BiTEs or if they've exhausted these other myeloma therapies?

Dr. Wildes: Great question. I tend to be a late uptaker, meaning I really want to see the data. I want to see the safety in my older patient populations. So I tend to not jump on bandwagons as early, but even for me, it's been hard not to be excited about all these new approaches. But I can tell you that even having CAR T studies up in here at Siteman Cancer Center, but those trials are really unattractive to my older patients when I tell them the duration of their hospitalization and some of the toxicities, particularly the neurologic toxicities are very worrisome to them. I certainly wouldn't discourage categorically older patients from considering those trials, but at least my experience so far has been they haven't been as attractive because those individual patients had prioritized their quality of time over achieving depth of response with their myeloma and that sort of thing.

I think they're exciting. As we learn more about them, we understand better who is at risk for toxicity, how to manage those toxicities. I'll look forward to utilizing them more widely in my older patients. But at the moment, it hasn't had as much uptake. As I said, in my case, mainly due to the patient's priorities and preferences not being in line with being on those trials at the moment.

Jenny: Yeah. I'm curious about the neurotoxicity when you talk about that because does that happen more in lymphoma and leukemia than in myeloma? Some of the cytokine release?

Dr. Wildes: Yeah. I think it's an evolving story and that may end up being how it plays out, but it certainly remains on the potential considerations. But yeah, I agree. It's an evolving story.

Jenny: Yeah. That's so interesting. Well, it'll be so interesting to see what happens with all of that and specifically for this population because wouldn't that be great if they do figure out how to make those remissions long-term and you pass away from something else. In myeloma, that would be great. Well, not the passing way, but --

Dr. Wildes: Right. Exactly. I know. I say that same thing. And I feel strange when I say and I'm like, “Okay. That's not exactly what I mean. But you know what I mean.” I say all doctors’ goal is for their patients to pass from a disease that's in someone else's, a different doctor's domain.

Jenny: Yeah. It's hard. This life is hard. I'm wondering what patients can do to increase their fitness status to really prepare themselves to obtain their best myeloma care regardless of the age.

Dr. Wildes: Yeah. I think I have two main recommendations for that. First is be ready to be your own advocate. Just by virtue of participating in things like this, I can see that those who are listening are wanting to equip themselves to really advocate for themselves, obtain the best care that they can. I think one of the components of that advocacy is like we talked about earlier, making sure that you're reporting side effects that aren't acceptable to you, that are not what you expected or you're just not sure if this is what you should expect and what can be done to help mitigate that. I think telling your doctor what is important to you is so important. I think one of my favorite days, I mentioned my Winnebago driving patient. When he came to me, we were doing RVD-lite. He said, “I can't do this anymore. I need to travel. I need to roam.” And we switched to ixazomib so that he could have an all oral regimen. And when he came back, he looked like a renewed spirit. He said, “I cannot tell you what it did for me to be able to go back to the life I loved, of just traveling in this beautiful country.” And that never would have happened if he hadn't come to me and said, “This is what is important to me,” and that we could find a creative solution that met his goal and was ideal for his myeloma.

The second thing I would recommend is probably not going to be what anyone wants to hear, but I think exercise is such good medicine for our bodies for a few reasons. One, just helping you maintain that physiologic resilience that there's going to be storms along this journey. And whether it's an infection that was unexpected or developing peripheral neuropathy, exercise is actually one of the only things that's been proven to help improve chemotherapy-induced peripheral neuropathy, that nerve damage from prior chemo.

This is certainly difficult. I don't want to gloss over the fact that the fatigue from treatment is real. Many patients will have had significant decline in their function leading up to their diagnosis. They may have had pain for months and really, by the time they are getting to their diagnosis, have lost significant muscle mass as their activities shrank and shrank because they were in so much pain by the time they finally got to the diagnosis.

And there may be fear. Jenny, you and I were talking earlier about fear about fractures and that sort of thing. I would encourage patients who have, over the course of their journey, had a very sedentary period particularly if there were specific bone issues to request consultation with a physical therapist who can really evaluate, “Are there specific muscle areas that are weak and should be targeted?” I am very interested in falls in older adults. And we do know that if a person who has been very inactive and even having falls goes straight to a walking program. They will actually increase the risk of falls. So they really need to start first with consultation with a physical therapist to work on any sort of muscle imbalances that may have developed, to strengthen those muscles, to work on their balance and then undertake a regular exercise program. And as I mentioned, that'll give that physiologic, that physical resilience for whatever lies ahead.

Jenny: Well, there are a lot in what you just said. I had two questions about that because we did a show with the physical therapist. She was saying, “You can lose muscle mass in just three weeks,” and like going through a transplant or something like that. So even when you're going through something like that, you don't feel like doing anything. You're just feeling like, “Why am I so tired?” So just moderate exercise can overcome that like a lot faster. Even things, doing things in bed or just to keep your muscle mass up is really important.

Then I'm just wondering how the cytokines are related to exercise. So it'd be interesting to have somebody do a study on what happens with your IL-6 levels as patients exercise or don't exercise following myeloma treatment. That would be really interesting.

Dr. Wildes: Absolutely. You bring up the exercising around the transplant period. Ten years ago, there was a study, which I think was largely allogeneic stem cell transplant patients and tended to be younger patients, but they randomized the patients to usual care or exercise during the transplant period. And what was fascinating is that the patients who exercise had shorter length of stay and actually recovered their blood counts faster, which was fascinating to me. Because getting to exactly your point, there was something physiologic going on that allowed them to recover their blood counts faster. That's not a self-reported “just feeling more energy” or something like that. There's something going on at the molecular level there that's really, really interesting.

Yes. We'd love to see how that plays out in the myeloma setting.

Jenny: I wonder why we don't get our IL-6 levels checked. I think they are related to other things too beyond the myeloma. But I think that would be an interesting lab to start capturing from myeloma patients to see if patients have this chronically high levels for things like that. But yes, I know you don't feel like doing anything when you're going through transplant. But I have had friends say, “I got on a stationary bike actually while I was still in the hospital going through transplant and just force myself to do it.” And he recovered a lot faster even when he  had two transplants they could compare. So I think there's definitely something physiological about that.

This show brings me to the conclusion yet again that as patients, we really need to have a myeloma specialist in our corner because to know how to treat in such a nuanced way for individual things that might be all over the place for comorbidities or other medical conditions that patients are dealing with, we really need people like you. So I strongly recommend that people go get a consult with a myeloma specialist. And the data keeps coming out over and over again that you live longer if you do because of these very reasons in my opinion.

I want to open it up for caller questions. So if you have a question for Dr. Wildes, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Perfect. Hi, Dr. Wildes. I just have a really quick question for you. Coming from someone who is a daughter to a parent who has cancer and potentially a grandparent who might have cancer, in what ways would you recommend I could be more hands on or helpful in that process? Because I think there's a lot -- as a child of someone who has cancer, there's a lot we can do. I just want to make sure if you have any recommendations of ways I could be more hands on in that process.

Dr. Wildes: Wow. Great, great question. And I'm sorry that you're going through that. I think the things that immediately come to mind are number one, take care of yourself. Make sure that you're not neglecting your own health in taking care of them. As myself, the adult child of aging parents who can be very set in their ways, I think making sure that you keep the relationship -- holding onto the dual goals of helping them maintain their autonomy, but then encouraging them to maybe look at things with fresh eyes if their approach is one that you really perceive is being suboptimal. I think you're in a great position, too, to possibly be an advocate for them to have issues checked out that they may not be very forthcoming with. This is a totally different direction, but my perception is that many of my older patients at that greatest generation mentality will deny depression and other psychosocial symptoms that they really could benefit from having addressed. It's really not until the adult child then in tears saying, “Dad, this is not you. You used to really enjoy whatever hobby or grandkids or what have you.” It's often that plea from the adult child that gets them willing to say, “Okay, yeah. This is a part of the symptoms I'm dealing with. And I need help in this.” I hear way too often, “No, I can just power through this.” And I say, “This is a medical condition. Depression and anxiety are medical conditions that need to be addressed the same as we would address if you have pain or nausea.”

Caller: Thank you so much. That's very helpful. I mean it sounds like even exercise might even be -- an encouraging exercise might be really helpful as well, just with how the results of how a patient's who is exercising, how helpful it can be. This is great. Thank you so, so much.

Dr. Wildes: You're most welcome.

Jenny: Thank you so much. What a great question. Dr. Wildes, thank you so much for joining us today on Myeloma Crowd Radio. This is a really important topic. It's clear that you are a great expert on this topic. You were the perfect person to choose to address this. We are excited to see what other research that you're doing and what that ends up showing for this patient population because it's the majority. Almost the majority of myeloma patients are in this situation. Thank you just so much for joining us today and for sharing your expertise with us.

Dr. Wildes: Oh, thank you. It was great fun and a delight. Have a great day, everyone.

Jenny: Okay, thanks. Thank you so much for our listeners for listening to Myeloma Crowd Radio. We encourage you to tune in next time to learn more about the latest in myeloma research and what it means for you.