Multiple Myeloma - Episode 12
EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD
Alfred Garfall, MD:I’m curious to hear what you all think, but I feel like with time, my adjustments for age and frailty have more been in dose and intensity rather than withholding medications.
Nina Shah, MD:Yes, yes.
Alfred Garfall, MD:I still feel like triplet and even quadruplet therapy are appropriate in the very old population, maybe with an attenuated dose and frequency.
Ola Landgren, MD, PhD:If you talk about practical management here, if you use Revlimid [lenalidomide], would you start out at a lower dose for a patient who is older? What’s each cutoff about, and what dose would you use?
Alfred Garfall, MD:For someone who’s age 81, and especially with renal insufficiency and a low clearance, I would even maybe start at 10 mg. However, I’ve also given full-dose Revlimid to patients in their 70s who are very well, and it is very idiosyncratic as to who can tolerate it and who can’t. Even some younger patients can’t tolerate the full dose. I try to give patients the benefit of the full dose as long as their performance status is good, even if they’re on the older side.
Ola Landgren, MD, PhD:In this patient, would you give Revlimid, or would you do something else?
Alfred Garfall, MD:I would probably give Cytoxan [cyclophosphamide]based therapy first. I would anticipate with this patient, with correction with calciumand there are probably elevated light chains as well—that in a cycle the renal function would be more in a range where I’d feel comfortable giving Revlimid. I do think the long-term data with IMiD [Immunomodulatory imide drug]–PI [proteasome inhibitor] combinations is strong enough that you should probably try to get an IMiD-PI combination, and once the renal function is stabilized with cycle 2 or so, it’s with dose adjustments for renal function.
Ajai Chari, MD:So CyBorD [bortezomib, cyclophosphamide, dexamethasone], and then if we see improvements of the kidney, you could switch to RVd [lenalidomide, bortezomib, dexamethasone] and then Revlimid?
Alfred Garfall, MD:Yeah. Even if you don’t get full improvement in the kidney function, as long as you’re satisfied that it’s stable, try to introduce Revlimid at an adjusted dose.
Ola Landgren, MD, PhD:And the Revlimid dose: Would you then maybe do 15 mg, or 10 mg, or another dose, assuming that the kidney would improve here?
Alfred Garfall, MD:Right. With normal renal function in somebody in their 80s, I would say 15 mg is where I would start as the high, but [recognize that] maybe you need to adjust beyond that.
Ola Landgren, MD, PhD:Would you do the bortezomib once or twice a week? How would you do that?
Alfred Garfall, MD:I think that’s 1 of the main changes I would make for older patientsonce-a-week bortezomib from the start. I’m really concerned about the risk of peripheral neuropathy early on.
Ola Landgren, MD, PhD:Would you do it differently, Ajai?
Ajai Chari, MD:I definitely wouldn’t use lenalidomide in this patient for cycle 1. She’s anemic, at 7.6, with an IgA of 7200 [APL], so there’s a good chance you’ll need to do a transfusion. Her neutrophil count is 1400. I doubt you’ll get through a whole cycle. Her creatinine is 2.2 mg/dL. She also probably is at increased thrombotic risk because she’s confused and has the bone disease, so she may be hypercoagulable from that perspective. Finally, getting lenalidomide in a timely fashion with somebody whose calcium is 14.8 mg/dL and IgA is 7200 [APL] is challenging.
I would definitely do a CyborD [bortezomib, cyclophosphamide, dexamethasone] backbone, adding daratumumab. Again, time is kidney. I’d normally completely agree that I would only do once-weekly bortezomib, but this may be a setting just for cycle 1. In fact, some of the newer, or the VMP [bortezomib, melphalan, prednisone] backbone even done in Europe, they do 1 cycle twice weekly and then go to weekly. I think this patient is in trouble if we don’t get to the disease burden quickly.
Ola Landgren, MD, PhD:If this patient came to me, I would probably consider admitting the patient. And then I would do CyborD [bortezomib, cyclophosphamide, dexamethasone] in the hospital twice a week with Velcade [bortezomib]. If the kidneys cleared, I would do outpatient treatment. I would probably choose Revlimid 15 mg as my plan, and then do once-a-week Velcade.
Nina Shah, MD:I agree. Actually, I might even go higher with the Cytoxan depending on what other volume situation, but maybe previously plasmapheresis. This person is very sick.
Ola Landgren, MD, PhD:Yes.
Nina Shah, MD:I’d just be aggressive if possible. It’s very hard to do this in a hospital, depending on cardiac status. I might even give carfilzomib, like a carfilzomib-Cytoxan-dexamethasone, because of the disease burden. But if the renal function normalized and it turns out the patient is doing great, this might even be a good person for DRd [daratumumab, lenalidomide, dexamethasone]. That’s up there too as a possible regimen.
Ajai Chari, MD:I would just use caution with carfilzomib in this population. For example, the CLARION study was a head-to-head study of KMP [carfilzomib, melphalan, prednisone] versus VMP [bortezomib, melphalan, prednisone], and there was no difference in the older population. I think the issue is it is a very potent drug. It’s very well tolerated, but older patients have a lot more cardiac comorbidities, and you would need to practice with due diligence to make sure there [are] no cardiac issues in this patient. I just think that needs to be thought out very carefully. When you look at the risk factors, the risk of heart failure overall is less than 5% across all studies. But in older patients, it can be as high as 15% to 20%.
Nina Shah, MD:Yes, it definitely has to be considered.
Ola Landgren, MD, PhD:There are obviously many different ways of doing these things. We use, as I already brought up, a lot of carfilzomib in our clinic. In my clinic, if this 81-year-old woman with all these labs being so off came to me, I probably would do CyBorD [bortezomib, cyclophosphamide, dexamethasone] for the same reasons, because it’s easy to give. If it really didn’t work, I would probably think about other options. I may have revisited carfilzomib, but I probably would have done CyBorD [bortezomib, cyclophosphamide, dexamethasone] too. But there’s nothing wrong with trying that.
Alfred Garfall, MD:Just to send a uniform message, because I can see this as kind of a mistake being made some times, almost nobody can’t get twice-weekly Velcade for their first cycle, right? No matter what supportive care we have to provide in the hospital, intensive-first cycle of therapy for patients like this is appropriate.
Ola Landgren, MD, PhD:Before we move on to the next patient, I want to bring up a little bit of a different twist to an older patient. Let’s say this patient was age 81 but had labs that were pretty OK. There was no renal failure. There was no hyperglycemia. The hemoglobin was just barely decreased. The work-up shows multiple myeloma. If the patient came to you and was in great shapesay, an 81-year-old who looked like a 60-year-old—how would you treat that patient?
Ajai Chari, MD:I would need to know more details. With the CRAB symptoms [elevated calcium, renal failure, anemia, bone lesions], what is abnormal?
Ola Landgren, MD, PhD:Let’s say there is 1 lytic lesion in L2, and the hemoglobin is 11 g/dL. The kidney function is fine, and all other labs are virtually within normal ranges. You do a bone marrow biopsy, which shows 40% plasma cells.
Ajai Chari, MD:Obviously if there’s a lytic lesion, you would treat. But I think with the decision of treating or not treating, I think, again, going back to what happens over time is very important.
Ola Landgren, MD, PhD:And also a patient who needs therapy.
Ajai Chari, MD:Absolutely. I couldn’t tell at first if you were alluding to this being a borderline smoldering.
Ola Landgren, MD, PhD:No.
Ajai Chari, MD:OK, so the patient needs treatment. If he or she is a relatively well patient, I might do DRd [daratumumab, lenalidomide, dexamethasone].
Ola Landgren, MD, PhD:So you would not use your RVd [lenalidomide, bortezomib, dexamethasone] with daratumumab? Now you’re switching to DRd [daratumumab, lenalidomide, dexamethasone]?
Ajai Chari, MD:It depends. The advantage is obviously with subcutaneous daratumumab. I think DRd [daratumumab, lenalidomide, dexamethasone] is so good if it’s the standard-risk patient. The difference between the triplet and quad in an 81-year-old, I’m not sure. It goes back to that risk-benefit.
Ola Landgren, MD, PhD:Nina?
Nina Shah, MD:I think I’d probably do RVd [lenalidomide, bortezomib, dexamethasone]lite or DRd [daratumumab, lenalidomide, dexamethasone]either of the those. It would just depend. If they have diabetes and have neuropathy, just do the sort of thinking about what you want to have as a sequelae of treatment.
Alfred Garfall, MD:I would take the same approach as Ninaeither DRd [daratumumab, lenalidomide, dexamethasone] or attenuated RVd [lenalidomide, bortezomib, dexamethasone]. What would you do?
Ola Landgren, MD, PhD:Probably RVd [lenalidomide, bortezomib, dexamethasone]lite. That being said, I told you about the trial that we have done with the KRd [carfilzomib, lenalidomide, dexamethasone]–daratumumab. When we opened that study, just a few weeks later there came a patient in with a diagnosis of myeloma in very good shape. The patient was 80 years old. The patient said, “I read about this study. I want to go on it. I know I fit all the criteria.” The patient went on the trial, went into MRD [minimal residual disease] negativity, and now is doing really great.
Ajai Chari, MD:I think an important distinction and discussion point with the RVd [lenalidomide, bortezomib, dexamethasone] versus DRd [daratumumab, lenalidomide, dexamethasone] is that we use RVd [lenalidomide, bortezomib, dexamethasone] based on the SWOG S0777 study, which was without the intent to transplant. However, that is not a transplant-ineligible population, right? The median age of that was only 63. It was twice-weekly bortezomib. There were a lot of GI [gastrointestinal], neuropathy issues with that. I think although it led to response rate, PFS [progression-free survival], and benefit, you cannot assume that the regimen can be given to your typical 81-year-old patient sitting in front of you. But then going back to the evidence-based high-level evidence, what is the high-level evidence, the RVD [lenalidomide, bortezomib, dexamethasone]lite? It’s a single-arm study from Dana-Farber Cancer Institute with great results, but there’s not really a randomized control arm, right? And the question also is, how long do you have to continue the bortezomib? It was given for over a year. So you’re giving weekly bortezomib. I think it was 3 weeks on, or initially it may have been a longer cycle. But that’s a lot of weekly visits, right? I think DRd [daratumumab, lenalidomide, dexamethasone] can be given on label. There are no dose modifications required. MAIA had a median age of 73. You can deliver the drugs as intended. And after the first 6 cycles, you’re monthly daratumumab, right?
Nina Shah, MD:And maybe subcutaneous, eventually.
Ajai Chari, MD:Yeah.
Ola Landgren, MD, PhD:If the patient said, “I don’t want to take this tablet. It makes me fatigued,” would you ever do daratumumab once a month as a new maintenance?
Ajai Chari, MD:I think that’s where we have to distinguish among clinical trials. You know, clinical trials are always treat to progression with triplet. I think that’s what reality is, and people don’t tolerate all these drugs, right? And so we can eliminate the drugs that are the least important or the worst tolerated for that patient, right? You’re going to monitor them with monthly labs anyway. You come in, get your squirt of daratumumab, and you go home.
Ola Landgren, MD, PhD:Do you think daratumumab is going to be a new alternative as maintenance for these reasons?
Ajai Chari, MD:It depends on the population, right? For the transplant population, it’s hard to beat the lenalidomide maintenance data, with the OS [overall survival] benefit as well. I think that is a high benchmark to beat. The maintenance studies that are being done are not daratumumab versus lenalidomide. It’s daratumumab plus lenalidomide, right? I think it’s premature to discontinue. But in this population, what we know is that when you look at real-world data versus clinical trial data, the median duration of therapy in the real world, at best, is probably 70% of study duration.
Nina Shah, MD:Yeah, I totally agree with you. If we do RVd [lenalidomide, bortezomib, dexamethasone]lite on this patient, are we going to do a year of Velcade? Probably not. I would probably get the 8 cycles, do an IFM [International Myeloma Foundation] study style, and move on to Revlimid maintenance for an 81-year-old. You know, something like that. You’re totally right about that.
Transcript edited for clarity.