EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD
Ola Landgren, MD, PhD:Moving forward into the clinical management with this case, we agree that at least on paper it’s a high-risk case, although there are a lot of pieces we don’t know. No one has this information. How would you treat this patient? Would it be different from the first patient for which we did not confirm high-risk status? How would you treat this patient, Alfred?
Alfred Garfall, MD:This is a case [in which] I would use daratumumab with RVd [lenalidomide, bortezomib, dexamethasone], mostly because I’m worried about this patient progressing very early during therapy or having a very short-lived response. This is the kind of patient for whom I want to make sure I can get to transplant and on to maintenance therapy. I think daratumumab adds some assurance that you can do that with such aggressive biology.
Ola Landgren, MD, PhD:Ajai?
Ajai Chari, MD:I agree, with a caveat that if the patient didn’t tolerate bortezomib, I would have a very low threshold for switching to carfilzomib.
Ola Landgren, MD, PhD:So you would not switch right away?
Ajai Chari, MD:No.
Ola Landgren, MD, PhD:Nina?
Nina Shah, MD:I would probably give this person KRd [carfilzomib, lenalidomide, dexamethasone] and do 6 cycles, transplant, KRd [carfilzomib, lenalidomide, dexamethasone] consolidation, modified maintenancesort of long-term treatment. I’m not saying that’s better than daratumumabVRd [bortezomib, lenalidomide, dexamethasone], but that’s probably what I would do in this situation.
Ola Landgren, MD, PhD:In my practice, I would probably use the KRd [carfilzomib, lenalidomide, dexamethasone] regimen. That’s what we have a lot of experience with. I would give 6 cycles. I would collect stem cells. Even if the patient was MRD [minimal residual disease] negative, I would have this conversation with the patient. If the patient strongly said, “I’m not going to do it,” obviously the patient would have the last word. But I would probably recommend to consider doing a transplant here with our program. What about the maintenance? What would you do then?
Ajai Chari, MD:If I could just clarify, I’m curious. What doses of carfilzomib are you using? You also alluded to daratumumabKRd [carfilzomib, lenalidomide, dexamethasone]. Can you speak to the use or not or daratumumab with KRd [carfilzomib, lenalidomide, dexamethasone]?
Ola Landgren, MD, PhD:That’s not an NCCN [National Comprehensive Cancer Network] Guidelines approved regimen, so I didn’t bring that up. But if the trial was open, I would offer for the patient to go on the trial. In that setting, I would do 56 mg/m2once a week with daratumumab and lenalidomide.
Ajai Chari, MD:And if you could get that approved, could you…
Ola Landgren, MD, PhD:I would definitely give it to this patient. It looks fantastic. We have treated close to 80 patients, and it’s a very, very well-tolerated therapy. It’s also very convenient. It’s given only once a week. I think with daratumumab becoming subcutaneous, hopefully in 2020, it’s not a bad deal. There are fantastic results, and there is very limited toxicity. That’s something I definitely would do. But the standard of care right nowI would use the NCCN Guidelines. I would use the 36 mg/m2twice-a-week dosage, but you could also, with updated NCCN Guidelines, use 56 mg/m2once a week. So give 20 mg/m2the first week and then 56 mg/m2once a week. That is in the new NCCN Guidelines.
Nina Shah, MD:That’s what we’re doing20 mg/m2and then 56 mg/m2for KRd [carfilzomib, lenalidomide, dexamethasone] based on other data that have been presented. Now we have another experience. I find it’s very well tolerated and very effective. I’m interested to hear, Olasince you would have taken this patient, done 6 cycles, had the conversation about transplant—let’s say the patient has less than 1 clone in a million and decides not to go on transplant. What do you do with this high-risk patient? Do you do 6 more cycles of KRd [carfilzomib, lenalidomide, dexamethasone] to complete a year? What do you do?
Ola Landgren, MD, PhD:If the patient came to our center and got 6 cycles of KRd [carfilzomib, lenalidomide, dexamethasone] with daratumumabif that was approved—or got KRd [carfilzomib, lenalidomide, dexamethasone] without daratumumab for 6 cycles, and we did a bone marrow biopsy and collected the stem cells, and we counseled the patient toward transplant, if the patient said, “I’m not going to do this,” and our MRD tests show MRD positive, I would say to the patient, “I don’t feel comfortable going right to maintenance. So if you’re opting out from transplant, I would like to propose additional cycles of KRd [carfilzomib, lenalidomide, dexamethasone].” Obviously, there is no literature here. I would probably say, Let’s do 2 more cycles and then do a new bone marrow biopsy and decide.” That probably would be my default from our experience. How would you do it?
Nina Shah, MD:That’s hard because you could give endless cycles of KRd [carfilzomib, lenalidomide, dexamethasone]. But eventually, it gets really hard on the patient if you do every-other-week carfilzomib. And lenalidomide gets a bit tough. Every couple of cycles, you’re decreasing something. I would probably go on the 8, maybe more than 8 cycles, and then modify after that to every-other-week carfilzomib, which is not necessarily an NCCN dose but is something that is more tolerable for the long-term care of these patients.
Ola Landgren, MD, PhD:What about supportive care? We still give bisphosphonates? As the standard of care, we also have RANK ligand inhibitors in the guidelines. What is your standard of care, Nina?
Nina Shah, MD:I am still a bisphosphonate person. I know there are some issues with renal deficiency, although that’s modifiable. I will sayand these are data I was not aware of until this past year at SOHO [the Society of Hematologic Oncology Annual Meeting]—that with Xgeva [denosumab], and this came out of the Mayo Clinic, or with the RANK ligand inhibitors, there is a hypothesis that after you stop it, because all these studies were done without a stopping of the RANK ligand Inhibitors, maybe the osteoclasts are actually more active because they have a rebound effect. So if we don’t bridge back with them, maybe you could actually be having more bone loss. That has made me very scared to stop it when people have been on it. I don’t know the answer about RANK ligands. I’d be interested to hear what you guys think.
Ola Landgren, MD, PhD:Ajai, what do you use?
Ajai Chari, MD:For patients with renal failure, I use denosumab. Outside of that, zoledronic acid. The concerns you raise have also been seen a little in the osteoporotic literature as well, independent of cancer. So I think the discontinuation is important. The other thing we don’t talk about enough is the hypocalcemia with denosumab, right?
Nina Shah, MD:Yes, it’s real.
Ajai Chari, MD:It’s the black box warning, and the biggest risk factor for that is really renal insufficiency in analyses done. Guess which population has that? Ours. Compared with other tumor types, they may not see it as much. But I think if you’re going to use it, it’s important to replete that vitamin D, monitor the calcium, and make sure patients are safe.
Ola Landgren, MD, PhD:You have participated in the GRIFFIN study, and you have presented some of the data. Have you seen the use of daratumumab in combination with RVd [lenalidomide, bortezomib, dexamethasone]that Zometa [zoledronic acid] could have a different adverse-effect profile?
Ajai Chari, MD:We have not seen that.
Nina Shah, MD:We haven’t seen it either.
Ola Landgren, MD, PhD:We have had a couple of patients who we had treated with the 4 drugs. Zometa has been the 1 with the biggest adverse effect.
Nina Shah, MD:Yes, some people just do not like it.
Ola Landgren, MD, PhD:They say the other drugs are nothing, but this drug, I don’t want that.
Alfred Garfall, MD:It’s the fevers and the flu-like syndromes, or bone disease?
Ola Landgren, MD, PhD:This is the worst experience with the whole case. The others are nothing. What type of bone-strengthening approach would you use?
Alfred Garfall, MD:In this patient, who had a creatinine of 2 at presentation, I would use denosumab. But in recognition of the adverse-effect issues that you mentioned, once the patient has had a response, I tend to back off to every-3-month denosumab instead of continuing monthly indefinitely. Use it monthly at first. In patients with normal renal function though, I still use zoledronic acid.
Nina Shah, MD:I was going to say, about this renal issue, in the trial that compared the 2, the limitation of creatinine was 2. There were people who did OK, and maybe there was less renal toxicity in patients getting denosumab. But those were people who weren’t at the end-stage renalyou know, it’s a very limited patient population for which you can say, “OK, these people for sure should get denosumab.” So I worry that’s the thing…
Ajai Chari, MD:I think there’s a difference between the eligibility and the toxicity, right? There may not have been a lot of severe renal failure patients, but we know that ATN [acute tubular necrosis] is an adverse effect of zoledronic acid that is not seen with denosumab. And the question is, do you want to take that chance in somebody who worked so hard to reduce those light chains and get that kidney? I want to protect those kidneys, and everything…
Alfred Garfall, MD:I think it’s basically safe to give zoledronic acid, but you are running a risk of rare events that can be bad in somebody with compromised function.
Transcript edited for clarity.