High-Risk Multiple Myeloma: Selecting Initial Therapy


Sagar Lonial, MD, FACP, leads the discussion on selecting the optimal proteasome inhibitor, bortezomib or carfilzomib, for patients with high-risk multiple myeloma.

Keith Stewart, MD, ChB, MBA: Sagar, you’re a bortezomib lover. I think it’s dreadful stuff, it gives everyone neuropathy. Have you maintained use of botezomib in your older patients?

Sagar Lonial, MD, FACP: We’ll use VRd [bortezomib, lenalidomide, and dexamethasone] in the high-risk group only. There hasn’t been a dara [daratumumab] upfront trial where the initial analysis showed a benefit for high-risk patients. If you put all the patients together and wait long enough, when all the high risk drops off, you’ll start to see, well, maybe it’s not so bad, but that’s a late effect. So, we’re using RVd [lenalidomide, bortezomib, dexamethasone] only in the high-risk patients.

Keith Stewart, MD, ChB, MBA: One of you mentioned the ENDURANCE trial, I think you did, Nina. There wasn’t a PFS [progression-free survival] or overall survival [OS] advantage to carfilzomib compared to bortezomib in standard-risk transplant ineligible populations. We had a previous trial with the melphalan, prednisone, carfilzomib vs melphalan, prednisone, Velcade, which also showed no PFS. However, there was significantly less neuropathy in the carfilzomib arm of the trial. Are you using carfilzomib or bortezomib up front?

Nina Shah, MD: I have to admit, based on the outcome of the ENDURANCE trial, for younger patients I like to use carfilzomib up front because the patients, for example, many of them don’t have cardiac abnormalities. I’d rather not risk the chance of neuropathy. If you’re going to dose it like the ENDURANCE trial did, there is still a significant amount of neuropathy that happens with bortezomib use. That’s a long-term adverse effect that’s difficult for the quality of life. I often choose KRd [carfilzomib, lenalidomide, dexamethasone] for my younger patients for that reason.

Keith Stewart, MD, ChB, MBA: We get all of our medical knowledge from Twitter these days, but I see people on Twitter pushing back on this, saying, “Why on earth would you use carfilzomib when the trial was negative?” Cristina, do you use carfilzomib?

Cristina Gasparetto, MD: I prefer bortezomib a bit more in the upfront setting. I like the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] a lot because of the rapidity of response and the depth of response. I’m chasing that a lot these days, particularly after transplant, for standard-risk and high-risk patients. I like the depth of the response that we see with the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone]. However, as mentioned earlier, the FORTE trial, which was presented at ASCO [American Society of Clinical Oncology Annual Meeting] from the Italian group, KRd [carfilzomib, lenalidomide, dexamethasone] continued for 12 cycles vs KRd [carfilzomib, lenalidomide, dexamethasone], transplant, 2 cycles of consolidation. Then the patients were randomized to carfilzomib in the maintenance setting, it was carfilzomib, lenalidomide, versus lenalidomide. When Francesca Gay, MD, dissected all the different genetics, the different patient populations, it was impressive how the carfilzomib was performing in this population of patients. I’m rethinking a bit, except for the 1q amplification, the numbers were low. She didn’t see a lot of benefit. But the deletion 17p and all the translocations, they performed well. So I’m changing a little. I know you guys are working on using carfilzomib for high-risk disease, but I’m comfortable with the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] because the data were quite impressive with the depth of responses.

Keith Stewart, MD, ChB, MBA: Sagar, have you added daratumumab to your standard regimen for all of your patients?

Sagar Lonial, MD, FACP: Yes. For standard risk, we do RVD-dara [daratumumab plus lenalidomide, bortezomib, dexamethasone], up front. We haven’t added it to the high-risk patients, but that’s the only subgroup we switched to KRd [carfilzomib, lenalidomide, dexamethasone] up front.

Keith Stewart, MD, ChB, MBA: So, you’re doing dara-RVD [daratumumab plus lenalidomide, bortezomib, dexamethasone] in a standard-risk younger patient, and KRd [carfilzomib, lenalidomide, dexamethasone] without daratumumab in high risk?

Sagar Lonial, MD, FACP: Yes.

Keith Stewart, MD, ChB, MBA: Why wouldn’t you use daratumumab? It didn’t make it worse.

Sagar Lonial, MD, FACP: It’s not clear that it makes it better.

Keith Stewart, MD, ChB, MBA: Are there any patients, Sagar, you wouldn’t take to transplant? We’ve got these 4-drug regimens with just 60% molecular CR [complete response] type of results. I don’t know the exact number, but it is in that range. Would you still transplant a patient in molecular CR, after 4 cycles of dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]?

Sagar Lonial, MD, FACP: Yes, I think that’s a really important question because there are a lot of mixed messages out there about the role of MRD [minimal residual disease] negativity, particularly at early time points. To me, the sustained MRD question is a much more important one. From the FORTE trial, that you heard about from Cristina, where patients got KRd [carfilzomib, lenalidomide, dexamethasone] with or without transplant, while the early data on depth of response looked the same whether or not you had a transplant, the long-term data suggested that using transplant improved PFS and sustained MRD negativity. The same is the case in the IFM trial, which randomized people to RVd [lenalidomide, bortezomib, dexamethasone] induction, transplant, or no transplant. Early on, it looked like if you got MRD at 10 to the minus 6, it didn’t matter. But with longer follow-up, PFS was better in the group that was 10 to the minus 6 and had a transplant. I think there’s still value.

Keith Stewart, MD, ChB, MBA: In that trial, the transplant doesn’t matter whether it was done early or late, right?

Sagar Lonial, MD, FACP: Well, they didn’t have a planned late transplant. So that’s off study. Not everybody who had the delayed option continued to a second transplant.

Keith Stewart, MD, ChB, MBA: I think I’m hearing from the group that there’s a mix of 3-, or sometimes 4-drug therapies up front now, more daratumumab use, and transplant is still generally recommended for most people for the time being.

Transcript Edited for Clarity

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