Multiple Myeloma - Episode 3

Case 1: Choosing the Right Therapy for Standard-Risk Myeloma

December 23, 2019


Ajai Chari, MD:The question is, what is a monoclonal antibody adding, toxicity-wise, versus benefit?

Ola Landgren, MD, PhD:I would like to come back to that. I actually asked you, Ajai, before, from the NCCN [National Comprehensive Cancer Network] Guidelines, and you were very savvy here to start bringing out all the data. The RVd [lenalidomide, bortezomib, dexamethasone] with daratumumab is actually not yet in the NCCN Guidelines. It probably will be, but it’s actually not yet. If you look in the NCCN Guidelines, you have the VRd [bortezomib, lenalidomide, dexamethasone] regimen. You could prescribe the RVd [lenalidomide, bortezomib, dexamethasone] with daratumumab, but then you have to have approval for commercial insurance and you could use it based on the data we’re discussing. But if you go back to the NCCN Guidelines today, the recommendation, if you’re not going to use RVd [lenalidomide, bortezomib, dexamethasone], or even CyBorD [bortezomib, cyclophosphamide, dexamethasone], or KRd [carfilzomib, lenalidomide, dexamethasone]… So let’s go back and look at the data. You called us out here and said, “When are they going to change?” Do you have to wait for the randomized study, or can you look at the data and be smart yourself? Let’s do the same exercise here. The VRd [bortezomib, lenalidomide, dexamethasone]—daratumumab: How much was the MRD [minimal residual disease] rate for that combination on the GRIFFIN study? Was it around 40%?

Nina Shah, MD:Forty-two percent.

Ajai Chari, MD:Forty to 50%.

Ola Landgren, MD, PhD:What was the KRd [carfilzomib, lenalidomide, dexamethasone] data presented in 2 phase II trials? That’s 50%. Why do you need an antibody if you have a superior proteasome inhibitor [PI]?

Ajai Chari, MD:That’s a great question. We don’t talk a lot about the doses, schedules, and number of days of treatment, right? KRd [carfilzomib, lenalidomide, dexamethasone] is a 28-day cycle. RVd [lenalidomide, bortezomib, dexamethasone] historically has been a 21-day cycle. So 4 cycles is actually an extra month of chemotherapy.

Secondly, the dosages matter, right? We all know that in the ENDEAVOR study, carfilzomib 56 mg/m2twice weekly was superior to bortezomib 1.3 mg/m2twice weekly. I don’t think anybody questions that. But when we start going down to different doses and schedules, you can give carfilzomib at 20 mg/m2, 27 mg/m2, which is the initial approval. You can give it at 70 mg/m2weekly based on ARROW. And you can give it at 56 mg/m2twice weekly. I think there is concern now about going to weekly 70 mg/m2with a concurrent IMiD [immunomodulatory imide drug]. I don’t think most of us are doing that. And so the question would be…

Ola Landgren, MD, PhD:Fifty-six mg/m2is the recommended dose.

Ajai Chari, MD:Then I would say, “Give me a study that showed that carfilzomib 56 mg/m2weekly is superior to VRd [bortezomib, lenalidomide, dexamethasone].”

Ola Landgren, MD, PhD:That has not been published, but you just said we don’t need randomized studies. There are studies showing that 56 mg/m2with daratumumab and IMiDs… They are going to be presented at this ASH [American Society of Hematology Annual] Meeting [& Exposition]. There will be 2 presentations. And they’re way higher than the VRd [bortezomib, lenalidomide, dexamethasone] with daratumumab in terms of MRD rates.

Ajai Chari, MD:But I would argue that we do have 2 randomized studies. We have daratumumab—VTd [bortezomib, thalidomide, dexamethasone] and daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. These are randomized, head-to-head studies.

Ola Landgren, MD, PhD:We don’t need randomized studies.

Ajai Chari, MD:No, but my point is that this is actually an era where we have more data than we did with the RVd single-arm study, right? So we actually have more data.

Alfred Garfall, MD:I don’t think any of us here are afraid to use daratumumab—RVd [lenalidomide, bortezomib, dexamethasone]. I think we all think it’s a safe regimen.

Nina Shah, MD:Yeah, we’ve all done it before.

Alfred Garfall, MD:The question is, does everybody need it? I think this discussion of the potency of the first-line therapy ignores what happens next, a little bit. Because with RVd [lenalidomide, bortezomib, dexamethasone], almost all our patients are going to be feeling better and doing better after a month or 2 of therapy. So what you’re really shooting for by adding more is the better long-term outcome. I don’t think we know for sure that adding daratumumab now is better than giving daratumumab later.

Ajai Chari, MD:But we know that daratumumab—VTd [bortezomib, thalidomide, dexamethasone] already led to a PFS improvement. It wasn’t just depth of response.

Alfred Garfall, MD:But what is the clinical significance of a PFS improvement when the patient progresses…

Ajai Chari, MD:I think it is spectacular, in 2019, to get a PFS improvement at 18 months when the median overall survival of myeloma can be as long as 10-plus years.

Alfred Garfall, MD:As I said, it is a potent regimen. I think if we see an overall survival benefit, we should use it for everybody.

Ajai Chari, MD:I’ll challenge you and say, “Give me a study where PFS2 is compromised.” Because you’re saying my concern about using a more effective regimen is that the subsequent line of therapy will be diminished. Has there been a daratumumab study where PFS2 has been compromised?

Alfred Garfall, MD:Show me a study where the control arm was allowed to get daratumumab at progression. That is how you might answer that question.

Ajai Chari, MD:But the overall survival is fraught with this question, right? Let’s stick to the question at hand. If you get daratumumab up front, does that lead to worse relapse such that your PFS…

Nina Shah, MD:We don’t know that yet. The data [are] just not mature enough yet.

Ajai Chari, MD:Well, POLLUX and CASTOR have both shown that PFS2 is not compromised.

Nina Shah, MD:That’s true for POLLUX and CASTOR, but what’s going to happen is we’re going to have these patients coming from GRIFFIN, and we don’t know what’s going to happen.

Ajai Chari, MD:But this is the same argument we saw with RVd [lenalidomide, bortezomib, dexamethasone]. “Oh, we’re going to use all 3 of our drugs up front? But what’s going to happen to these patients later?”

Alfred Garfall, MD:The question is, can you generalize the same?

Ajai Chari, MD:I think it goes back to, are you an early adopter or not?

Nina Shah, MD:So are you going to do daratumumab, KRd [carfilzomib, lenalidomide, dexamethasone], transplant? Daratumumab, KRd [carfilzomib, lenalidomide, dexamethasone], consolidation? Is that what you’ll do?

Ajai Chari, MD:I think the KRd [carfilzomib, lenalidomide, dexamethasone] question that Ola was raising is an important one, and I welcome your thoughts. I personally think if you’re going to use a quad, I’m not convinced that the carfilzomib 56 mg/m2once weekly dosage is going to be superior to bortezomib when you also have daratumumab and lenalidomide there.

Ola Landgren, MD, PhD:I think ASH 2019 will clarify that. I know of 2 presentations, and I’m giving 1 of them. I’m not going to tell you yet, because the data [are] not out there. However, I think the data are very strong. Let’s go look at ASH, and then we can have this meeting again in early 2020.

Transcript edited for clarity.