Case 1: Triple or Quad Therapies for Standard-Risk Myeloma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Ola Landgren, MD, PhD:What are the options here for induction therapy? I’m sure we have a little bit of difference in perspective, difference in opinion. That’s the beauty of medicine. Nina, how would you treat this patient?

Nina Shah, MD:Right now, the standard approach for a patient like this would be what is commonly known as VRd [bortezomib, lenalidomide, dexamethasone]. As you know, we like to make everything sort of an acronym in myeloma. But VRd [bortezomib, lenalidomide, dexamethasone] would be the standard. This is based on the SWOG S0777 trial, which showed that triple therapy is efficacious and better than doublet therapy. I think we all have decided, as a myeloma group, that 3 drugs is better than 2; and this is 1 of the reasons why we can use this as an NCCN [National Comprehensive Cancer Network]—accepted option for frontline therapy in multiple myeloma.

Ola Landgren, MD, PhD:Ajai, there are other NCCN Guidelines—approved combinations. Nina mentioned VRd [bortezomib, lenalidomide, dexamethasone] has the highest level of evidence. Is VRd [bortezomib, lenalidomide, dexamethasone] your choice, or do you have some other thoughts?

Ajai Chari, MD:I think that’s 2000 late, as you would say. It’s time to move. I think the current therapy is quads. We’ve already seen, from CASSIOPEIA, daratumumab added to VTd [bortezomib, thalidomide, dexamethasone] and compared with VTd [bortezomib, thalidomide, dexamethasone]. What was really surprising…We know that daratumumab is combinable with other drugs, so there are really no additional safety concerns. And there was deepening of response. What struck me the most about that study is with only an 18-month follow-up, you already see a PFS [progression-free survival] improvement. I think that is the first foreshadowing of doing quads. Of course there’s also GRIFFIN, because who uses thalidomide in the US? But the GRIFFIN is basically the randomized phase II with daratumumab—RVd [lenalidomide, bortezomib, dexamethasone] versus RVd [lenalidomide, bortezomib, dexamethasone], and it has already shown an increased depth of response, although PFS data are being weighted. The question is, are you an early adopter or not? I personally would probably, based on CASSIOPEIA and this better efficacy, be moving toward quads.

Ola Landgren, MD, PhD:Alfred, what is your thinking here?

Alfred Garfall, MD:I’ll break the tie. I would go with Nina on this one. Our standard approach is to use Revlimid [lenalidomide], Velcade [bortezomib], and dexamethasone in a typical patient like this who presents with myeloma. I think it’s likely that in the future we will all move toward quads, but our approach has generally been to wait for higher levels of evidence and overall survival data to make those kind of moves. However, we have been using quadruple therapy in select cases. Based on the CASSIOPEIA data, where there were clearly fewer early progression events and fewer early deaths from myeloma progression in the early phase of that trial—patients who have very aggressive presentations or don’t have a partial response within 2 cycles with the standard triplet regimen—we’ve been adding daratumumab, either after failure to achieve a good response with RVd [lenalidomide, bortezomib, dexamethasone] or up front. I agree with all that...

Ajai Chari, MD:I’m curious, though. You said you’re waiting for higher levels of evidence. Nina just mentioned the SWOG S0777 study. Prior to that, which was probably published maybe 2 years ago, what were you doing in the interim decade? Were you doing 2 or 3 drugs?

Alfred Garfall, MD:We were applying a similar approach. At that point, there were a lot of small phase II studies that were governing. Basically, the novel agents were tested in different combinations in phase II studies for a long time in the US because we weren’t comparing them, necessarily, in phase III studies to cytotoxic regimens. And so we were doing a lot of CyBorD [cyclophosphamide, bortezomib, dexamethasone], or Revlimid and dexamethasone, except for higher-risk cases where there were more aggressive presentations. We weren’t uniformly applying RVd [lenalidomide, bortezomib, dexamethasone] until that study came out, actually.

Ola Landgren, MD, PhD:You’re putting us on the spot here. You’re asking, what did we do before the data were out? The first presentation for the VRd [bortezomib, lenalidomide, dexamethasone] regimen, I think, was back at ASH [the American Society of Hematology Annual Meeting & Exposition] in 2008, and the NCCN Guidelines adopted it in 2009. The paper came out inBloodin 2010. The NCCN Guidelines were even before the publication, because there was 1 phase I/II trial that was presented at the ASH meeting. I think the field, or the earlier adopters of institutions and the guidelines, are very quickly picking these things up.

Ajai Chari, MD:Alfred was saying that he wanted higher-level evidence. Yet we know from practice patterns that the phase I/II study that you referred to basically changed the US induction therapy for probably at least 7 to 8 years before SWOG S0777 was presented.

Nina Shah, MD:This is a different era. Back then, we really didn’t have much of anything, and we knew that triple therapy was probably better. Now we’re talking about making something better even better. We have RVd [lenalidomide, bortezomib, dexamethasone] plus transplant plus maintenance. I know that’s another issue—about the transplant. But I think people are doing well. We have, potentially, KRd [carfilzomib, lenalidomide, dexamethasone]. That’s also being studied, and some people are early adopters of that. And then you’re talking about quads. How much more are we going to use for potential financial toxicity, etc, without the data? How far are you willing to go without the data to make an incremental increase in efficacy? I agree with you. We’re probably going to head in that direction. I guess I’m a little hesitant, regarding adopting it, until I get more definitive data from GRIFFIN. When this all comes out, we’re all going to say the same thing: “Oh, but they did it with transplant. What if we did it without transplant? What if it was daratumumab and KRd [carfilzomib, lenalidomide, dexamethasone], etc?” It’s going to be the same…

Ajai Chari, MD:You bring up an important point. There’s this reticence, or reluctance to use our novel therapies early. What is that predicated on? Because 1 of the questions is, are we harming downstream sequelae, right?

Nina Shah, MD:Yeah.

Ajai Chari, MD:But I think we have to recognize—and we talk about this more and more, which I’m glad—first of all, no myeloma overall survival curve to date is flat. We lose patients from day 1, and those are primarily high-risk, frail, and older with renal failure. But we don’t have a flat overall survival curve. No. 2, you can’t capture patients all the time. So there’s attrition. We know that the number of patients you start with diminish with first relapse, second relapse, and so forth. We’re also diminishing response rates and PFS with each successive relapse. Our best chance of getting disease control for long-term is really early—the initial induction and maintenance followed by first relapse. And then the final point is, what is the concern? I think quads for everyone forever is not sustainable. I don’t think any of us in this room would advocate for that, from a practical point of view, economically, or a toxicity point of view. But I think 1 of the benefits we’ve seen with CASSIOPEIA, even with a VTd [bortezomib, thalidomide, dexamethasone] backbone—which has been shown to be superior to CyBorD [cyclophosphamide, bortezomib, dexamethasone]—the daratumumab addition led to PFS improvement at 18 months with a transplant included. That’s really impressive.

Alfred Garfall, MD:I don’t think we’re so far apart, actually. My point is that to uniformly apply a regimen to everybody and say, “This is the standard of care, and deviating from it is wrong,” I think we need very high level of evidence. But we use those smaller studies to add it to patients whom we are worried about. Just as you said, even before SWOG S0777, those smaller studies gave you license and gave you safety data to be able to use these regimens for people you were worried about. But I still think I would ask what the limiting principle is, in terms of the intensification of first-line therapy. I think we’re probably going to have 2 new therapies for myeloma approved sometime in 2020—aBCMACAR [chimeric antigen receptor] T-cell and aBCMAantibody-drug conjugate. Certainly, there will be early phase studies that kind of throw them in with daratumumab—RVd [lenalidomide, bortezomib, dexamethasone]. What would be your limiting principle for when you make a 5- or 6-drug regimen as a first-line therapy?

Ajai Chari, MD:I think to that point, more is not always better, right? High-dose dexamethasone is not superior to weekly dexamethasone.

Alfred Garfall, MD:Right, exactly.

Ajai Chari, MD:VCRd [bortezomib, cyclophosphamide, lenalidomide, dexamethasone] is not superior to RVd [lenalidomide, bortezomib, dexamethasone]. Not all drugs are created equal, and not all quads are created equal.

Transcript edited for clarity.