Latest Data in Newly Diagnosed Multiple Myeloma

Jatin Shah, MD (Moderator): Continuing our discussion with newly diagnosed myeloma, lots of new data presented, but I want to focus on a couple of new trials that were updated, and one was ALCYONE, which looked at VMP plus or minus dara (daratumumab). And this is the first time that we see daratumumab presented now in the newly diagnosed setting in a phase III trial. We also have updated data now from the MRC XI trial, looking at Revlimid maintenance post-transplant. And so I think two important pieces of data. And so, your thoughts on that, and how that impacts newly diagnosed myeloma, and your approach for initial therapy.

Sagar Lonial, MD: Yeah, I mean, I think the data on dara up front supports what I think we all know in our minds, which is that daratumumab plus anything is better than anything in a randomized trial. I think the use of VMP as the control arm makes it a little bit challenging for us to extrapolate this data for our daily practice. And I think as we think about daratumumab being brought up front, we have to think about what are the right endpoints to measure benefit for adding that fourth drug in. Is it MRD negativity at four cycles? Is it MRD negativity at eight cycles? What’s the right benchmark? Because I think that, to me, is a little bit…it’s the big question.

I think the use of VMP as the control arm makes it a little bit challenging for us to extrapolate this data for our daily practice. (because VMP is rarely used in the U.S ) 

Suzanne Lentzsch, MD, PhD: Yeah. Dr. Mateos, again, presented nice data from her international trial, VMP plus-minus daratumumab. I can only echo what Dr. Lonial already mentioned, that the data for the U.S. market are of limited value because I think you rarely use VMP. I think we…almost all of us exclude melphalan from our daily practice. But again, it really underscores the concept, and that daratumumab up front can really change the progression-free survival and the depths of response. I think she presented also nice data on MRD negativity, and her data clearly showed an advantage of daratumumab. So if we say that MRD is the kind of, you know, probably a future or new endpoint, I think that study clearly showed that dara (daratumumab) should probably be a part of future frontline treatment.

I think that study clearly showed that dara (daratumumab) should probably be a part of future frontline treatment 

Ravi Vij, MD, MBA: Yeah. I think this is the first of probably more to come. The four-drug regimens are now starting to show benefit over three drugs. And I think the other thing is that I echo, that nobody in the United States I think uses VMP. But the question is if this gets FDA approval and dara (daratumumab) is approved for frontline use, can we use it off-label with other combinations? I’m a little skeptical that will happen, but if it does, that will allow us to use maybe dara (daratumumab) with other drugs that we’ll be more likely to use, either with Rev/Dex or Revlimid/Velcade/Dex combinations. But I think if it doesn’t happen, the DRd versus Rd trial will probably do a readout next year, I would imagine.

Suzanne Lentzsch, MD, PhD: Yeah. Frontline, yeah.

Ola Landgren, MD, PhD: You know, I think that it’s quite impressive to see how the Spanish group, it’s also a Janssen-sponsored study, how they were able to build on their old VISTA combination with Velcade, melphalan, and prednisone in such a short period of time, enrolled 700 patients together with multicenters and presented here at ASH. It happened very fast. And, in fact, the paper came out today in the New England Journal of Medicine as an original paper [Mateos et al. N Engl J Med 2018; 378:518-528]. So I just saw it this morning online. I think that’s very impressive. 

I agree with everything that we have heard, that I don’t think it’s gonna really impact the treatment landscape here in the United States because we don’t use melphalan and prednisone. I think I used it 10 years ago or something like that when I worked in Europe. I think it’s important for other countries outside the United States, for sure. 

I also think that the message of the hazard ratios kind of is something we can look into here. So the hazard ratio is actually quite impressive. It’s a 50% reduction, but the control arm is also very inferior. So when we look at hazard ratios, the first thing you should do is also to see what the control group delivers, because if you have a very poor control group, it’s very easy to get the good hazard ratio. They reported 20% MRD rates in the combination of daratumumab with VMP. Just to put it in context, if you use RVD, you probably have about a 40% or so MRD rate with the MRD assays they have used in this paper. This is flow-based assays. And if you use KRD, you can probably take it up to 60%. So, although we don’t have head-to-head in randomizations, I think there is some direction from those early surrogate markers to…

Jatin Shah, MD (Moderator): And to your point with MRD, I think there’s two questions on that. One is the actual endpoint of MRD in this newly diagnosed trial, but the actual theme you mentioned is the time as well. So when should you be doing that as well? So four months, eight months for transplant ineligiblepatients should we be doing it at 12 months after they get the full therapy? So any thoughts on that in terms of when we should be looking at that?

Sagar Lonial, MD: Yeah. I don’t think we have any idea. You know, I think MRD is not a static endpoint, and so I think having sustained MRD negativity is what probably has the most meaningful value. Does it mean anything in cycle 4? I don’t think we know. Obviously, it’s good, but the sustained MRD is like Bart’s old CR duration, right? If you MRD at four, but you’re not at six, that’s probably a really bad subset of patients. But even that we don’t know for certain. So I think we have to be standardized in terms of the test we use, when we use it, and how we use it.  

sustained MRD negativity is what probably has the most meaningful value 

Suzanne Lentzsch, MD, PhD: I think there’s more and more criticism on that, how do we test MRD. Flow cytometry is widely used, but the problem is that we lose plasma cells, you know, when the samples float around for more than 24 hours and automatically get MRD-negative. So I think the timing, that’s correct. When do we do MRD negativity? It doesn’t make sense to do it at four months for all patients, because if you are clearly only in a partial remission, you don’t need to estimate, you know, the MRD negativity. What is the impact of the dynamic to achieve MRT negativity on the outcome? Those are all open questions. We know it’s important, but we need also, again, fine-tuning here.

Ravi Vij, MD, MBA: Yeah, I agree. And in my own practice, I still observe the context of clinical trials do not look for MRD because they do not know what to do with the information. I think once we can make decisions that are going prospectively with the results, it would have added value.

Ola Landgren, MD, PhD: But we have worked very hard on MRD, and we have set up a flow cytometry, and we also have sequencing-based assays in real time. We have that for standard of care. To me, it’s very obvious that the sequencing-based assays are going to be the ones that they’re gonna look for. They are more sensitive and they are more reliable predictors of progression-free survival. And there was actually an abstract that was an oral presentation here at ASH from Hervé Avet-Loiseau, [Abstract 435: Minimal Residual Disease in Multiple Myeloma: Final Analysis of the IFM2009 Trial] which was the final updated analysis to the IFM 2009 randomized phase III trial. And they showed, on top of “The New England Journal” publication this year that was based on flow cytometry MOD, now they reanalyzed with sequencing-based assays that were 10 times more sensitive. And if you do that, they found that the PFS was the same for patients transplanted versus not transplanted. They did it in an up-front setting. That was not the primary endpoint, but it addresses the issue of the importance of having a good assay based on sequencing.  

To me, it’s very obvious that the sequencing-based assays are going to be the ones that they’re gonna look for. They are more sensitive and they are more reliable predictors of progression-free survival. 

Sagar Lonial, MD: But that, just to put that in context, because I agree that was really interesting data, that was a 12 to 18 months post-initiation of therapy. And so it’s hard to say, transplant or no transplant, when you have already made that decision by the time you have that data, right?

Ola Landgren, MD, PhD: There are a lot of caveats. So I didn’t mean to say that it’s definitive. I think we, in general, we usually like to see two studies showing the same thing, then we kind of tend to believe it. But it’s a large randomized trial. And I think the key message I get out of this is that having a good assay is very important. 

Sagar Lonial, MD: Yes. Agree.

Ola Landgren, MD, PhD: And they actually said that we need to revise the criteria and say that 10 to minus 6 should be the new definition. That was their message. So that was their opinion.

Sagar Lonial, MD: And it’s interesting, in ALCYONE, the same finding occurred. If you were MRD negative at 10 to the minus 5 in this study, it didn’t matter which arm you were on, your PFS looked exactly the same.

Ola Landgren, MD, PhD: Right.

Jatin Shah, MD (Moderator): Yeah.

Jatin Shah, MD (Moderator): So no matter how you got to the MRD, you did equally well, and so… A couple of things. Lots of learned lessons from this experience, but clearly, one is that you can combine dara with lots of different therapeutics. Is this applicable to the U.S. patient population? It’s a bit unclear about that. There’s other therapeutics like VRD and KRD, which also have higher MRD rates, and so those combinations will be important to look for. We’re really trying to nail down this exact assay for how we do it, and when we do it, and how we interpret. And then how we act upon it will be important as well.