Paul G. Richardson, MD: I think it’s a beautiful lead in for Nina then, to say if you now have an active patient who has clearly declared themselves, how do you think about an individualized approach to induction therapy? If we can, we can keep this relatively succinct, but Nina, if you wouldn’t mind taking a run at this in terms of frailty scores, clinical symptoms, molecular status, transplant eligibility, and age.

Nina Shah, MD: I think one of the difficult things when you meet a patient with multiple myeloma [MM], it’s like snowflakes, no 2 are alike, and you have to think about each patient as somebody individual and what makes them qualify to get treatment. We just talked about smoldering multiple myeloma [SMM] and how even those criteria, going from SMM to symptomatic MM have changed over the years. In general, we do use the standard CRAB criteria: hypercalcemia, renal insufficiency, anemia—I usually use the rule of 2 grams below the lower limit of normal for that gender—and the presence of lytic bone lesions. Now that we’ve gotten better at diagnostic procedures and found better ways to look at things, I generally send the patients for a PET [positron emission tomography] scan to look at those bone lesions, because I get a good idea of those that are active and not hypermetabolic, etc.

Now we have the SLiM CRAB, which includes the light chain ratio of 100, so that’s involved over uninvolved of 100 or greater, and then the bone marrow plasmacytosis of 60% or more, and more than 1 lesion on MRI [magnetic resonance imaging], which tends to be a narrow-based lesion. Those are a little bit difficult sometimes to find because rarely do you send your patient for a whole-body MRI, although some insurance companies prefer that over PET CT. I have no idea why. If I knew the code to the insurance company peer-to-peer thing, I would probably not be sitting here right now.

In any case, any of those things can lead to the diagnosis of MM, and it’s really important to, actually even some patients with SMM who come to you, you should do a full evaluation because you don’t want to miss something. If you find any of those 7 criteria, then it’s worth considering that you should have to treat the patient. There are some other criteria we’ve had in the past, for example, maybe the patient has amyloidosis, other things that you have to think about such as neuropathy, there’s some sort of POEMS [Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes] syndrome, and all these other things that you can think about, but this is sort of the garden variety, bread and butter.

Now, when you’re making the decision of how to treat these patients, it really is an individualized approach, even more so now than ever, because we have so many options. We think about the patient as a person. What do they want? Some patients want to go to work; some patients want the most aggressive therapy possible. Some patients only want to live at least 5 years because their kid is getting married, for example. You must know what the patient’s goals are and what the patient can handle.

For this, we do have tools. I really like the IMWG [International Myeloma Working Group] frailty calculator to help us assess where the patient is, especially when you’re making decisions about transplant eligibility. Gordon Cook MBChB, PhD, FRCP, had a nice EMN [European Myeloma Network] overview paper in June of 2020, looking at this and how these things were calculated and how you should use them, and how people progress being not frail to frail both in life and as they are patients with MM having undergone therapy. I think it’s good for us to remember those factors for patients with MM.

Once you’ve decided that a patient is transplant-ineligible, for example; of course, I am a recovering “transplanter” as everybody knows, so I think everybody is transplant-eligible. However, there are a few patients who may not want to go to transplant or aren’t transplant-eligible, and you can think about that with these frailty calculators, or other circumstances where they can’t be going to transplant. Now we have options for these people. We used to say VRd [bortezomib, lenalidomide, dexamethasone], VRd-lite. I think that’s a great regimen if you choose VRd [bortezomib, lenalidomide, dexamethasone]-lite. It’s well tolerated, many of our transplant-ineligible patients tend to be older, and this is well tolerated in that patient population. As you know, at Massachusetts General Hospital, they have a nice, long, extended VRd [bortezomib, lenalidomide, dexamethasone]-lite regimen that does very well.

But now we have other options. I have been impressed with the MAIA trial data, which compared DRd [daratumumab, lenalidomide, dexamethasone], to lenalidomide and dexamethasone, which has consistently shown increased PFS [progression-free survival] for the triple versus double regimen. One of the great things about this trial is it allows us to have another option, which does not necessarily have to include bortezomib, which some patients don’t want to get for various reasons. For example, they may have diabetes and peripheral neuropathy, or they just can’t handle it. Generally, I find that daratumumab is a very well-tolerated drug, so if I was going to think about daratumumab or bortezomib in these transplant-ineligible patients, I am comfortable giving DRd [daratumumab, lenalidomide, dexamethasone] as an induction regimen.

We also know from the European data that you can also consider a quadruplet regimen. I was actually very impressed that they did this study and they enrolled very quickly, the ALCYONE trial, which looked at DARA-VMP [daratumumab, bortezomib, melphalan, prednisone] versus VMP [bortezomib, melphalan, prednisone], and showed consistently that the quad regimen was better.

When you think about quads, and we’ll talk about them in a minute for transplant-eligible patients, we think about quads as being very toxic. All these patients were transplant-ineligible by European criteria, which generally was more of an age-related criterion. But these patients did very well, and they had an overall survival advantage, which was demonstrated at ASH [the American Society of Hematology annual meeting]. I think there is a role for adding daratumumab up front, and now we’re getting more and more data for the transplant-ineligible patients.

For those patients in the MAIA trial, LEN [lenalidomide] is 25 mg, and you’re supposed to continue that indefinitely. Do we really do that all the time with our transplant-ineligible patients? Probably not. That’s not an easy thing to take forever. I suspect that a lot of people had dose reductions, and in the real world they probably will. Therefore, if you’re thinking about how those data in the publication are going to compare to your patients, you should keep that in mind.

Moving on to the people you think are transplant-eligible, and we’re going to talk about transplant versus not I think a little later, so I don’t want to necessarily go into that right now. But there are a bunch of regimens. Our standard for a long time, was what I would say is the “Honda Accord” of induction therapies, was VRd [bortezomib, lenalidomide, dexamethasone] to give to these patients. But now we know there are other regimens that are possible.

Now, just a brief word about the ENDURANCE trial, which looked at KRd [carfilzomib, lenalidomide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone] and was presented by Shaji Kumar, MD, at ASCO [the American Society of Clinical Oncology annual meeting], that didn’t show any PFS difference. I want to point out that that trial did not have transplant included in it. We really can’t say for transplant-eligible patients, whether KRd [carfilzomib, lenalidomide, dexamethasone] or VRd [bortezomib, lenalidomide, dexamethasone] is better. However, an interesting thing I noted in that data was that patients got to their response quicker with KRd [carfilzomib, lenalidomide, dexamethasone], and I thought about that a lot because sometimes you are on a schedule when you have a transplant-eligible patient, to consider where they’re going to go next. You want to keep them at their schedule, and you want to make sure they get into their remission as fast as possible. Regarding transplant-eligible patients, I think VRd [bortezomib, lenalidomide, dexamethasone], and KRd [carfilzomib, lenalidomide, dexamethasone] can be considered.

What I think has really made a splash recently are the DARA-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] data in the United States, and I’m just speaking for the US population now because the GRIFFIN trial was a US-based population that was enrolled. These patients were randomized to receive DARA-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone]. The end point here was achievement of stringent complete response at the end of consolidation—a very specific end point—not a PFS end point, and it’s a phase 2 randomized trial. Right now, their MRD [minimal residual disease]-negativity data, as Jonathan Kaufman, MD, just talked about, is very good. We’ll talk about what those things are a little bit later in our discussion here, but those are options as well.

All these things are options for how you approach the patient with newly diagnosed MM and when to treat. When you think about transplant eligibility or not, you can use these calculators. I think the most important thing is to talk to the patients to see if they want to go for the transplant, if they have the support, and if you think that they are a good transplant candidate, something we think we’re good at, maybe we’re not as good as we should be, and we think about looking at bortezomib or other drugs for high-risk therapy.

I’ll just point very briefly to the FORTE trial, which showed some very nice data in the high-risk group using KRd [carfilzomib, lenalidomide, dexamethasone]. That was not a bortezomib/carfilzomib comparison, but I have been impressed by those data. So that’s the overview of treating and where we start about ineligible or eligible. We’ll talk a little bit more about the specifics of each of those trials, but that’s how we start our approach when we treat our patients with myeloma.

Paul G. Richardson, MD: Yes, and I think that’s beautifully put, Nina. I think the important point about the FORTE trial was exactly what you described, which was so interesting, the MRD data was similar, but PFS stands out as a gold standard. I was struck that clearly in that high-risk group, that ability to target the proverbial stemness of disease with high-dose melphalan clinically translated into PFS benefit, and that was very real.

I think what was an important confounder in that analysis, not a confounder, but something we’re going to learn about, is what kind of maintenance did folks get, carfilzomib, lenalidomide or lenalidomide alone, which we would all agree is an inferior maintenance strategy for high-risk disease now. That will be an important caveat. However, I do agree with you. I think the FORTE data tell us that there clearly is a role for targeting this stemness and eradicating it, because in high risk in particular, it generates a reservoir of disease biology that can be very adverse in the longer term, and we certainly all see that. I think it’s beautifully summarized, Nina, and thank you because you captured so nicely not only induction therapies in terms of how you approach a patient, but also what we learned at ASH.

I would concur with you about the GRIFFIN data. Jonathan Kaufman did a really nice job of showing not only that continued benefit from the quad, but what was so interesting was the benefit of the quad in consolidation. We’re going to come back to that in a minute, and we’ll ask David to take that on, about what did the GRIFFIN data tell us about consolidation, because that’s an important question.

Transcript Edited for Clarity