Joseph Mikhael Multiple myeloma Multiple Myeloma Specialist Research

Multiple Myeloma Treatment | Joseph Mikhael, MD

3-drug vs. 4-drug combinations

Multiple myeloma expert Dr. Joseph Mikhael discusses the use of 3-drug vs. 4-drug combinations for front-line treatment.

Multiple Myeloma Treatment

Joseph Mikhael, MD: Quadruplets vs. Triplets

March 2022

At the American Society of Hematology (ASH) 2021 conference, Dr. Joseph Mikhael explains how new research on 3-drug vs. 4-drug combinations for front-line treatment for multiple myeloma from the GMMG-HD7 trial is changing the standard of care.

The interview has been edited only for clarity.

I think there is a general sense in the myeloma community that we are moving from triplets to quadruplets.

Dr. Mikhael

3-drug vs. 4-drug combinations


The Patient Story: You had 660+ patients enrolled in the GMMG-HD7 trial. What is the importance of this study?

When we look at the State of the Union of Myeloma right now, we’ve shown over the last decade that going from two drugs to three drugs was important and better for patients, that it gave them a deeper and more durable remission, typically before a transplant and had them in remission for longer.

That the next wave of questions are “Well, if three is good, are four better?” So we’re taking our typical three drug combinations in this case, something called VRD or the Velcade, Revlimid and dexamethasone, and adding a fourth drug to it.

There are two studies that looked at this. The big one, the German Myeloma Group study, where we added isatuximab, which is a CD38 antibody very similar to daratumumab, and added the isatuximab in one arm and not the other. And I think there are a few reasons why this study was important.

  • 1. It is the first large phase III study that we’ve seen adding a fourth drug, or this quadruplet, to the VRD.
  • 2. Their primary endpoint wasn’t just response rate, but was actually MRD negativity rate, or minimal residual disease negativity, where we look for the tiniest amount of disease left. So people have to have a very, very deep response to achieve that MRD negativity. And indeed, the MRD negativity rate was considerably higher in the four drug combination versus the three drug combination.

I’m just Joe. I’m not a prophet. But if I were to predict the future, I’m pretty sure we’re going to be going towards quadruplets in myeloma, and with lots of options.

Dr. Joseph Mikhael
Moving to quadruplets

It’s still too early to make final changes and to immediately jump to quadruplets. But I think there is a general sense in the myeloma community that we are moving from triplets to quadruplets.

The other study was the GRIFFIN study. It was a randomized study, but phase II was much further along than we were anticipating. In this case, daratumumab was added to the VRD before the transplant, for a little bit of consolidation after the transplant, and also actually in maintenance.

In that study, again, it looked like adding the daratumumab at every step of the way deepened someone’s response compared to just getting VRD.

Historically, we’ve known in myeloma that when response is deepened, it tends to last longer. Both studies are still too early for us to really comment on progression free survival, or how long someone stays in remission. But typically, as we said, that depth of response correlates to the duration of response. And so it’s very encouraging.

I’m just Joe. I’m not a prophet. But if I were to predict the future, I’m pretty sure we’re going to be going towards quadruplets in myeloma, and with lots of options. It’s not just going to be one exact four drug combination. I think we’re going to be looking at different ones with isatuximab and daratumumab.

Hope for the future

The Patient Story: How much longer do people have to wait before we can have faith that quadruplets are as promising as these studies are showing?

It’s a great question, and nobody exactly knows the answer. But we keep building this case. I mean, the case is becoming more evident, and it’s also important that more than one study be done because that that helps us. It gives us greater benefit for the proposed quadruplet. I think in a year from now, we’re going to have much more mature data and there may be an opportunity not long thereafter actually for this to influence the FDA. 

In fact, in the U.S., we actually have a quadruplet approved. Daratumumab VTD, or Velcade, thalidomide, and dexmethasone. We just tend not to use thalidomide here in the U.S. for lots of reasons. So replacing that with VRD, as I say, will likely happen over this next year, and I think it will be something moving forward. It speaks to a philosophy that I think is worth mentioning, which is that we are recognizing that what we do earlier on in someone’s disease course has a long term impact.

I’ve sometimes joked and said, “saving the best for last is great for a Hallmark movie, but not really for myeloma.” We’re learning that what we do in those that first line or the first two lines of therapy has a long-term implication.

So we want to be careful if we add any more toxicity because someone’s going to listen to this and say, “Well, if four is good, why don’t we go to five or six?” We have to really be careful about the impact it has on a patient’s quality of life as well.

But one of the benefits of these fourth drugs that we’re adding is they tend not to come with a lot of risks. Every drug comes with some risk, of course, and I think we’re finding that sweet spot with the four. I think one of the unanswered questions is, “How long do you continue those that combination, and do we need that fourth drug in maintenance?” That’s what we’re trying to sort out.

I think we’re going to develop stopping rules for myeloma.

Dr. Joseph Mikhael

The Patient Story: Because a lot of this is being used before the transplant and then not being tested as maintenance therapy?

Typically now we use lenalidomide maintenance, but many of them are now testing whether we can add a second drug to maintenance. And I think that’s an overall theme that we have been seeing over the last few years, going back to the notion of intensely treating the disease earlier.

And of course, we balance that benefit with the side effects the patient experiences. It’s one thing to say, “OK, a few months of all these drugs.” But if I tell the patient, “Well, you’re going to be on this heavy-duty maintenance therapy for the long term,” it’s more difficult.

Not trying to be a prophet, but if I could predict the future, I think we’re going to develop stopping rules for myeloma. I think we’re going to be able to understand better. And some studies presented at ASH this year were looking at when you can de-escalate therapy when someone reaches that MRD negativity or undetectable disease level. And those are the kinds of questions that we hope we answer with time.

Because if I’m a patient or their care partner or caregiver reading this today, I want to hear from Dr. Joe, “When can I stop treatment? Don’t just give me more and more.”  The goal is not to treat everybody forever. The goal is to treat in a strategic way that can get people down to as little treatment as possible to keep their disease in check.

Overall landscape of possible treatments

The Patient Story: And in order to do that, we’ll just need more of these clinical trials. But specifically tests, for one thing.

Correct. And that’s what’s wonderful– I mean, I’ve been treating myeloma for over 20 years. I have never seen a more exciting year than the year that we’re in right now. The number of trials that are being done to answer these methodical questions are occurring and are heavily influencing the field, despite what’s happened with the pandemic and all the challenges. It’s been very encouraging to know that we’re working very hard to answer these questions for patients.

Older populations

The Patient Story: In the study with isatuximab,  the median age was about fifty-nine and a half years old. The median diagnosis for myeloma tends to be more like sixty-nine or seventy. Do we know if the results translate to that population?

So studies are being done looking at this same combination in patients who are typically older and maybe not going to a stem cell transplant. Last year, or even just this past spring at our ASCO meeting, one of the most important studies was the long-term follow-up of the MAIA study, where we gave three drugs -daratumumab, lenalidomide and dexamethasone- to patients who were not planning to go to transplant, and their average time in remission was about five years. The average age on that study was seventy-three.

So we thought for a while, “Oof, can we really do triplets in more frail patients?” Well, now we know we can. So now we have to ask the question “Will quadruplets work?” And maybe we modify the drugs a little bit, give them a little less intensely. But really, we’ve seen huge advances in both sets of populations and really across the board of myeloma.

Side effects

The Patient Story: At least with this GMMG-HD7 trial, it looked like side effects were comparable in terms of the triplet versus of quadruplets. In other words, even adding the isatuximab didn’t significantly increase these side effects for patients. Is that right?

That’s been one of the benefits of these monoclonal antibodies.  As I mentioned, every drug comes with some risk, and it does slightly increase the risk of infection. And then there can be what we call “infusion reactions” when people first receive it.

But you’re very right– compared to many of the other strategies before when we’ve added more drugs, the adverse events or side effects have been appreciably less with this group. And that’s so important because safety is paramount, especially when we’re starting first line therapy, where we want to protect patients.

We always want to protect patients and be as safe as possible with them, but especially in this largest group of people that are being treated. We want to be very careful before we roll out quadruplets that we understand the safety profile of this combination.

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