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The phase II GRIFFIN study, presented at December's American Society of Hematology (ASH) virtual meeting, assessed the efficacy and safety of the addition of daratumumab into the lenalidomide, bortezomib, and dexamethasone (RVd) backbone in transplant-eligible newly diagnosed patients with multiple myeloma.

名媛直播 has brought together three expert leaders in the field: moderator , is joined by , and , for a virtual roundtable discussion on the GRIFFIN study in this third of five exclusive roundtable episodes.

Episode one: Early Transplant or Delayed? Multiple Myeloma Experts Debate

Episode two: Selinexor OK'd for Myeloma, But Does That Make It a Good Drug?

Episode three: Many Questions Surround GRIFFIN Study

Episode four: FORTE Raises Question of Excessive Treatment in Myeloma

Episode five: CAR-T for Myeloma Excites at ASH, but Questions Remain

Following is a transcript of their remarks:

Vinay Prasad, MD: I'm back with Aaron Goodman and Dr. Abdallah from Kansas, and we are talking about the GRIFFIN study. Now, gentlemen, the GRIFFIN study just came out at ASH and it was a most interesting study. It was a randomized phase II study that looked at the addition of daratumumab, a CD38 antibody, to RVd, which is the standard of care in this country. I don't care what anyone says, RVd remains the real standard of care. It has the best data as frontline regimen.

The addition of daratumumab was able to do something in this randomized phase II study. It was able to deepen responses. There was more stringent CR. There was a little bit more MRD. But in terms of its effect on PFS, and its effect on OS if you reserve Dara for the second-line setting, there are a lot of open questions.

We have no idea what it would do if you just gave Dara later and yet the GRIFFIN study, to my knowledge, has impacted the NCCN guidelines, and now the NCCN guidelines allow providers to choose Dara-RVd as the initial treatment of newly-diagnosed myeloma. I wonder if I could get both your opinions on this trial. A small, randomized phase II study, surrogate endpoint CR rates, what are your thoughts? Aaron Goodman, let's start with you.

Aaron Goodman, MD: Yeah. Why even run randomized phase III studies anymore? You get NCCN world experts to approve. Daratumumab, as expected, you add a very potent drug that has activities, a single agent in a refractory myeloma to our standard therapy, then you're going to see an increased CR rate, and I actually won't be surprised. I would bet the PFS will probably be better in the randomized study.

Prasad: Sure.

Goodman: Again, I won't be surprised, four drugs versus three. We've seen thousands of trials of three versus two that always shows that. But I think the most important point that you brought up is whether daratumumab upfront or whether it can safely be delayed at first or second relapse will impact overall survival. That will take a little bit longer to figure out, but not too much longer if you waited and patients who were in the RVd arm of the randomized trial that is accruing currently had access to daratumumab.

Prasad: They have to have access to daratumumab. That's an important point. They have to have access to Dara on progression. Go on.

Goodman: Yes, because you're right. If they don't have access, then it doesn't really... we know daratumumab is beneficial, and if they don't have access to that drug then, of course, it might show an overall survival advantage that really isn't true, at least in the United States where they would have access to daratumumab.

I just think we're jumping the gun. I am enthusiastic about these therapies as much as my colleagues. I want to help our patients just as much and not be a naysayer to every drug. But we have the study accruing, going on, where you're going to answer this question. Can't we wait? We've been burned too many times in oncology, at least in my short practice as an attending physician, where we've jumped the gun on randomized phase IIs, or even single-arm phase IIs, where randomized phase IIIs are negative or perhaps even detrimental to patient wellbeing, i.e., the BELLINI study.

Prasad: That's well-put. I love Dara, but I don't love GRIFFIN, and that, you can have both ideas in your head. Dr. Abdallah, what are your thoughts on GRIFFIN?

Al-Ola Abdallah, MD: I will be honest with you, well, we're going to have to have a debate then, me and Aaron. Let's say the progression-free survival is better and the overall survival is the same. Then why are we not doing transplant upfront then? I would say.

Prasad: [LAUGHTER] You're coming back to transplant? Yeah.

Abdallah: Yeah. The people who are agreeing about that based on the overall survival is similar. Okay, well, what if the GRIFFIN trial is going to be overall survival similar? Let me point out something. With all my respect to the colleagues who like the daratumumab, yes, it deepens... it has a good, a longer... depth of the response is deeper.

Prasad: It's deeper. It's deeper. More MRD negativity.

Abdallah: Nobody actually disagrees with that.

Prasad: No one.

Abdallah: The three questions I will get asked by the patients... I'm sure they will ask what type of depth of the response and all this stuff. But they're going to ask is it curable or not curable to add the daratumumab? We don't have an answer for that and I bet you we'll never have an answer until 8 or 9 years or 10 years from now.

You can't rely on sustained MRD negativity to tell you that if I have a sustained MRD negativity for X amount of years, that means you can stay in remission forever. That's not the answer for that because there are patients who are still MRD positive in my clinic, and actually they have M protein and they've been off the treatment for about 20 years, and they're still following me without any treatment. These are the old days. We never gave maintenance therapy for these patients, so we can't rely just on MRD negativity.

Number two, overall survival. Is that going to add something in addition to the daratumumab? I think that's also a very important question. Daratumumab is not a toxic medication. Everybody agrees with that.

Prasad: Yes.

Abdallah: But what's the whole benefit in terms of lasting? It's the progression-free survival. If it's going to add an extra, I don't know, 6 months or a year, then the debate is going to come back again with why are we even delaying the transplant if that's what we also...? Using an overall survival in this case, using it as an excuse, we have the same overall survival, not to do the transplant early versus late. That's my biggest concern.

Now if -- and I hope that's not true, and I hope I'm wrong -- what if the daratumumab and the RVd, the Dara-RVd, versus RVd ended up with the same progression-free survival? That's a negative. That's a...

Prasad: That's a totally negative, a stone-cold negative.

Abdallah: Why? Tell me, all relapsed myeloma, who is the physician that stops actually? All our myeloma physicians consider daratumumab as the backbone to treat myeloma in the first relapse and second relapse. It's a very important player as a combination therapy, so not only we lost a player, maybe we lost a lot of patients that could have benefitted from that. We're actually hoping that CAR-T and the BCMA drugs will be a little bit beneficial, but we don't know yet. We don't know.

We know that daratumumab because they have been there for a little bit longer time. I'm hoping I'm going to be wrong, but we don't have... the median progression-free survival for RVd and transplant is around 50 months. We're only 2 years and we're not seeing any separation in the progression-free survival between the RVd and the Dara-RVd. We're only seeing an MRD negativity but how long is this going to last? That's the question we're asking.

Prasad: I agree with you. I think that none of us will dispute the fact that Dara is a good and important drug in multiple myeloma. We all use it, we rely on it, and we need Dara. Dara has been called by some the rituximab of multiple myeloma. I don't call it rituximab of myeloma, but I think it does play an important role. We do use it in the relapsed and refractory settings in the second-line setting and beyond. The question of GRIFFIN, the question of these frontline studies is, is the routine upfront use of Dara in combination with the standard backbone VRD better than saving it on the backend? I think PFS1 won't answer the question because if PFS1 is prolonged it's a tautology that's true by definition alone.

Of course, if you give all the drugs that you have in the myeloma tool bag right up front, you're going to have a longer PFS1, but you won't have anything left to give the patient. You can add in some Elo and you can add in all sorts of things, so that's not the right question.

The right question is, VRD then a Dara-containing regimen, or Dara-VRD and then a regimen probably with or without Dara? It depends. That's the question, whether or not you get a longer overall survival.

GRIFFIN, unfortunately, is a small randomized phase II trial. One of the mistakes I see in oncology made too often is people will hang their hat on a survival benefit or a PFS benefit seen in an underpowered phase II study.

Now, underpowered phase II studies are notorious for false negatives -- that in other words they'll find no benefit when a benefit in fact exists -- but they are also underappreciated for the potential for false positives, that when you do find a difference in a non-primary endpoint, it is possible that that difference is exaggerated or spurious entirely. We saw that with Lartruvo, a catastrophic regulatory failure that was on the market and then when a phase III trial showed no benefit. To Aaron's point, we need phase III studies. We need to test the sequence strategy and that's the open question for daratumumab.

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