Thread by @ManniMD1

I confess that after #ASH21 I likely will use more quads.
but it isnt because Isa-RVD vs RVD showed ⬆️1 timept MRD🙄- or that GRIFFIN (DRVD vs RVD) showed signal for PFS benefit.

Read on for a 🧵on uncertainty, equipoise, decision making as an oncologist
@AaronGoodman33
#mmsm

Before we delve in, there are two facts that the evidence seems to indicate:

Fact 1:
-MRD is undoubtedly prognostic, those that achieve (and sustain) MRD neg tend to have better outcomes than those who dont achieve and sustain MRD neg.

Fact 2:

Youd be neglecting the history of myeloma literature, if you looked back and didnt notice that interventions to deepen response (and achieve MRD negativity) havent always translated to increased overall survival, if those interventions were given later in disease course.

Case in point is IFM-2009- auto up front (versus later) 🚫 increased survival.

One can argue that IFM-2009 was in an era where MRD measurements werent so sensitive, and that the trial wasnt "designed" to look at OS or MRD.

But, I ask of you- was GRIFFIN designed to look at PFS?

Consistency in logic is important.
GRIFFIN (D-RVD vs RVD) was a Phase 2 trial powered for a primary endpoint of stringent complete remission. Not MRD. Not PFS.

We now have an update where there is "a signal" for increased PFS in a trial not powered for PFS.

And one must note that the arm which received RVD induction only got R maintenance, and the arm that received DRVD induction received Dara and R maintenance.

Can we tease out the value of dara induction (versus maintenance) from this trial?

NO

At #ASH21, we heard about Isa-RVD versus RVD, a large randomized Ph3 study actually powered for MRD negativity..

Well, we know from FORTE that a single time point of MRD negativity can be fleeting. It is sustained MRD negativity that is more predictive.

Well, obviously the trial met its primary endpoint- MRD neg of 50% versus 35% at end of induction.

So what do we do now?

#ASH21 sent me into introspective mental angst about the trials that the idealistic version of me wants versus the data we have.
We now know from GRIFFIN and Isa-RVD vs RVD study, that quads deepen responses, and don't add lot of additional crippling toxicity (in fit trial pts)

I want data that tells me if my patients live longer or live better (increased quality of life). Or that combining is better than sequencing. But will I get that? Are future trials going to answer that question for newly diagnosed myeloma? The answer is NO.

To answer that question, you will need a trial with endpoint of PFS2, OS, or longitudinal/robust quality of life assessment.

We just won't get it. The confirmatory Phase 3 PERSEUS will take long to result and is also powered for PFS, which doesn't answer sequencing

So what do we do in the interim? Do we wait for data that isn't coming?
I ask of myself the Q:
Quads offer increased OS? Maybe?
Quads offer increased PFS2? Maybe?
Quads offer a greater cure fraction? Maybe?
Quads add toxicity?Perhaps a little, but not bad

So are quads a slam-dunk based on the above? No.
But those who havent adopted quads based on current data may wait for data that'll never really convincingly come.
We have to have honest discussions with ourselves about these questions.

What makes me sad is that we will likely see trial after trial of 4 vs 3 powered for surrogate endpoints, just like we saw trial of 3 vs 2 in the last decade.

Triplets will be preferred for fit, young patients only in control arms of trials, otherwise quads for fit pts 💔

Based on the above reasoning and after hours of introspection-I will use quads more often- with assumption that there will be long-term benefits, and that the additional toxicity (patients get to decide, not me) may be worth it. And that in future, there will be other options.

Ultimately, my job as an oncologist is not to stick to my dogmas and beliefs on what trials SHOULD ask, but to offer my patient the best treatment based on what IS out there.

This captures all of what being an oncologist is for me.

Thank you for sticking through
END.