Thread by @ManniMD1

The OPTIMUM trial just published in @JCO_ASCO is an important step forward for dedicated approaches to truly high-risk disease.

Lets talk about this trial in detail 🧵

ascopubs.org/doi/abs/10.120…

Non-paywalled link:

drive.google.com/file/d/1LkaST7…

#mmsm

So lets first talk philosophically about add-on trials in myeloma.

There is no shortage of trials in myeloma adding active drugs and showing improved PFS or response rate.

Such trials are usually large trials run for regulatory approval.

These trials can over-treat standard risk disease and expose them to unnecessary therapy in intervention arm, and also under-treat high-risk disease in control arms.

(Example- MAJESTEC-7 where teclistamab is being added to dara/len/dex and given indefinitely to older pts 💔)

Yet, this trial is different.

This specifically targeted a population for whom under-treatment is less of a problem- those who have the highest risk biology.

This trial enrolled patients with greater than two high-risk features or those with high-risk disease on gene profiling

This was a Phase 2 trial- see power calculations below- 85% power to detect a roughly 5 month PFS difference.

Although manuscript says that primary endpoint was 18 month rate of PFS- I did not see a power calc specific for that in the pre-published protocol?

What did the intervention arm get?

Basically Dara-VRd + Cyclophosphamide as induction, followed by auto-SCT (with velcade during ASCT process) followed by Dara-VRd consolidation followed by Dara-VD consolidation then Dara-R maintenance

That is a lot of treatment!

The practice of using bortezomib immediately before/during/following auto-transplant is controversial, but a large randomized trial has shown no benefit to this practice, so this is not something I would do.

ashpublications.org/blood/article/…

So what was the control arm?

The control arm were patients enrolled on a concurrent clinical trial (Myeloma XI).

These patients were either recieving cyclophosphamide-len-dex or carfilzomib-cyclo-len-dex

Although this is not a substitute for randomization, it is much better than comparisons against historical controls or real-world studies.

The control arm are patients that are enrolled on clinical trials and receiving contemporary care.

Case in point:

Look at the left- a comparison of selinexor against real-world data. See how the curves separate from the very beginning. Seli wont save lives quickly-this curve reflects residual confounding in the dataset.

Look at right in this study- a more realistic curve.

Primary Endpoint of study met, 18 month PFS=82 versus 66%.

Longer follow-up awaited.

30 months PFS 77% for intervention arm versus 49.7% for carf/cyclo/len/dex and 34.1% for len/cyclo/dex

Odd that toxicity data during induction was in the supplement, and toxicity data during consolidation for those who had already completed earlier consolidation cycles was presented in the actual manuscript.

High rates of neuropathy (given twice a week velcade), GI tox etc.

You can see in this diagram, that despite intensity of treatment- discontinuation due to toxicity rates were low, but unfortunately despite all of this treatment, there were still progressions, with only 74 out of the 108 patients making it to the maintenance phase of treatment.

Yet, I will say that for such a tough to treat population, to even do a dedicated trial, and then show such results is a major accomplishment and a step forward for the field. Kudos to the team.

Some unanswered questions remain.

1) Would we have gotten the same results for these patients with much less therapy?

If you look at MASTER, 3 year PFS was 50% for those with similar high-risk (2+ HRCA) features- and that was with a lot less intense therapy- that is a protocol I would want for myself.

It is thus possible, that even for the highest-risk disease, similar long-term outcomes (overall survival) are achieved with less treatment. Obviously-we need to improve OS.

Also, we cannot how isolate effects of induction versus continued maintenance on efficacy here.

I would love for Table 1 to highlight actually how many patients with plasma cell leukemia were enrolled in final analysis.

Did I miss this? If I did, would love to be corrected.

Manuscript says at one point 9 "eligible" patients had PCL, not sure if they were all enrolled?

In summary- this is not just your usual add-on trial demonstrating ⬆️PFS. This is a dedicated effort to provide a customized intense treatment approach for the highest-risk disease. Despite some caveats and questions, undeniable step forward for field.

Thanks for reading!
END.