Thread by @VincentRK

My thoughts on the DETERMINATION trial in myeloma presented in the Plenary session of #ASCO22 and published simultaneously in @NEJM #ASCO22VR

1) This is not a trial of transplant vs no transplant.

2) It's ~ the 5th RCT of early vs delayed transplant

3) As with prior RCTs it shows prolonged PFS with early transplant but similar overall survival. That's because transplant works, but the timing doesn't matter as far as survival is concerned.

You do the same trial many times of course you are going to get the same results.

4) The timing is however affected by other factors besides survival.

Patient preference - some want to get it over with. Some want to love current life and do it later. We need to respect this.

Feasibility - some places cannot collect and store stem cells forever

Insurance - some places coverage for delayed transplant may not be possible

Cost - in some places out of pocket cost of initial non transplant therapy is way too expensive compared to transplant

Risk - in some high risk patients other trials show benefit of early transplant

Age - as we look at patients over 65 and over 70 at some point the results of this trial are no longer generalizable. With increasing age you are no longer looking honestly at early vs delayed transplant but rather transplant vs no transplant. So prefer early.

5) History is important to keep in mind. In prior trials done way back where one arm received a transplant and the other arm did not get a transplant at all, overall survival was significantly longer. 5 year OS 52% vs 12% in the IFM trial.

Prolonged PFS captures this efficacy

6) But if on intent to treat the non transplant arm is given the opportunity to get a transplant later, survival differences will go away. It's like giving Dara early or late, not now or never.

That a lot of patients in the delayed arm don't get the transplant doesn't matter.

7) In the 1993 SWOG trial that Dr. Barlogie did of early vs delayed transplant only 50% of patients in the delayed arm got a transplant. Overall survival was identical between the arms just as in DETERMINATION.

8) The transplanters look at this and say if you wait you won't give the transplant so do it now. The non transplanters would look at same data and say if I get same overall survival by doing half as many transplants why do a transplant for all early.

9) It is important to recognize we don't know the future. And so when interpreting a randomized trial you have to go by intent to treat analysis not by treatment received.

10) So when you first see a patient if they truly can have an early or delayed transplant & the intent is there, the. DETERMINATION shows transplant works, it prolongs PFS, but when you do it doesn't matter as far as overall survival. But you have to have the intent & feasibility

11) What do I make of the PFS. It's amazing and that may be enough for some patients to choose early transplant because they can be on just Len for many years. And if they are less that 65 they can do one now and one later and get the best of both worlds.

12) For some patients the thought of a transplant in the peak of their life is just not appealing and it's important to be honest with them and acknowledge we have no data that doing a transplant early as opposed to later is going to prolong their life.

Same this we saw with IFM 2009.

Or in the SWOG trial by Dr. Barlogie himself.

Or in the French trial by Fermand from the 1990s

Or the forgotten IFM trial that was never published.

13) To me the DETERMINATION trial simultaneously proves the efficacy of transplant as an important treatment modality while at the same time reaffirming that patient selection and choice is of paramount importance and we cannot be dogmatic about the timing of transplant.

14) We are not the ones getting the transplant. They are. So it's important to provide the details, the pros and cons, and take into account the factors besides survival that I mentioned.

Patient preference is critical. So is age, feasibility, risk, cost, insurance.

15) What about the subset analysis. Too small numbers. I wouldn't dwell on them

16) What about the PFS benefit being being longer than the previous trials.

I think it shows Len maintenance till progression works better post transplant than post VRd alone. I usually give it till progression.

Have to go for meetings. Happy to answer additional questions.

*than

*live

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