The first randomized trial of CAR-T in multiple myeloma.
nejm.org/doi/full/10.10…
Ide-cel versus a choice of five regimens for relapsed multiple myeloma!
Lots to learn and process from this trial- so let us get started with this deep-dive 🧵
#mmsm
nejm.org/doi/full/10.10…
Ide-cel versus a choice of five regimens for relapsed multiple myeloma!
Lots to learn and process from this trial- so let us get started with this deep-dive 🧵
#mmsm
What was the intent/purpose of this trial?
This was not necessarily aimed for us to figure out what the best option is for patients with 2-4 prior lines of therapy, but to fulfill regulatory requirements for approval (given prior approval was based on single arm study).
This was not necessarily aimed for us to figure out what the best option is for patients with 2-4 prior lines of therapy, but to fulfill regulatory requirements for approval (given prior approval was based on single arm study).
What was the patient population enrolled in this study?
Had to have 2-4 prior lines of therapy.
84% had prior auto
65% triple refractory
6% penta-refractory.
No clear single best standard of care in this population-important to highlight.
Had to have 2-4 prior lines of therapy.
84% had prior auto
65% triple refractory
6% penta-refractory.
No clear single best standard of care in this population-important to highlight.
What control arm options were allowed?
1. Dara/pom/dex
2.Dara/vel/dex
3. Ixa/len/dex
4. Carf/dex
5. Elo/pom/dex
1. Dara/pom/dex
2.Dara/vel/dex
3. Ixa/len/dex
4. Carf/dex
5. Elo/pom/dex
What was not allowed?
1. Alkylator based regimens- cylophosphamide based triplets can get mileage here
2. CD38 + Carfilzomib combo
3. Carf+pom/dex
However, it is important to note that dara based regimens in dara refractory patients have no prospective data to support them!
1. Alkylator based regimens- cylophosphamide based triplets can get mileage here
2. CD38 + Carfilzomib combo
3. Carf+pom/dex
However, it is important to note that dara based regimens in dara refractory patients have no prospective data to support them!
What regimens ended up being utilized in control arm?
Variety- but most commonly dara/pom/dex and elo/pom/dex.
Variety- but most commonly dara/pom/dex and elo/pom/dex.
How many patients intended to get ide-cel actually got ide-cel?
i.e intent to treat :)
225 out of the 249 who underwent leukapheresed (254 were assigned to ide-cel group).
i.e intent to treat :)
225 out of the 249 who underwent leukapheresed (254 were assigned to ide-cel group).
Did more people withdraw in control arm (dis-satisfaction with control arm) compared to intervention arm, prior to getting treatment?
A little perhaps- 5/132 withdrew in control arm prior to receiving treatment due to "patient/physician reasons" compared to 2/254 in ide-cel arm
A little perhaps- 5/132 withdrew in control arm prior to receiving treatment due to "patient/physician reasons" compared to 2/254 in ide-cel arm
What did the investigators expect at time of designing trial? What were power calculations like?
94% power to detect an improvement in median progression-free survival from 9 months with standard regimens to 14 months with ide-cel.
Lets process that.
94% power to detect an improvement in median progression-free survival from 9 months with standard regimens to 14 months with ide-cel.
Lets process that.
As we will find out later- the control arm massively underperformed that.
And although ide-cel did not underperform all that much, they didn't aim/expect much (14 mo for a very expensive CAR-T therapy!)
And although ide-cel did not underperform all that much, they didn't aim/expect much (14 mo for a very expensive CAR-T therapy!)
So how did the control arm do?
PFS of only 4.4 months.
This is perhaps the most rigorous evaluation of "repeating dara based triplets" that we have- and it sure seems that performance of these regimens is very marginal unfortunately.
PFS of only 4.4 months.
This is perhaps the most rigorous evaluation of "repeating dara based triplets" that we have- and it sure seems that performance of these regimens is very marginal unfortunately.
Also, I suspect activity of ixa-len-dex is close to nothing in patients who are refractory to len and other PI's. It is almost as good as a (toxic) placebo in my opinion.
How did intervention arm do?
PFS of 13.3 months (intent to treat basis- the right way to do it- this includes all patients randomized to ide-cel)
This is a little marginal. Amazing that a one-time dose did this- but lets not forget the cost and toxicity.
PFS of 13.3 months (intent to treat basis- the right way to do it- this includes all patients randomized to ide-cel)
This is a little marginal. Amazing that a one-time dose did this- but lets not forget the cost and toxicity.
More people died in the ide-cel arm due to toxicities.
36 out of 250 Grade 5 AE's in ide-cel (14%)
8 out of 126 Grade 5 in SOC (6%)
36 out of 250 Grade 5 AE's in ide-cel (14%)
8 out of 126 Grade 5 in SOC (6%)
OS data is immature-but so far "slightly" more people have died in ide-cel arm (30% vs 26)
How will curves look with longer follow-up? Time will tell.
We cant say yet people living longer by getting ide-cel earlier- but there maybe more treatment related death with ide-cel
How will curves look with longer follow-up? Time will tell.
We cant say yet people living longer by getting ide-cel earlier- but there maybe more treatment related death with ide-cel
Goes to show how MRD negativity is flawed endpoint for multiply relapsed disease, MRD negativity rates dismally low for both ide-cel arm and SOC arm (20% versus 1%).
Remember- almost everyones disease eventually relapsed anyways even with ide-cel
Remember- almost everyones disease eventually relapsed anyways even with ide-cel
Quality of life data not provided.
I suspect will be much better with lack of continuous treatment for those who survive initial toxicity of CAR-T.
I suspect will be much better with lack of continuous treatment for those who survive initial toxicity of CAR-T.
Cytopenias not to be underestimated with ide-cel.
Grade 3-4 neutropenia 76%, median time of 1.7 months to recover.
Thats a longer duration than auto-transplant.
Grade 3-4 neutropenia 76%, median time of 1.7 months to recover.
Thats a longer duration than auto-transplant.
We are all tempted to compare to cilta-cel.
The CARTITUDE-4 trial is positive on a press-release, but please remember, the patient population in that trial will be less heavily pre-treated (1-3 lines is enrollment criteria)- so not fair to compare median PFS b/w these trials.
The CARTITUDE-4 trial is positive on a press-release, but please remember, the patient population in that trial will be less heavily pre-treated (1-3 lines is enrollment criteria)- so not fair to compare median PFS b/w these trials.
In summary, ide-cel beats some options for PFS in a heavily pre-treated population, but has a higher treatment related death signal. The prospect of one time tx is exciting from a patient perspective, and independent cost analysis are needed to help contextualize findings.
Also perhaps disappointingly, the ide-cel curve shows no signs of cure/plateau .
Everyone eventually progresses 💔. Perhaps newer products will be better, but this is no cure for myeloma.
Everyone eventually progresses 💔. Perhaps newer products will be better, but this is no cure for myeloma.
Some other pearls:
⭐️Median time from leukapheresis to ide-cel infusion was 49 days.
⭐️52% of patients in control arm got leukapheresed at relapse with intent of getting ide-cel
⭐️ Bridging allowed, but 2 week wash-out required. Many other requirements too 👇
⭐️Median time from leukapheresis to ide-cel infusion was 49 days.
⭐️52% of patients in control arm got leukapheresed at relapse with intent of getting ide-cel
⭐️ Bridging allowed, but 2 week wash-out required. Many other requirements too 👇
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