Thread by @NicoGagelmann

CAR T-cells have huge potential for multiple #myeloma.

It's an individualized treatment, complex process, associated with high costs->risk for huge inequality worldwide.

Lets advocate for hope & improvement, together.

🧵on what's new with #ASH22 abstracts

#MedTwitter #mmsm

Mini background of CAR:
-designer proteins that redirect T cells towards a defined surface antigen on tumor cells
-construct contains four essential components
--extracellular antigen recognition
--hinge, spacer
--transmembrane domain
--intracellular signaling domains

Let's categorize the overview of #ASH22 abstracts to structure &sharpen our minds:
C-clinical results in relapsed/refractory #myeloma
E-earlier lines of treatment
R-refined design
A-adverse effects after CART infusion
D-disparities

Shout out to Alzheimer's community! /1

Clinical #ASH22:
-interim results
-phase 1, GPRC5D-targeted autologous CART
-n=21
-response in 12/14 (1‑month)
-median duration of response has not been reached -median follow-up short: 4.0 months
-CRS in 11/17, grade 1/2; ICANS in 2/17, grade 1 ash.confex.com/ash/2022/webpr…
/2

Prior anti-BCMA treatment #ASH22:
-n=50, retrospective, ide-cel
-antibody-drug conjugates (n=38), bispecifics (n=7), and CAR T (n=5)
-median of 9 prior lines
-1/3 high-risk cytogenetics, 50% extramedullary #myeloma
-compared with no prior treatment👇 ash.confex.com/ash/2022/webpr…
/3

Earlier lines #ASH22:
-KarMMa-2 cohort 2a
-early relapse after frontline (progressive disease <18 months)
-n=37, median follow-up 22months
-overall response 84%, complete 46%, MRD at 1year 70%
-duration of response 15months, median PFS 11months ash.confex.com/ash/2022/webpr…
/4

1st line high-risk #myeloma FasTCART #ASH22:
-high-risk: cytogenetics, EMD, LDH, IgD/E, mSMART3.0
-n=13
-overall response 100%, complete response 69%, MRD- 100% at any time
-CRS in 3/13, no ICANS
/5

Designs #ASH22 part 1:
-T Cells expressing a fully-human anti-BCMA CAR with a heavy-chain-only antigen-recognition domain
-n=25
-durable responses & early within 14 days after infusion
-CAR blood levels ~ CD4+CCR7+ infusion cells
-median PFS 65 weeks
ash.confex.com/ash/2022/webpr…
/6

Design #ASH22 part 2:
-next-generation CART
-fully human single-chain variable fragment, optimized spacer, 4-1BB costimulatory, CD3ζ activation domains
-primarily naive-like & central memory cells
-manufacturing 5-6 days (!)
-65 enrolled->55 treated ash.confex.com/ash/2022/webpr…
/7

Cytopenia after anti-BCMA CART #ASH22 part 1:
-n=90
-≥grade 3 at day 0, 60, 120, 180 & 360 post-CART was 39%, 33%, 28%, 13% & 7%, respectively
-poor recovery in 1/3->marrow findings for MDS and associated with lines of prior therapy ash.confex.com/ash/2022/webpr…
/8

Cytopenia after anti-BCMA CART #ASH22 part 2:
-academic CART 🇪🇸, n=30
-Median time in months to complete resolution of neutropenia, thrombocytopenia and anemia was 4, 12 and 3months
-CRP and CRS duration associated with the duration of neutropenia ash.confex.com/ash/2022/webpr…
/9

Immune recovery #ASH22:
-n=76
-1/3 of patients without recovered IgM, CD3 and B cells at 2 years post-CART
-1/2 without recovered IgA levels->poor response to vaccinations and susceptibility to infections ash.confex.com/ash/2022/webpr…
/10

Disparities #ASH22 part 1:
-n=215, ide-cel
-70% self-identified as Non-Hispanic White, 17% Non-Hispanic Black, 10% Hispanic, 3% Asian, Pacific Islander, American Indian, or Alaskan Native.
-differences in systemic inflammation, safety, and PFS
ash.confex.com/ash/2022/webpr…
/11

Disparities #ASH part 2:
-shown to make a point: CART not accessible in most of the world->and if, probably "only" academic
-robust, scalable, affordable first indigenous HCAR19 product 🇮🇳 for #lymphoma ash.confex.com/ash/2022/webpr…
/12

In conclusion, response rates are stable across designs. Duration and relapse being the most important features to understand. Toxicity seems minimal (CRS or ICANS). Hematotox seems different from lympoma, more research needed...#mmsm
/13

Let's actively confront huge disparities that come with the (commercial) CART products. That doesnt mean not to use them but to choose wisely, fairly & to discuss best options for the most instead of the few. Otherwise, we all loose in the long run.
👉thelancet.com/journals/lanha…
/14

Many works stem from inspiring groups & researchers @End_myeloma @fdezdelarrea @ovanoekelen @NoopurRajeMD @DrGauravNarula @NIH @BerdejaJesus et al. And shout-out to @VincentRK, his New England review was my first text about myeloma, with heavy impact.
/15

Helpful resources:
haematologica.org/article/view/h…
pubmed.ncbi.nlm.nih.gov/34923107/
pubmed.ncbi.nlm.nih.gov/31492448/
thelancet.com/journals/lanha…
nature.com/articles/s4137…