Thread by @HadidiSamer

Why peripheral neuropathy incidence is lower and cardiac toxicity is higher with carfilzomib when compared to bortezomib in multiple myeloma?

#mmsm
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Peripheral neuropathy with proteosome inhibition:

❓likely caused by inhibition of a serine protease that is critical for neuronal cell survival called HtrA2/Omi

✅ carfilzomib has lower levels off-target protease inhibition (including activity at HtrA2/Omi protease)

❓How common is peripheral neuropathy with bortezomib

IV, twice weekly initial dosing: 35% (>=G3 in 13%)>SC,twice weekly: >=G3 in 6%>SC weekly dosing (ex’s👇)

What about carfilzomib?

Initial trial (PX-171-003-A1)- FDA AA with single agent activity~24% (PN >=G3:1%)

❓How common are cardiac AEs with carfilzomib?

An excellent summary table @andrew02114 👇

Notice also the renal AEs

❓why cardiac toxicity is more common with carfilzomib compared to bortezomib?

Not very clear, maybe related to endothelial damage, or increased PP2A activity and inhibition of AMPKα/autophagy regulatory axes 👇(Efentakis et al Blood 2019)

Another nice summary table of cardiac AEs with carfilzomib 👇 (Waxman et al JAMA Onc 2018)

AEs are imp and need to watch for

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