Topline Presentation Points

Acquired Resistance 

  • Proteasome Inhibitors – Proteasome Subunit mutation, XBP-1 mutation 
  • All IMiDs and CelMods – CRBN pathway 
  • Daratumumab – Loss of CD38 
  • CAR-T/TCE – Loss of BCMA

Gene Expression levels of Cereblon, Mutations in the Cereblon pathway and CRBN pathway change 

A majority of MM patients now receive bortezomib and lenalidomide in first line therapy and maintenance 

  • Ideal therapy at time of first progression would be non cross reactive, with novel MOA, well tolerated and effective 
    • Pomalidomide – same MOA, low toxicity 
    • Carfilzomib – same MOA, superior to Bortezomib in relapse 
    • Cyclophosphamide – same MOA (unless not transplanted), good partner, not as effective 
    • Daratumumab and Isatuximab novel MOA, low toxicity 

Lots of options in drug sensitive early relapse 

What to do in the inevitable lenalidomide and / or daratumumab refractory patients ? 

  • Pom Dex PFS in Len refractory 7 months
    (Dimopoulos MA, et al. ASH 2020. Abstract 412.)
  • Carfilzomib/Dexamethasone 19 months
    (Dimopoulos MA et al. Lancet Oncol. 2016;17:27-38.)
  • KCd: 21 months
    (Mateos MV, et al. Blood. 2020;136(suppl 1):8-9.)

The future may be to combine the most effective drugs? 

  • CANDOR: CAR-DARA-DEX vs CAR-DEX
    (Usmani SZ, et al. ASH 2019. Abstract LBA6.)
  • KdD Led to Improved Overall Response Rates
    (Dimopoulos M, et al. Lancet. 2020;396:186-97.)
  • IKEMA (Isa-Kd vs Kd): Elderly Patients With RRMM
    (Facon T, et al. Presented at: ASCO Annual Meeting; June 4–8, 2021; Virtual. Abstract 8026.)
    (Facon T, et al. Presented at: 26th Congress of the EHA; June 9–17, 2021; Virtual. Abstract EP980.)

The Real Dilemma of Relapsed Multiple Myeloma 

  • All patients will eventually develop resistance to relapse therapies

What Is the Future for Relapsed Multiple Myeloma? 

  • Overview: ~ 20 new therapeutics 
    • Small Molecules: Iberdomide, Venetoclax, Selinexor, Melfulfen 
    • Antibodies: Daratumumab, Isatuximab 
    • Antibody Drug conjugates: Belantamab 
    • BITES/Bi-specifics: AMG701, Teclistamab, CC93269, REGN4548,Talquetamab, Cevostamab… and many more 
    • CAR-T: Ide-cel, Ovra-cel, Cilta-cel, LCARB38… many more