Topline  Presentation Points

MM Is Not One Disease 

  • MGUS to Active MM transition period is different among patients. Diagnosis is made at variable time-points during the transition, so degree of end organ damage is different. 
  • Management strategies are focusing on changing myeloma to a chronic illness for majority of patients, probably curative for a subset. High risk disease remains a challenge. 
  • Advances in understanding myeloma biology has led to new therapeutic targets. 
    • MM Pathways 
    • BM microenvironment 
    • Immune regulation and modulation
      (Martinez-Lopez J et al Blood 2011)
      (Usmani et al Leukemia 2012)


Defining High Risk Disease at Diagnosis in 2021
 

  • Clinical Phenotypes 
    • EMD  (Extramedullary multiple myeloma) and pPCL  (primary Plasma Cell Leukemia)  
  • MM Biology 
    • Cytogenetics/FISH 
    • Translocation (14;16) – MAF over-expression 
    • Translocation (14;20) – MAFB over expression 
    • Gain & Amplification of chromosome 1q21 – over expression of several proteasome genes 
    • Deletion 17 p – monoallelic loss is bad, biallelic loss is worse. 
    • Translocation (4;14) 
  • Poor Risk by Gene Expression Profiling 
  • Gene mutations 
    • BRAF, K-RAS, N-RAS (low incidence at diagnosis, usually late events)
  • Blind Spots – that can lead to ‘unexpected’ poor responders or unexpected ‘early relapse’  
    • Poor assessment of MM disease biology at diagnosis and relapse: 
      • Highly dependent on the quality of random pelvic bone biopsy 
        • Can fix by creating standard operating procedure/process steps for sample ‘pecking order’. 
      • No assessment of FDG avid focal bone lesions or EMD 
        • Can fix by concomitant biopsy of such lesions as ‘routine’ practice. However, not patient friendly. 
        • [Patient] Only examined at finite time points 

We are still learning how to incorporate immunome and BM microenvironment status in MM patient assessment. 

We are still optimizing how best to assess depth of response/detect MRD status.

Treatment Strategies for High Risk MM 

  •  SWOG 211 Schema Phase II
    (Usmani SZ et al. Lancet Haematol 2021)
  • The Emory Experience: RVd Induction, Consolidation and Maintenance in HRMM
    (
    Joseph N et al. JCO 2020)
  • KRd in TE NDMM (Phase II)
    (Jasielec JK et al, Blood 2020;136(22):2513-2523.)
    (Gay F al, ASH 2020; abstract 141)


Emerging Treatment Strategies 

  • Response-Adaptive Phase II Study Daratumumab Combined with Carfilzomib, Lenalidomide and Dexamethasone (Dara- KRd) in Newly Diagnosed Multiple Myeloma
    (Bhutani M et al, ASH 2020; 1388)
  • KarMMa: High-risk subgroups
    (Raje et al., ASH 2020: Abstract 3234)
  • KarMMa-4: High Risk NDMM
    (ClinicalTrials.gov)
  • CARTITUDE 2: High-Risk Cohort
    (Einsele et al., ASTCT 2021)
  • BMT-CTN SOSS 2021 Concept: Incorporation of BCMA Directed TCT Strategy 
  • SWOG 2021 Concept: Incorporation of BCMA Directed Bispecific In Induction/Maintenance Strategy 
  • Phase I/II Study of Carfilzomib, Lenalidomide, Dexamethasone and the Anti-B-Cell Maturation Antigen (BCMA) Antibody Drug Conjugate Belantamab Mafodotin in Newly Diagnosed, High-Risk Multiple Myeloma 
  • Venetoclax Is Active Combined With Bortezomib/Dexamethasone And With Carfilzomib/Dexamethasone 
    • In contrast to the CLL experience, TLS appears to be uncommon in MM; ramp-up dosing has not been necessary 
    • Venetoclax (daily dose up to 1,200 mg) has an acceptable safety profile in R/R MM, predominantly in patients with t(11;14) abnormality and favorable BCL-2 family profile