Fei Fan Blood Cloud Classroom October Myeloma Literature Intensive Reading Workshop

• Research background:

• SMM falls between monoclonal gammopathy of unknown significance (MGUS) and active MM, with disease progression attributable to tumor growth, genetic evolution, and immune evasion
  .
  Early treatment of SMM is controversial, and international guidelines for the management of high-risk SMM vary
  .
  

• Early intervention of SMM requires optimal risk stratification to avoid undertreatment and overtreatment
  .
  The International Myeloma Working Group (IMWG) validated the Mayo 2018 score and proposed a 20/2/20 criterion (serum free light chain [sFLC] ratio >20, M protein >2 g/dL, or bone marrow [BM] plasma cells [PC] >20% as risk factors).
  
  。 However, more than half of these high-risk (≥2 risk factors) patients with SMM (usually enrolled in clinical trials) did not progress within the first 2 years, and one in five patients may be progression-free at 5 years; Conversely, nearly 20% of intermediate-risk (1 risk factor) and 10% of low-risk (0-risk factor) patients unexpectedly develop active MM
  shortly after being diagnosed with SMM.
  Therefore, there is still room
  for improvement in the current risk stratification criteria.
  

• There is growing recognition that circulating tumor cells (CTCs) are key to metastasis/spread of MM tumors, and their number in peripheral blood (PB) may be a potential surrogate indicator of tumor spread and overall tumor burden in BM, suggesting that CTCs can serve as a powerful biomarker of disease exacerbation
  and disease aggressiveness.
  We hypothesized that replacing BM PC with CTC and adding immune biomarkers to PB to identify patients with stable tumor burden but at risk of disease progression due to loss of immune surveillance could refine the IMWG 20/2/20 model
  .
  

• STUDY METHODS: This analysis was performed in the first 150 SMM patients enrolled in the iMMunocell study, and tumors and immune cells in PB were continuously evaluated
  every 6 months for 3 years from enrollment.
  According to IMWG criteria, TTP is defined as the time
  from entry into research to progression to active MM.
  

  
  

• Research results:

• The cut-off value for risk stratification was 0.
  015% CTC, and the median TTP of CTC > 0.
  015% versus 0.
  015% of patients ≤ 17, respectively months and not reached, the estimated 2-year disease progression rate was 63% and 15%, respectively; Median TTP was not achieved in 20% of patients with BM PC> and 20% ≤, with an estimated 2-year disease progression rate of 31%, respectively.
  and 18%.
  
  The 0.
  015% CTC cut-off value has better prognostic value than the 20% BM PC standard (Figure 1).
  
  

Fig.
1 TTP of 150 patients with SMM stratified according to 0.
015% CTC(A) and 20% BM PC(B).

• The enrolled patients were stratified according to IMWG 20/2/20 criteria, and the proportion of low, intermediate and high-risk patients was 40%, 40%, and 20%, respectively, and none of them reached the median TTP, and the estimated disease progression rates at 2 years were 2%, 27%, and 44%, respectively.
  According to the complete minimally invasive 20/2/0.
  015 standard stratification based on the same scoring system of IMWG 20/2/20 model, the proportion of low, intermediate and high-risk patients was 45%, 37% and 18%, the median TTP was not achieved, not reached and 21.
  3 months, and the estimated 2-year disease progression rate was 4%, 25% and 53%,
  respectively.
  The 20/2/20 and 20/2/0.
  015 models produced similar risk stratification (C-indices of 0.
  76 and 0.
  78, respectively; Figure 2).
  
  

Fig.
2 TTP of 150 SMM patients stratified according to 20/2/0.
015 model (C) and 20/2/20 model (D).

• In multivariate analysis (Figure 3), the sFLC ratio >20, M protein>2g/dL, and CTC > 0.
  015% showed independent prognostic value, and > 20% BM PC had no prognostic value
  .
  Among them, CTC > 0.
  015% was associated with a 4.
  3-fold increase in the risk of disease progression, slightly higher than the sFLC ratio of >20, and almost twice that of M protein > 2g/dL
  .
  

Figure 3 Multivariate analysis of TTP

• Combining the 20/2/0.
  015 model with immune risk scores based on the percentage of SLAN+ and SLAN-nonclassical monocytes, CD69+ HLADR+ cytotoxic NK cells, and CD4+CXCR3+ central memory T cells (20/2/2/0.
  015 model), patients were divided into low (0 risk factors), medium-low (1 risk factor), medium-high (2 risk factors), and high risk (≥ 3 risk factors) groups.
  The estimated 2-year disease progression rates were 0%, 20%, 39%, and 73%,
  respectively.
  The median TTP in patients with high-risk SMM is 11 months (Figure 4).
  
  The C-indices for the 20/2/0.
  015 and 20/2/2/0.
  015 models are 0.
  76 and 0.
  80
  , respectively.
  

Fig.
4 TTP of SMM patients stratified according to the 20/2/2/0.
015 model

• Discuss:

• The study showed that CTCs outperform BM PC in assessing tumor burden and that discrete innate and adaptive immune cell types complement each other
  in predicting disease progression.
  However, the results suggest that there are some inconsistencies between PB and BM immunobiomarkers, and further mechanistic studies are needed to understand the biological link
  between altered cell distribution and disease progression.
  

• CTC counts in patients with plasma cell disease have been challenging because of their low
  frequency in PB.
  However, highly sensitive flow cytometry assays enable CTC detection and precise quantification in
  patients with benign and malignant states.
  

• The limitations of the 20/2/20 model are BM PC assessment at the time of diagnosis, the lack of continuous BM assessment during follow-up, and the assumption that patient PC load and cytogenetic risk are constant
  over time.
  

• Low or intermediate-risk cases with early unexpected progression have a high immune risk score
  according to conventional criteria.
  The study shows that the absence of minimally invasive risk factors, including high immune risk scores, can identify a subset of patients without progression, which will open up new possibilities
  for personalized immunotherapy.
  

• A larger series of additional analyses are required to determine the consensus cut-off value
  for CTC for SMM risk stratification.
  Follow-up analysis of the iMMunocell study will investigate whether risk stratification according to the 20/2/0.
  015 criterion can further improve SMM staging
  .
  

A randomized, open-label study of lenalidomide plus dexamethasone versus no treatment observed at a median follow-up of high-risk SMM for 12 years

https://pubmed.
ncbi.
nlm.
nih.
gov/36067617   （IF=10.
002）