Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance

Abstract

Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with “progressor” MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.

Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma

“…While the study demonstrates several strengths, there are a few limitations that need to be considered. The results apply to RRMM only and are not reflective of the relationship between PFS and OS for MM overall: the PFS-OS relationship in patients with newly diagnosed MM may be different than in patients with RRMM since newly diagnosed MM is slower to progress and has different disease dynamics than RRMM [ 38 – 40 ]. Studies that had median PFS data but did not reach median OS were excluded from the analysis, as were studies in which required data were distributed across multiple publications.…”

Upregulated Expression of ERBB2/HER2 in Multiple Myeloma as a Predictor of Poor Survival Outcomes

“…Contemporary treatment strategies for multiple myeloma (MM) still fail in a significant portion of patients due to the emergence of resistance in MM clones to active anti-MM drugs [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Effective treatments capable of preventing or overcoming cancer drug resistance are urgently needed [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

“…Contemporary treatment strategies for multiple myeloma (MM) still fail in a significant portion of patients due to the emergence of resistance in MM clones to active anti-MM drugs [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Effective treatments capable of preventing or overcoming cancer drug resistance are urgently needed [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. The tumor microenvironment (TME) in MM has been shown to play a pivotal role in disease progression by facilitating the immune escape of MM cells via both immune suppression and activation of signaling pathways that prevent apoptosis and stimulate their proliferation [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma

“…With multiple genetic hits and branching disease evolution, MM, genetically, is a complex disease. Much previous work investigating the molecular mechanism of MM has established clear and close relationships between chromosomal aberrations, somatic mutations, activation of signaling pathways and RNA expression, as extensively reviewed elsewhere [ [8] , [9] , [10] ]. The emergence of technologies to define MM, such as high-throughput RNA sequencing and single-cell sequencing analysis [ [11] , [12] , [13] ], will greatly contribute to the understanding of MM pathogenesis.…”