Landscape of myeloma-defining genomic events across genomically defined proposed new entities: monoclonal gammopathy (MG), early detection of multiple myeloma (EMM), and multiple myeloma (MM)29,47
| Myeloma-defining genomic events . | Clinical entity . | ||
|---|---|---|---|
| MG* . | EMM† . | MM . | |
| Complex SV events | ✓✓ | ✓✓ | |
| Mutations in driver genes | ✓ | ✓✓ | |
| Copy number changes (ie, deletions) | ✓✓ | ✓✓ | |
| APOBEC‡ | ✓✓ | ✓✓ | |
| Early age of initiation in patient's life | ✓✓ | ✓✓ | |
| Canonical IGH translocations | ✓ | ✓✓ | ✓✓ |
| Hyperdiploidy | ✓ | ✓✓ | ✓✓ |
| MYC§ translocation | ✓ | ✓✓ | |
| Myeloma-defining genomic events . | Clinical entity . | ||
|---|---|---|---|
| MG* . | EMM† . | MM . | |
| Complex SV events | ✓✓ | ✓✓ | |
| Mutations in driver genes | ✓ | ✓✓ | |
| Copy number changes (ie, deletions) | ✓✓ | ✓✓ | |
| APOBEC‡ | ✓✓ | ✓✓ | |
| Early age of initiation in patient's life | ✓✓ | ✓✓ | |
| Canonical IGH translocations | ✓ | ✓✓ | ✓✓ |
| Hyperdiploidy | ✓ | ✓✓ | ✓✓ |
| MYC§ translocation | ✓ | ✓✓ | |
Monoclonal gammopathy (MG) represents cases without evidence of genomic drivers. In the 1960s, Dr Jan Waldenström argued that patients who had monoclonal proteins without any symptoms or evidence of end-organ damage represented a benign MG.5-8 Based on careful chart reviews of individuals with monoclonal proteins, in 1978, Dr Robert Kyle introduced the concept of “monoclonal gammopathy of undetermined significance” (MGUS) given that, at diagnosis, it was not possible with available methods (ie, SPEP to define the concentration of M-proteins and microscopy to determine the plasma cell percentage in bone marrow aspirates) to determine which patients would progress to multiple myeloma (MM).6 The application of low-input whole-WGS technology45,46 has circumvented previous problems related to volume of clonal plasma cells and contamination by normal plasma cells and allowed for the interrogation of the WGS landscape of MGUS.47 As illustrated in this table, the distribution of genetic events reveals striking differences and the existence of 2 biologically and clinically distinct entities of asymptomatic monoclonal gammopathies: (1) one entity characterized by a sufficient number of myeloma genomic events to confer malignant potential and that is associated with progressive disease (early detection of multiple myeloma; EMM) and (2) another entity with a lower burden of genetic events characterized by a high likelihood of a prolonged, indolent, and clinically stable course (MG). Future prospective studies are needed to definitively address whether a (small?) proportion of cases with genomically defined47 MG eventually can convert to EMM or not. If there is only a very low rate of conversion, then the term benign monoclonal gammopathy5-8 is probably accurate for this genomically defined47 clinical entity of MG.
Early detection of multiple myeloma (EMM) are cases with MG in which genomic drivers already have been acquired.
APOBEC, as the name suggests, is a class of enzymes that was originally identified as an enzyme that edits messenger RNA species by deaminating cytosine to uracil, which in this case produces a stop codon and truncated protein. MYC includes a family of regulator genes and protooncogenes that code for transcription factors.
Activation of MYC leads to increased expression of many genes, some of which are involved in cell proliferation.