Additional molecular genetic diagnostics for multiple myeloma

Approx. 10% of all hematological neoplasias are plasma cell diseases such as multiple myeloma (MM) or plasma cell leukemias. As is the case for other hematological diseases, molecular genetic diagnostics can be viewed as increasingly relevant in the diagnosis, prognosis and therapeutic stratification of MM. This is especially true given that MM in genetic terms is a highly heterogeneous neoplasia. MLL currently offers a molecular genetic panel that includes the BRAF, KRAS, NRAS and TP53 genes.

Over 50% of patients with multiple myeloma have mutations in one component of the MEK/ERK pathway (Morgan et al. Leukemia 2018). NRAS, KRAS and BRAF mutations for example have been identified in between 19 - 24%, 21 - 27% and 4 - 9% of patients, respectively. It should be noted that these mutations are almost exclusive with respect to one another and occur together in only about 2% of patients (Chapman et al. Nature 2011, Walker et al. JCO 2015). Although multiple kinase-encoding genes are involved, they all share a similar domain structure and the same downstream pathway, making them viable candidates for targeted therapies.

Mutations in the TP53 gene, initially detected in 3 - 8% of patients, are associated with del(17p) and have a poor prognosis. In advanced stages of disease, the frequency of TP53 mutations progressively increases with each relapse, showing a frequency of up to 75% in advanced stages. These mutations closely correlate with resistance to drug therapy.

Patients with NRAS mutations, as opposed to patients with KRAS mutations, respond more poorly to the proteasome inhibitor bortezomib, while the presence of a NRAS mutation did not affect response time or time to relapse under dexamethasone treatment (Mulligan et al. Blood 2014).

In contrast, the presence of the BRAF V600E mutation in early stage multiple myeloma is associated with a good response to standard therapies such as immunomodulators, proteasome inhibitors and alkylating cytotoxic agents (Rustad et al. Blood Cancer J. 2015). As is the case with other malignancies, the use of BRAF and MEK inhibitors is often deployed in advanced stages of disease in the clinic - even though it remains inadequately investigated in clinical studies.