Myeloma is an incredibly complex genomic disease. Gene alterations can cause cell metabolic pathways to become activated or silenced. If pathway activation causes an oncogene (tumor promoter) to become more highly expressed, aggressive cancers are quite likely to develop. On the other hand, inactivation of a tumor suppressor gene can cause cancers to grow unimpeded by the body’s normal immuno-protective mechanism. Immunotherapy research aims to promote tumor suppressor genes and impede naturally occurring oncogenes.

The immune system has many checkpoint inhibitors necessary to keep it under control. If they weren’t in place the system would misidentify body elements (neurologic tissue, connective tissue) as “foreign” and attack them, resulting in diseases such as multiple sclerosis and rheumatoid arthritis. If immune inhibition is too robust, however, needed cancer suppressor genes may become inactive, thereby allowing new cancer cells to flourish. Inactivation or loss of the short arm of chromosome 17 (17p53 deletion) causes just such a loss, resulting in very high-risk myeloma.

During the 56th American Society of Hematology (ASH) Annual Meeting, there have been many posters and presentations on immune system regulation to control myeloma. Altering the activity of immune checkpoint inhibitors seems to be the most promising approach. If we can turn off or inhibit the factor holding the immune system from attacking cancer cells, the potential effect would be a vigorous attack by NK (natural killer) cells. PD-L1 expression has been detected on tumor cells and represents just such a target, a place to turn off the factor which is turning off the immune system. PD-L1 pathway is one of cancer’s defenses against the immune system. It is complicated to explain and certainly much more complicated to actually do. The field is promising but it is very early and actual results in actual patients seem a long way off.

Agents targeting specific molecular pathways can be effective across many tumor types. During ASH there were posters and presentations in which drugs beneficial against more common cancers are being utilized against myeloma. Myeloma’s incredibly complex genomic heterogeneity makes certain subsets of patients likely to contain those same pathway alterations. Dr. Todd Golub of Dana-Farber Cancer Institute stated there are a median of 5 clones/subclones in each new myeloma patient making the presence of these common cancer pathways likely. Will it work? If it does, will the killed clone be the dominant one, or just a secondary subclone?

Estimates of up to 40% of myeloma cells may have KRAS or NRAS mutations. making them susceptible to TKIs (tyrosine kinase inhibitors) used in leukemia. BRAF mutation and MAPK pathway mutation is thought to be present in 8% of myeloma mutations, making them possibly susceptible to BRAF inhibitors such as vemurafenib. Small numbers of myeloma patients have been shown to have molecular alterations of IDH, IGFR, ALK, FHFR3, and P13K-AKT, all of which can be targeted with currently available drugs. Whether these genetic mutations are truly “driver” genes in myeloma, or merely present, and whether the drugs would really be effective or not is unknown. Still the research and possibilities are exciting.

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