Multiple myeloma is a cancer of the plasma cells, which are a type of white blood cell that circulates in the blood. Normally, plasma cells make antibodies that help protect the body against infection. In a person with multiple myeloma, cancerous plasma cells (that is, myeloma cells) crowd out normal plasma cells. The antibodies produced by myeloma cells are abnormal—these are called M proteins—and are not useful in fighting infection. Myeloma cells also produce incomplete parts of antibodies called light chains.
Plasma cells transform into myeloma cells as a result of genetic mutations that cause them to multiply uncontrollably. The nature of the mutation—there are several different types—influences how disease prognosis and treatment outcomes.
To understand how genetics affects the behavior of myeloma cells, it is important to understand a little bit about chromosomes and DNA. Normal cells—that is, non-cancer cells—have 23 pairs of chromosomes, which are structures made of DNA. This set of chromosomes is referred to as the genome. Using samples from the bone marrow, doctors use several tests to look at the genome in myeloma cells to determine the nature of the disease.
The main test used as part of routine clinical evaluation in myeloma patients is fluorescence in situ hybridization (FISH). This test provides information about chromosomes specifically.
For FISH, myeloma cells from a bone marrow biopsy are collected and treated with special dyes that attach to specific parts of chromosomes, which makes it possible to detect changes in myeloma cells. Of particular importance is determining the presence and nature of any structural changes in these chromosomes—for example, whether any chromosomes have been duplicated (hyperdiploid), if parts of chromosomes are missing (deletions), or if pieces of chromosomes have swapped places (translocations). FISH results are usually available within a few days.
In addition to this cytogenetic test, there are other, newer tests that are able to look even deeper at a patient’s genetics and assess changes at the DNA level. These tests are gene-expression profiling and next-generation sequencing.
Gene-expression profiling measures the activity of thousands of genes, including how efficiently the cells make proteins. Probes attached to specific portions of genes are used to assess how “active” they are.
Next-generation sequencing provides a readout of the entire genome. This method provides the greatest level of detail regarding changes to the genome and may help predict how a patient’s myeloma will behave over time and with different treatments. In the MMRF Molecular Profiling Protocol, next-generation sequencing was used on samples collected from 500 patients whose myeloma had relapsed. Over two thirds of these patients were found to have mutations (changes in myeloma cell DNA) that could be targeted by a specific treatment.
Myeloma management is moving toward a more personalized approach to treatment, and obtaining a patient’s genetic profile is required for personalization. For example, some chromosomal and DNA abnormalities are associated with shorter survival, so patients with these abnormalities are considered to have high-risk disease. These patients have more aggressive disease and may need higher-intensity or longer-duration treatments.
The MMRF CoMMpass study—which evaluated the genetic information of 1,150 patients with newly diagnosed active myeloma—described eight different myeloma subtypes based on specific genetic changes. The results of this study helped classify patients so that they can receive more specific—and thus more effective—treatment based on their genetic profile.
Another study called MyDRUG (Myeloma – Developing Regimens Using Genomics), which is one of the first and largest precision medicine studies in myeloma ever conducted, put the CoMMpass findings into clinical practice. The MyDRUG researchers are evaluating drugs designed specifically for the DNA mutations identified. The results from MyDRUG will hopefully allow doctors to select treatments that are most likely to help patients and truly benefit their disease outcomes. The MyDRUG trial is led by Dr. Shaji Kumar at the Mayo Clinic in Rochester, Minnesota, and the MMRF’s Dr. Daniel Auclair and is enrolling patients at 17 cancer centers and academic research institutions throughout the United States. You can listen to Dr. Kumar review the MyDRUG trial and other innovative clinical trials here. Or you can read our MyDrug Study blog post.
Confused? Don’t worry you can contact an MMRF Patient Navigator at the MMRF Patient Navigation Center at 1-888-841-MMRF(6673) and they can help you with any remaining questions you have.
MMRF CoMMpass Study.
The MMRF and University of Michigan Molecular Profiling Initiative.
Precision Medicine Brochure.