Why You Should Have Your Multiple Myeloma Genome Sequenced

Not all multiple myeloma (MM) is the same. In fact, the MMRF CoMMpass Study, has shown that there are at least 12 subtypes of myeloma. Since each of these subtypes has a unique combination of genetic mutations and gene expression levels, researchers think the separate subtypes might respond differently to various treatments. Knowing the genetic makeup of your tumor could help lead to a treatment tailored to be most effective for you.

What is genome sequencing?

MM genome sequencing is the process of examining your tumor DNA, the molecular instructions for the cancer cells in your bone marrow. DNA tells cells what to do, how to operate, where to go, and when to go there. It even tells cells which other cells they should interact with.
DNA is made up of long strings of 4 different chemicals strug together on a backbone of sugar molecules. The four chemicals are adenine, thymine, cytosine and guanine, and are abbreviated A, T, C, G. These four components are strung together in a varying order, or sequence, such as ATTGTCACGGGT. The DNA in each cell, if stretched out, is 2 miles long!. Scientists have discovered that each set of three chemicals in a DNA sequence, like GGT, codes for one amino acid. Amino acids are the chemical building blocks of proteins, and there are 21 different types. Proteins are assembled by cells according to the blueprints found on DNA, and proteins are responsible for how a cell functions. In this way, DNA is like the queen bee in a hive, whereas the proteins are like the worker bees. The worker proteins are all made from the instructions provided by the queen DNA; the worker proteins are the molecules that actually accomplish the work of the cell. Genomic sequencing analyzes and reports the order of the DNA chemicals, and can indicate if the order of chemicals has been altered compared to a normal sequence.

The DNA in cancer cells is made up of the same molecular “stuff” as the DNA in normal cells, but the sequence may have been rearranged. Sometimes the changes are really small—involving only a single letter of DNA that is changed from the normal sequence. Other times the changes are giant—big chunks of DNA swap places. Or entire genes, which are defined DNA sequences which code for a particular protein, are copied several times. All of these genetic changes alter the way the “beehive” operates. Those worker bee proteins made from changed, or mutated, DNA sequences are no longer doing the job they should be. The proteins have been changed to perform different jobs based on the blueprint of the mutated cancer DNA.

Sequencing DNA allows doctors to understand those cancerous DNA blueprints by glimpsing the instructions for how your tumor is working. Changes in the tumor DNA sequence can affect how fast it is growing, how it is trying to avoid detection by the immune system, and even how it might respond to therapy.

If you have your MM sequenced both before receiving any therapy and after receiving therapy, researchers can also investigate how your tumor DNA changes over time. Tumor DNA doesn’t just sit lazily in the cell. It continues to change and adjust, or mutate, which may help the tumorfind ways to evade the immune system or become resistant to certain therapies. Identifying these mutations can allow your doctor to change treatments to something that might work better.

Why should I have my genome sequenced?

Kathy Giusti, MMRF co-founder and president, has said, “When it comes to cancer, all knowledge is power—even when that knowledge is scary.” This is particularly true of cancer genome sequencing. Getting your genome sequenced may mean you find out that the type of myeloma you have is particularly aggressive with a poor prognosis. However, it can also reveal that the DNA mutations or changes that signal this subtype can be targeted for treatment. Kathy’s own tumor genome sequencing revealed that she had a translocation called t(4;14), which means parts of chromosomes 4 and 14 had switched places. This information pinpointed an aggressive form of myeloma with a poor prognosis. However, Velcade (bortezomib) was being developed, and individuals with a t(4;14) chromosomal change tended to respond well.
Knowing her myeloma was likely to be aggressive was devastating, and yet that knowledge allowed Kathy to move toward the best treatment option available. As more patients undergo genome sequencing and more data are collected, more is understood about myeloma. The Multiple Myeloma Genomics Initiative (MMGI), an MMRF undertaking to sequence myeloma genomes, recently discovered a mutation in the BRAF gene. That mutation has been previously identified in skin cancer genomes and is targeted with the drug vemurafenib. Vemurafenib is currently being studied in myeloma patients with the BRAF mutation.

Genome sequencing can give you information about your prognosis, your treatment options—even how your cancer is changing in response to treatment. Learning this information may be intimidating, but it may also help identify the best treatment available for you.
In addition to helping you now, myeloma genome sequencing can be quite beneficial to patients in the future. The MMRF has rapidly advanced the understanding of the myeloma genome and how it affects patients’ outcomes. It has also advanced many treatments to combat myeloma through the Mutiple Myeloma Research Consortium, an organization of 25 academic centers which helps initiate clinical trials to test new therapies . To further understand the genetic makeup of multiple myeloma, the MMRF launched the CoMMpass Study in 2011. This study follows 1,154 patients from 73 cancer centers across North America and Europe through their entire journey with the disease. The patients enrolled in this study provided bone marrow samples when first diagnosed and continue to provide samples at relapse over at least 8 years. The CoMMpass Study has revealed new mutations, as well as genomic differences among African-Americans, who are more than twice as likely as white Americans to be diagnosed with multiple myeloma.

As genomic sequencing becomes faster and cheaper, more information on this disease will be available to researchers, doctors and, ultimately, patients. This will help provide answers to some important questions: which drugs might work better for you based on your genetic subtype of myeloma? Will you respond to transplant? Which combination of drugs works for you? What is your risk of having the disease come back?

How can I pay for genome sequencing?

Many insurance companies recognize the value of genomic testing and are willing to pay for it, but additional options are available. In an effort to provide genetic information to patients with relapsed or refractory MM and their physicians, the MMRF has partnered with the University of Michigan for the Molecular Profiling Initiative (MPI). Five hundred patient samples will be sequenced over 2 years. This clinical-grade (CLIA) genomic sequencing is currently available free of charge at 22 different treatment centers, with more facilities expected to participate in the coming months. The tumor genomic profiles obtained from these samples can be used to identify appropriate clinical trials and treatment options for patients. For more information, please read this press release from the MMRF.

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