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Intraclonal Heterogeneity a Hallmark of Myeloma Progression

Reuters Health • The Doctor's Channel Newscast

NEW YORK (Reuters Health) – An increase in clonal complexity precedes the transformation of smoldering myeloma to malignant multiple myeloma, researchers have shown.

“As such,” they infer, “the invasive clinically predominant clone typical of MM (multiple myeloma) is already present at the SMM (smoldering myeloma) stage and would be amenable to therapeutic intervention at that stage.”

Writing in the July 19th online publication of Leukemia, the investigators note that research has focused on identifying mutations that drive malignant progression, as these represent potential therapeutic targets. For the present study, they analyzed the evolution of genetic changes as benign monoclonal gammopathy of undetermined significance (MGUS) transforms to smoldering myeloma and then symptomatic multiple myeloma.

Dr. Gareth Morgan, with the Institute of Cancer Research, London, and colleagues performed genomic sequencing on four samples of MGUS, four of high-risk SMM, and 26 of malignant MM, as well as two samples of plasma cell leukemia, the ultimate disease stage.

They found that the pattern of mutations increased progressively in complexity and number with disease stage. For example, the median number of single-nucleotide variants was 13 in the MGUS exomes, 28 in the SMM group, 31 in the MM samples and 59 in the leukemic plasma cells.

The team had previously demonstrated a high degree of intraclonal heterogeneity in terms of single-nucleotide variants in presenting myeloma, and in the current analysis they saw that a similar level of heterogeneity existed at all disease stages. “This intraclonal heterogeneity at the MGUS stage is consistent with clonal diversity arising early on in the process of myelomagenesis and with clonal competition being an essential requirement from the earliest phases of disease,” they point out.

To investigate changes in subclone populations in relation to the development of clinical symptoms, the researchers conducted a detailed analysis of paired samples of SMM and MM taken at least 21 months apart from three patients. They found that at both stages many subclones occurred at low frequencies, “a feature that would be anticipated if disease progression was the result of clonal competition.”

As for treatment implications, “it all boils down to a simple message,” Dr. Morgan wrote in an email to Reuters Health.

“The issue is that, with there being multiple populations in the cancer, if a selective pressure such as treatment with a single drug is applied we will select for drug resistance and can (enhance) progression,” he elaborated. “So for treatment, the lessons are to use combinations of drugs to try to kill all the cells, and treat early before the cancer has become too complex.”

Dr. Morgan added that there is also a message about targeted treatment and precision medicine in cancer. “This approach uses treatment to specific mutations and only kills cells with those mutations. You can see the issue with this when a cancer is made up of subclones of different sizes. If a mutation is present in 10% of cells it could be removed but you might not see a clinical response.”

Summing up, he concluded: “The message is, target mutations in the trunk of the cancer that occur early on in its natural history, rather than those that occur late where all that would happen is pruning of the tree.”

SOURCE: Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms
Leukemia 2013.