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Researchers Investigate Genetic Changes That Drive The Progression Of Myeloma

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Published: Jul 26, 2013 4:32 pm

Findings from a recent study conducted by a group of European re­searchers show that genetically diverse abnormal plasma cells, known as clones, are pres­ent in all stages of myeloma, from its precursor stages through to its symp­tom­at­ic stage.

These sets of abnormal plasma cells compete against one another, the re­searchers argue, and pro­mote disease progression through a Darwin­ian evolu­tion­ary model — not by ac­cumu­la­tion of additional muta­tions over time, as was previously believed to be the case.

In addition, the investigators found that abnormal plasma cells acquire more genetic mutations as myeloma precursor diseases progress to symptomatic myeloma.

The largest gain in genetic mutations occurred by the time patients progressed from monoclonal gammop­athy of undetermined significance (MGUS) to high-risk smoldering multiple myeloma, both precursors to multiple myeloma.

The researchers state that these findings suggest that the majority of genetic mutations needed to develop myeloma have already been acquired early in the course of the disease, even before symptoms appear.

Since the abnormal plasma cells that are dominant in symptomatic myeloma are already present in high-risk smoldering myeloma, the researchers believe it likely “that high-risk smoldering myeloma is not a distinct disease entity, but is rather a transition state between MGUS and multiple myeloma where the sub-clonal structure is evolving.”

The study authors do not directly address the issue of whether or not, based on their findings, high-risk smol­dering myeloma should be actively treated. They do note, however, that their findings suggest that high-risk smoldering myeloma “would be amenable to therapeutic intervention.”

The European study sheds important new light on the genetic changes that accompany the progression of myeloma. It should be noted, however, that only a very small number of MGUS and smoldering myeloma patients were included in the study. Thus, further research of a similar nature is still needed before the study’s findings can be considered conclusive.

Background

All cancers are defined by one common characteristic: uncontrolled cell growth. In multiple myeloma, the be­havior of plasma cells is no longer tightly regulated, which allows them to multiply out of control.

When functioning properly, plasma cells produce a variety of infection-fighting proteins called antibodies. When a person has multiple myeloma, however, their plasma cells begin overproducing one type of ab­nor­mal antibody, known as a monoclonal protein, that cannot effectively fight infections. In addition, the growth of myeloma cells may inhibit the production of normal blood cells,

Researchers currently believe that the uncontrolled growth of plasma cells occurs over the course of a multi-step process, which gradually transforms functioning plasma cells into cancerous myeloma cells. This transformation requires mutations in the genes that control cell growth and differentiation.

There are two stages of myeloma prior to symptomatic disease: patients first develop MGUS, which can pro­gress to smoldering multiple myeloma and then multiple myeloma.  Most people who develop symp­tom­atic myeloma, though, are not diagnosed until their disease is in the full-blown multiple myeloma phase.

Patients with MGUS or smoldering myeloma have an increased level of monoclonal protein in their blood but none of the symptoms associated with multiple myeloma. The current standard of care is to regularly moni­tor patients with MGUS or smoldering myeloma, but to hold off on treatment until the disease progresses. People with MGUS are less likely than those with smoldering myeloma to progress to multiple myeloma and typically have longer survival than those with smoldering myeloma or multiple myeloma.

Multiple myeloma is characterized by high levels of abnormal plasma cells and monoclonal protein, symp­tom­atic disease, and ultimately, end organ damage. Once the disease has progressed to this stage, treat­ment is necessary.

Plasma cell leukemia is a rare but aggressive form of myeloma that can arise on its own or from myeloma that has progressed.

It was previously believed that myeloma disease progression occurs as a person’s plasma cells acquire more and more genetic mutations over time.

Recent studies show, however, that a person’s myeloma cells are not all genetically identical at a given time.  Instead, there can be several sets of myeloma cells.  Each of these clones has an identical genetic make-up, but the various clones have different genetic make-ups.  In addition, there may be one or more dominant (particularly prevalent) clones; however, the dominant clone can change over the course of the disease, with the presence of a given clone rising and falling over time.

Study Design

In the current study, researchers from the U.K., Italy, and Spain aimed to determine the genetic factors that drive progression of myeloma-related diseases.

Genome sequencing is a technique that can be used to determine the exact makeup of a patient’s genetic information (scientifically referred to as DNA).  By comparing the sequence of genes in a healthy cell to the sequence of a cancerous cell, mutations can be identified and studied.

The full genome of a myeloma cell was first sequenced in 2009 (see related Beacon news).  Since then, researchers have continued to sequence the genomes of myeloma cells from more patients to better un­der­stand which genetic mutations are responsible for multiple myeloma.

The investigators of the current study therefore sequenced the genes of cells from four people with MGUS, four people with high-risk smoldering myeloma, 26 people with multiple myeloma, and two people with plasma cell leukemia, including four cases of high-risk smoldering myeloma that progressed to multiple myeloma.

In order to more precisely define the genetic changes leading to disease progression, the researchers com­pared the genetic sequences of these abnormal plasma cell samples to the genetic sequences of nor­mal plasma cells and identified all mutations. While some genetic mutations do not have any known con­se­quences, other genetic mutations lead to mutations in cell proteins.  Depending on the affected pro­tein’s function, mutation of the protein can lead to myeloma or other types of cancer or disease.

Study Results

Gene sequencing showed that the median number of changes in the DNA that would cause mutations in cell proteins increased with disease progression: MGUS (13), high-risk SMM (28), myeloma (31), and plas­ma cell leukemia (59).

According to the researchers, this finding indicates that MGUS is much less genetically complex than mye­loma, but high-risk smoldering myeloma is very similar to myeloma in terms of genetic complexity.

Samples taken from patients before and after progression from smoldering myeloma to multiple myeloma showed that these patients’ abnormal plasma cells had around 19,000 mutations during both stages of the disease compared to healthy plasma cells.

Among these mutations, 93 percent were present in both the smoldering myeloma and myeloma samples.  However, 81 percent of the mutations were present in less than half of the tumor cells, and only 3.3 percent of the mutations were present in more than 90 percent of the myeloma cells.

The researchers state that these results suggest that smoldering myeloma and multiple myeloma contain many clones, most at low frequencies, and that disease progression occurs as a result of competition be­tween the clones.

One of the patients who progressed from smoldering myeloma to myeloma received treatment with Revli­mid (lenalidomide) and dexamethasone (Decadron). After treatment, one of the patient’s plasma cell clones became less dominant after treatment, with mutations present in 80 percent to 100 percent of cells prior to treatment, but 0 percent to 20 per­cent after treatment.  At the same time, a number of clones were un­af­fected by treatment, and one clone became more dominant at progression, with mutations in 0 percent to 20 per­cent of cells while in the smoldering phase and 40 percent to 60 percent after progression.  The investi­ga­tors suggest that resistance to treatment may explain the latter results.

An average of 433 novel and unique genetic mutations were acquired during the transition from high-risk smoldering myeloma to myeloma.  In addition, many mutations present during smoldering myeloma re­turned to normal after progression to myeloma. On average, 19 mutations were gained and 36 were lost each month.

Only a few of the new mutations were in regions of the genome that pertain to proteins, and only one smol­der­ing myeloma patient developed a mutation during the transition from smoldering to symptomatic mye­lo­ma that would result in a protein mutation.  The researchers state that the affected protein, known as RUNX2, which is essential for the maturation of cells that form bone, could be responsible for disease pro­gres­sion.

For the other smoldering myeloma patients who progressed, the researchers did not find any new dupli­cated or deleted chromosomal regions after progression to myeloma.  They state that these findings sug­gest, for at least these three cases, that changes in the number of chromosomal regions occur in earlier stages of the disease and do not contribute to the progression from smoldering myeloma to symptomatic myeloma.

The researchers note that disease progression could also result from segments from two chromosomes being swapped (translocation). They found that one patient acquired a translocation involving chromosomes 13 and 21 that disrupted the BRCA2 gene, which is involved in the repair of chromosomal damage. A dif­fer­ent patient acquired three different translocations involving the UNC5D gene, which suppresses the growth of tumor cells.

For more information, please refer to the study in the journal Leukemia (abstract).

Photo by victor_sween on Flickr – some rights reserved.
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4 Comments »

  • Glyn said:

    I was diagnosed with MGUS back in Autumn 2010. I did not realise that this was a specific indicator of possible myeloma until some six months later when I was confirmed as having the cancer.

    As you might imagine, this came as somewhat of a shock, as I had had no indication of this – it only arose as a consequence of annual blood tests after a mild heart attack back in 2002!

    The diagnosis was followed up – pretty quickly – with 18 weeks of chemotherapy (by tablets) then a stem cell extraction and transplant and four weeks’ rehabilitation in the Christie Hospital in Manchester.

    Since then (after a few months re-assimilation to normal life) I have returned to my old habits of sporting activity – playing golf, umpiring cricket & field hockey, etc.) I have four-weekly infusions of calcium (Zometa) in my local hospital – plus the inevitable blood tests – but this is the only ongoing treatments I have, and so far, so good. The latests tests indicate that the paraprotein levels oscillate but are not, so far, problematic.

    I am much reassured by seeing previous correspondence showing several years’ history – I only hope that same will happen to me !!

    All good wishes to fellow suffers.

  • Jan Stafl MD said:

    Thank you Beacon Staff for a detailed analysis of this Leukemia journal study. I suspect genomic analysis of bone marrow or plasmacytoma biopsies will become the standard of care in the near future. It should help delineate the risk of progression of “smoldering myeloma” to outright MM, allowing timely treatment. And especially in recurrent or refractory MM, it may open up new pathways of treatment for many.
    In my case, a genomic analysis of the original rib plasmacytoma biopsy from two years ago recently revealed the presence of a BRAF V600 mutation, found in only 3-4% of MM. This helps explain why I have a recurrence less than a year after my ASCT. More importantly though, it gives me the possibility of using BRAF inhibitors, three of which are now FDA approved for metastatic melanoma, where >50% of pts. have this mutation. I am presently on Kyprolis, but am exploring further options, either in a trial, or using approved treatment for other cancers in my hometown Eugene.
    The MM journey takes unexpected turns, full of challenges and opportunities, for all of us. May we all live life to the fullest every day! Jan

  • Suzanne Gay said:

    Fascinating, but depressing…I’m up against genetics & molecular biology, and all the time I am swimming or laughing, evil is going on inside, invisibly.

  • nancy shamanna said:

    Thanks for this interesting article. Thousands of mutations go into making myeloma, which surprised me. Towards the end of the article, the BRCA2 gene is mentioned. It seems that the disruption of this gene leads to increased risk of breast, ovarian, prostate, pancreatic,and malignant melanoma cancers. The mutations can also lead to bone marrow suppression, and a sort of anemia (Fancom), which can lead to leukemia. (Source..Wikipedia).

    With all of the research going into all of the cancers which are affected by this gene, perhaps some overlap of knowledge will occur, and help the myeloma research also.