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February 2014 Archives : Myeloma Voices

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A recent editorial in Leukemia authored by doctors Shaji Kumar and Vincent Rajkumar of the Mayo Clinic in Rochester, MN, provides a thoughtful overview of the current status of minimal residual disease (MRD) assessment in myeloma. In it, the authors raise three questions: What are the implications of MRD negative status? What is the best method to measure it? And what do the results mean for treatment?

In introducing answers to these questions, the authors identify key aspects of the IMF's Black Swan Research Initiative, including how to interpret MRD test information; which tests to use; and most importantly, how to use MRD test results to improve outcomes and achieve true cure for myeloma patients.

From the patient perspective, it is important to realize that a negative result (MRD-Zero) does not automatically mean a patient is cured. We are learning that sustained MRD-Zero combined with other test results such as stringent CR (sCR) plus negative imaging and/or scan results can indeed translate into cure for a subset of patients. But there is more work to be done.

A Promising MRD Testing Method

The first project of the Black Swan Research investigators team was to identify the most useful MRD method. Flow cytometry was identified as a promising technique, and a collaboration was established with EuroFlow and the University of Salamanca (now also Pamplona) to develop a very sensitive, reproducible method with a computer software readout to truly standardize the method. 

Within the last year this research project has been highly successful and the results will be presented to the myeloma scientific community at a workshop in Salamanca, Spain March 20-21. Groups from the US, Europe and the Asia-Pacific region will participate in this IMF-co-sponsored meeting to reach consensus on this new flow cytometry method for MRD testing. It is strongly anticipated that this can become the new standard test which be both widely available and affordable (approximately $100 per test). The full educational rollout of this test will occur in the coming months.

Development of this test is not the end of the story, but it provides an immediate benchmark for ongoing trials and comparisons with other methods. In the short term, MRD testing is complementary to other methods of response assessment and trial endpoints.

MRD Testing and Treatment Strategies

The important third point is how to change treatment strategies based upon MRD test results? Should treatment be stopped if sustained MRD-Zero is achieved? Is it more prudent to consider some consolidation and/or maintenance therapy? Obviously trials are needed and are in development now. If MRD is positive in the setting of high-risk disease can specific back-up therapy be recommended?

Again, a key area within the BSRI is to determine the sensitivity/resistant patterns of residual clones and initiate appropriate clinical trials. Another scenario is if the residual MRD has an "MGUS signature" pattern. Interestingly, this is probably the most secure situation right now in which we can recommend careful follow-up "off therapy" to see if the residual MGUS is sustained--indicating a functional cure state.

So it is obvious that much exciting work needs to be done--BUT having a reliable test and interpretation strategies are key steps in moving the search for a cure forward!

Stay tuned on this...there is definitely much more to come soon.

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.
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This week there are several interesting items in the news that help us understand how and why monoclonal gammopathy of undetermined significance (MGUS) occurs, and when it may or may not turn into active myeloma.

Matthew Drake and the Mayo Clinic bone research team worked with a group from Sheffield University in the UK to illustrate that the bones in MGUS patients are not normal. MGUS patients have weakened bones versus age and sex matched controls. There is increased porosity ("more holes") in surface bone and reduced bone strength. This is important and at the same time quite puzzling. It is important since we now need to be looking more closely at this to assess if bone treatments, such as we use in active myeloma, need to be considered also for MGUS patients. But the puzzling part is that we associated bone problems with the "B" in "CRAB," features characteristic of active myeloma. 

So we need a new level of scrutiny about the type and severity of bone damage that indicates transition to active myeloma. These indicators are: a positive PET/CT scan; definite lesions on a whole-body low-dose CT scan, and or/multiple lesions on an MRI scan. Just reduced bone density is not specific enough or sufficient. This is certainly not the end of the story in terms of understanding what is happening in MGUS versus the major change that occurs with serious bone destruction in active myeloma.

Another interesting story that caught my attention is the report of the full genetic sequencing of sharks that have cartilage, but no true bone like humans. It turns out that sharks are completely missing all the genes needed to make bone. It also turns out that they are also missing genes linked to the immune and blood system which are part of the same complex. What you may not know is that sharks rarely develop "bone" cancer (such as myeloma). It was thought that this was because cartilage blocks cancer formation. 

I carried out research years ago which revealed that there is some evidence for this idea. If you add cartilage components to myeloma cultures, growth of the myeloma is slowed - a little, but not a lot. Despite this there was a phase of great enthusiasm about "shark cartilage" treatments. And some short-term benefits were seen. But now it is clear that sharks lack hard bones and also lack the cells that can link in with myeloma cells to increase myeloma cell growth. Having hard strong bones is excellent. But these bone cells, if triggered the wrong way, can lead to bone destruction, immune defects, and ultimately myeloma in some cases.

Our old ideas have been turned upside down! It is not the presence of cartilage which makes the difference, it is the absence of bone cells.

Triggering the activity of the myeloma cells is the key aspect of myeloma and true bone destruction. A study from the Swedish team shows that increased Freelite levels are still a reliable indicator of disease progression to active myeloma. Yet another study looking at the overall cell genetics shows that many genes are involved in the activation of MGUS and the predisposition to MGUS in the first place.

So, lots of things in the news. Always many new things to learn. Every new detail allows us to understand better and guide patients with critical decisions for recommended diagnostic testing and treatment choices. 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.