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Black Swan Research Initiative's Distinctively Different Pathway to a Cure

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Earlier this year the IMF launched the Black Swan Research Initiative, a breakthrough approach to finding a cure for myeloma. Following in our footsteps, others are ramping up their myeloma research efforts. This is great news for myeloma patients, and in science it's particularly useful to have lots of people examining data in different ways.

But BSRI's unique approach to finding a definitive cure for myeloma continues to set it apart from all other myeloma research efforts in the following fundamental ways:

  • BSRI is an actual research project aimed at finding a functional cure for myeloma, not an open-access platform to support external research. 
  • A core tenet of BSRI is that many patients might be cured and don't know it - because previously we have lacked the sophisticated tests necessary to determine that Zero Minimal Residual Disease - MRD-Zero - has been achieved. The change in available testing will inform and refine BSRI protocols to highlight a pathway to a cure. Using the latest procedures involving flow cytometry and full DNA sequencing, we will be able to detect down to less than one cell per million of myeloma.  Thus, we can identify who has been cured, and what combinations of therapies led to that cure.
  • Using Big Data to look for individual differences, as others are doing, is expensive, difficult and - if the process includes developing a new drug for each patient - time-consuming. What makes more sense is BSRI's strategy of using Big Data to find the similarities among patients in large, distinct groups. If the BSRI testing protocols find, for example, a patient with "Category A" characteristics has reached MRD-Zero, then the same treatment course can be applied to others in Category A. Will the cured patient's therapy regime work on all similar patients? No - but when it does work that will yield a new, more refined set of characteristics, a "Category A-1" that responds in like manner. And so on.
  • Others are attempting to use individual molecular data to develop new targets for drugs. In other words, find a mutation, target the mutation. This sounds great but is a long, arduous process that in general does not work. Better to avoid the mutations that occur in myeloma cells over time by treating the myeloma early. To do so, BSRI proposes administering therapy that is known to work in combinations of multiple mechanisms. Improved detection of the disease and its clones will allow us to monitor the therapy - and determine what's working - from an early point in the disease.

Understanding the molecular genetics of minimal residual disease (MRD) and using the best combinations of drugs to eliminate the MRD will lead to cures. To get there, we are currently carefully designing precise studies in clinical trial settings that will begin early next year.

In the meantime, we wish all myeloma researchers success. When it comes to the Black Swan Research Initiative, we expect success.

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. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. 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. Friday summer hours are 9 am to 3 pm PDT. Thank  you.


14 Comments

Excellent explanation. Had not been totally sure of the methodology. Thank you, Dr. Durie.

Thanks --- appreciate the feedback !

"A core tenet of BSRI is that many patients might be cured and don't know it - because previously we have lacked the sophisticated tests necessary to determine that Zero Minimal Residual Disease - MRD-Zero - has been achieved. The change in available testing will inform and refine BSRI protocols to highlight a pathway to a cure. Using the latest procedures involving flow cytometry and full DNA sequencing, we will be able to detect down to less than one cell per million of myeloma. Thus, we can identify who has been cured, and what combinations of therapies led to that cure."

I thought that was already being done.

"Multiple Myeloma (MM) is considered to be an incurable disease, but in some patient long-term survival can be achieved after high dose chemotherapy followed by autologous or allogeneic stem cell transplantation. Those patients, who achieved molecular remission, have a high probability of long-term disease-freedom and of cure."

"The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of MM in an auto-/allo SCT approach."
https://ash.confex.com/ash/2011/webprogram/Paper42900.html

What is the difference between Black Swan and what Dr. Kroger presented at ASH a few years ago? Seems like the same concept to me. Everybody knows that if you want to cure cancer patients you need to apply curative therapy upfront. Unfortunately few patients are ever cured after they relapse.

"To do so, BSRI proposes administering therapy that is known to work in combinations of multiple mechanisms."

Dr. Emil "Tom" Frei is credited for showing that in the 1950's for childhood leukemia. That is hardly a new, innovative idea.

Thanks for your comments, Mark. Those are some interesting points for me to respond to.

MRD needs to become more sensitive and standardized - so yes, we've been working on that, but it is an ongoing global effort by the BSRI team. At the same time, patients are being precisely restaged to determine if the word "cured" can be applied. Obviously careful validation is required, and this too is a global effort.

As for the use of drug combinations, this indeed is not a new approach. A classic example is the curative regimen for testicular cancer developed by Dr. Larry Einhorn in 1987. What IS new is the application of this methodology to myeloma as BSRI is doing.

Finally, there is the expectation that this approach can succeed because we have multiple active drugs, new ways to classify patients and the ability to monitor the residual disease at unprecedentedly low levels. All of this allows us to push forward to achieve a cure.

Having been diagnosed two years ago, I am happy to say I am in complete remission!! My doctor has been checking my blood since my transplant and is now saying that I 'could be' cured. Two questions:

1) What is a reasonable amount of time to get low numbers before determining that the patient "is" cured?

2) Is there any tests that are reasonably priced to learn my more accurate counts?

I am happy to be where I am now. But it would be a huge relief to drop this subject from my daily thoughts.


On a different topic:
I am a volunteer fireman and recently learned that "53% of firemen" are subsequently diagnosed with multiple myeloma!!! Is the IMF aware of this, and if so what are their actions?

Thanks a bunch for your response.

Phil

Phil,

IANAD (I am not a doctor) but just wanted to make sure to address your comment about firefighters from a statistical standpoint. You mention that 53% of firemen are diagnosed with multiple myeloma. This is incorrect.

With that said, you would be correct to say that firefighters have a higher risk of MM than the general population. Some studies suggest that firefighters are more likely to be diagnosed with multiple myeloma than the general population. That is so say that if you selected the same number of firefighters and non-firefighters from the population, the general population might have a certain rate of diagnosis, but that firefighters would have a 50% higher diagnosis rate. So let's say for argument sake that you had a rate of 1% of the population experiencing MM, then you could expect the rate to be 1.5% in firefighters. Keep in mind that this is just an example and neither 1% or 1.5% are real numbers.

Hopefully that helps a bit.

Jim

Being diagnosed with MM, I was treated with chemo and a transplant over the previous two years. My question is, how concerned should I be about secondary cancers? I have since been diagnosed with melanoma which was removed. But I am now concerned about things that I cannot see or have symptoms of..?

Are there any tests to determine if I have any of those 'other' things lurking out there? How worried should I be?


NOTE: It would be a great idea to post in a FAQ those questions that people send to you that are relevant to others so that they could review them.

Thanks,

Phil

Although this isn’t the appropriate place to address personal medical questions, creating an FAQ answering questions like yours that may be generalized to others is a good idea. Thanks for the suggestion, Phil.

You mention 1 cell per million as a potential cure for multiple myeloma. Is that a low enough level? I know that reagent grade chemical have impurities of one part per million (ppm). I worked in the integrated circuit industry and we were doping (adding and controlling impurities)to levels of one part per 10 million, which meant we had to grow silicon to around 1 part per billion.

Thanks for the comment, Jon. That is correct – lower than one cell per million is hoped for and needed. Actually Zero is best. The DNA test should show less than 1 per billion.

For many years, I have been wondering if any kind of survey has ever been issued to ask us questions that would determine if we have had similarities in events in our lives that would be indicators to the cause of our MM. the survey would likely be 50 questions long and would ask questions such as:

At what age did you have your first x-ray and what was it for?

¨ a broken bone

¨ teeth

¨ chest

¨ other _____________

i. What were the results i.e. cast, several more X-rays’, healed, continuing problems, tooth fillings (what kind, gold, mercury, porcelain). Please explain below.

___________________________________________________________________________________________________________________________________

In what city did you grow up and what was the major industry there?

¨ City _________________

¨ Industry

o Industrial

o Agricultural

o Research

o Manufacturing

o Other ________________________

Did you ever work in any of those industries?

¨ Yes

¨ No

If yes, which one? _________________________

If no, what jobs have you held and what were the physical conditions (sitting, standing, bending, lifting, etc)?

If no, what jobs have you held and what were the inert conditions (inhaling fumes, chemicals, etc)?

Please explain___________________________________________________________________

The idea is that a study be done. I think most of us would be willing to complete the survey if it would lead to the cause of our MM or even if it could categorize the type (as in the BSI article referring to “Category A”. The results might give answers similar to the ones in studies that linked smoking to lung cancer and asbestos to mesothelioma.

Please respond to me so I can know your thoughts. If the idea has merit I would like to work on it a survey and tallying the results.

Thanks,

Shirlee Fuqua

323.931.9301

So, if this means that BSRI focus on clinical trial, but not basic research?

Thanks!

No. Finding a treatment that produces a cure is definitely a clinical aspect of the project. However, developing the molecular tests, sequencing, monitoring, risk selection and drug combination optimization requires fundamental lab studies.

Dr Durie,

Thank you for doing this blog and for your work in the field. I just to make sure I am understanding this so I'll rephrase what you wrote and if there is anything I am wrong about, please correct me. :)

There are patients in the general population that had MM but are now essentially cured as far as our current generation of tests detect. The problem is that our tests to detect molecules that indicate MM are now the bottleneck in determining if a patient is cured or simply has such small levels that they've "beat" the test. As such we need more precise tests to be able to look at patients that may be cured vs patients that are in remission.

Am I understanding this correctly?

Thank you again,

Jim

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