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The promise and challenges of "Personalized Medicine" for myeloma

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A recent publication in New England Journal of Medicine brought to attention the fact that tumors do not have a single genetic type or signature.  Multiple biopsies revealed diverse genetic patterns within the same cancer samples in the same patients.  No longer can we rely upon a single biopsy to tell the whole story.  Perhaps even more sobering, we need to get used to the notion that planned therapies must encompass considerable genetic diversity and not target a single mutation, which most likely will be only one of a host of mutations.  Commentaries in the Wall Street Journal and from Reuters (London: Kate Kelland) emphasize the same points.

So what does this mean for developing new and better therapies for myeloma?

Firstly, multiple genetic abnormalities (or mutations) are a characteristic feature of myeloma.  When myeloma bone marrow samples are checked, typically numerous chromosomal (or genetic) changes are found.  The potential for multiple genetic subtypes has been known for many years.  In 1984, I questioned whether it was helpful to describe myeloma as a "monoclonal disease" when obviously many genetic subclones were evident at the molecular level (Brit J. Haematology, 1984, 57, 357-363) What is confusing is that the subclones frequently continue to produce the same monoclonal protein, thus masking the underlying heterogeneity.  In a follow-up paper in 1985, I showed that new subclones with additional genetic features are responsible for relapse, and that these new genetic features are part of what can be called "sequential clonal evolution" or stepwise changes that produce myeloma cells resistant to treatment.

So myeloma is sneaky: it can evolve over time.  Multiple pathways within the myeloma cell are involved.  The end result is that no single drug is likely to shut down myeloma cell growth because too many side or back-up pathways can work around any blocked path. In addition, the pathways are going to vary from myeloma cell to myeloma cell and from patient to patient.

This is why combinations of drugs are so important to block off escape routes to renewed myeloma cell growth and further mutations and evolution.  Targeting key pathways is crucial--but not just one pathway!  Some drugs, such as IMiDs (eg. Revlimid), we know are multifunctional.  This means they have effects upon multiple pathways, and that may be a major aspect of the benefit of these agents.

As far as the exact chromosome abnormalities found in myeloma, such as loss of chromosome 13, loss of part of chromosome 17 (17p-), and translocation t(4;14), there are not as yet drugs that target specific pathways affected by these chromosomal changes.  Nonetheless, it appears that Velcade� has particular benefit in patients with t(4;14).  It may turn out that using drug combinations that shut down multiple pathways may be broadly effective for a majority of patients.  Of note, the combination of Velcade (or carfilzomib) plus Revlimid plus dexamethasone (VRD) has substantial benefit for >95% of newly diagnosed patients.  So, without knowing exactly why it works so well, the strategy of multi-pathway blockade seems to be unusually successful.  Studying patients who fail to have success with VRD (or CRD, Cytoxan + Revlimid + dexamethasone) should prove to be especially revealing.

Thus, although the idea of personalized medicine is instantly appealing, it may be that broader strategies to include a majority of patients will prove to be both simpler and more effective.

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17 Comments

Hello Leland:

Please give a call in to the Hotline and we can answer your question more easily. We can give you some Carfilzomib study links; there are a number of ASH abstracts and webcasts on our website as well.

Our number is 1 800-452-2873.

Myeloma, like cancer in general, is an unbelievably complex disease and the more we learn, the more we realize how much we don't know. Multi-drug therapy and re-visiting treatments which once worked but subsequently became ineffective, is an essential part of treatment because of the constantly evolving nature of myeloma---evolution occuring even within a single tumor! New drugs and approaches are necessary as we confront myeloma as a marathon, not a sprint. Thank you Dr. Durie for your clear explanation.

My brother just passed away from multiple myeloma, one year after diagnosis. He needed a personalized treatment. He was started on the routine standard of care. VTD...It made his disease worsen. It was aggressive and he needed specific tests that indicated that at the beginning to personally treat him aggressively. He never knew just what was the statis of his chromosomes, etc He couldn't catch a break. Stem cell transplant lasted less than 90 days and the IT was back with a vengence. Each patient at every center in the world needs access to sophisticated testing to indicate the severity of the disease and then decisions can be made. One size does not fit all. Why can't there be a data bank to indicate to newly diagnosed patients others who have many of the markers that they have so that a comparative treatment could be prepared???

I've also been told that chromosome abnormalities can change during the course of treatment. Is that correct? As such, "personalized treatment" may need to change and we should be doing FISH/cytogentics testing more often?

While this question may not be specifically related to this blog's topic, what kind of monitoring tests should my doctor be ordering for my Smoldering MM? I was diagnosed in 2006 and it has thankfully been stable since then. My M-spike is monitored as is a full chemistry panel, CBC, and protein ELP. Are there other tests that should be monitored periodically in addition to these?

Thank you,
Janet

Hi Janet,
All the tests your physician is doing to monitor your asymptomatic myeloma are correct. In addition, according to Dr. Morie Gertz of the Mayo Clinic, patients with smoldering myeloma should be monitored every six months with skeletal x-rays to rule out bone damage. There are also tests to monitor the possible output of monoclonal light chains in the blood and/or urine (UPEP and serum free light chain assay) that should be done. Here is a link to our publication Understanding Your Test Results: http://myeloma.org/ArticlePage.action?tabId=1&menuId=156&articleId=3177&aTab=-4&gParentType=menuitem&gParentId=156&parentIndexPageId=5&parentCategoryId=72
Please call the IMF Hotline if we can be of further help.

Thank you for all your studies to benefit multiple myeloma patients. My mom began w/ severe back bone pain 20 years ago at age 59 & was diagnosed 5 months later, with advanced MM, I believe 40% of her marrow was affected. She responded well to intense chemo, from mid July thru mid Feb, then for 8 1/2 years was receiving monthly aredia infusions plus getting interferon 3 times a week ( which I realize it is questionable now as to whether or not the interferon really does help MM). Since 9/02 she's been on many different therapies, unfortunately, i do not personally have a record of everything - but dexamethasone, thalidomide/dex and has been on revlimid ( possibly w/ a steroid) velcade, combinations. Typically she was fairly stable for about a year each time. She also had an autogolous stem cell transplant which only lasted about 2 years before her MM became active.
Your article makes me wonder if she should be going back to trying older therapies or not. Her lates treatment was velcade/dex and melphalan - the melphalan given every 9th week. Unfortunately, her MM has not responded. Her oncologist says he has no other therapies to try. I just wonder if there comes a time to give up, or based on your article of how MM is continuously changing whether therapies should be looked at again and retried in possibly new combinations? I should add, she does not have any chromosomal involvement, is now 79, has significant PN, which was why she stopped thalidomide.
Her back bones are significantly affected - ( 4 inches of height already lost in her spine from waist to neck when finally diagnosed correctly in 7/93) and now the spine is quite compressed & she is hunched over significantly, so since she cannot straighten up at all, she measures about 10 inches shorter than her original height pre-myeloma. She has been a fighter, at times says she's just got to give up, other times she sounds like she's hoping there's something else to try.
Based on this article, I feel like we should be trying something that's been tried before. Also, based on another article you wrote- she's never had her sugar level tested while on dexamethasone or steroids...is there any point in testing it post-treatment?

Hello Lisa,
Thank you for your comment and question. Balancing the treatment of your mother's disease and her quality of life is of utmost importance. With that in mind, it seems like there are several decent options like subcutaneous Velcade or a number of clinical trials - pomalidomide, carfilzomib, elotuzumab etc. www.clinicaltrials.gov is great trial search tool you might want to explore.
Dexamethasone affects one's sugar levels while on the steroid. Once the patient is off the dex, that side effect soon disappears. If you haven't already seen Dr. Durie's very interesting blog about sugar, I suggest giving it a read - http://myeloma.org/MtEntryPage.action?source=/imf_blogs/myeloma_voices/2012/03/sugar.html
Please call the IMF Hotline at (800) 452-2873, we can be of further help.

My brother has multiple myeloma and is hospitalized now. He had been taking chemo in pill form for 4 years which became ineffective last year. He is anemic and has Thalasemia(sp). He has had about a months treatment of Velcade thru a portal, and has been getting blood transfusions,as needed, just had one a day ago. He now has a pneumonical patch in each lung and needs help with his breathing. The antibiotics have not helped that much, I guess the infections keep coming. He gets fever last 4 days that come and go. He has a boil, but it hasn't burst and his stomach is bloated. His readings(blood) are not good and his doctors seem puzzled.They have taken him off the Velcade. Is there something that could be mentioned to his team of doctors to try or look into that might help him in any way in his dire situation. He is in his 60s. We need help. Thank you.

Dear V. Martin--
Please call the Hotline so that we can get a better idea of your brother's treatment history and what options might be available to him. We look forward to hearing from you. The number is 800-452-2873.
IMF Hotline Staff

Hi, I'm now in my fifth year with MM. I was offered trans plant and turned it down. All the individuals I met have already died. Not an option I want to follow. However after beeing on Thalomid and Prednisone for the last three years my numbers keep going up and down. Somewhat stable. I have found that Activated Barley which can be ordered over the net has boosted my immune system and makes the side effects of my medicine not so horrible. I am also currently taking Soursop from south america. Don't know how thats going yet until my next round of blood test. That happens tomorrow! Do you have any Ideas, feeling on this coarse of action. I do feel much better and allot stronger, not as tired etc. Your comments would mean the world to me.

I was diagnosed with Smoldering Multiple Myeloma in February 2011 and have been monitored ever since. About 3 days ago, I developed really bad lower back pain and then two days ago, developed bad pain in my breastbone. I haven't done anything that would cause either pain, and it's bad enough to bring me close to tears. Should I be worried about this? Could this be related to the myeloma? Also, the last time I saw my doctor was Feb of 2012, could I go from smoldering to stage 1 in the span of a few months?

Jackie I don't know what your going through; but a friend of mine has MM. I know God has put natural plants on earth. There is a couple things you can try; they wont hurt to try. One is three teaspoons of pure maple syrup with a teaspoon of backing soda. Heat up in a small sauce pan til the baking soda melts with the mixture. Do this two to three times a day. Next there is a product out that's called (HZ) you can get at a very little cost. I believe you can get this at a GNC store. God bless you and may your life be many more to come.

Hello Jackie,
One can experience bone pain and still be smoldering. That said, it's advisable to contact your doctor and inform him/her what you are experiencing - perhaps an imaging test is in order.
Please call the IMF Hotline if we can be of further help.

I took a low dosage of Revlimid for almost two years,alsolow dose of dexamethsone, with aredia treatment every two months. My result were great but my body had a bad reaction by slowly developing NP,some memory confusion. Now I need to start treament again and want to know why I can't stay on the low dose of Revlimid but with a different plan as to when I take it, (such as instead of everyweek ..every other week). I responed well and for along time had no side effect. But I am not a dreamer, I realize this illness is deadly and unpredictable... I know I will need to move on to some of the other more toxic drugs at sometime.

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