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Big news (not unexpected): myeloma relapse cause discovered

by Dan D on Mon Sep 09, 2013 2:33 pm

https://myelomabeacon.org/pr/2013/09/09/researchers-discover-root-cause-multiple-myeloma-relapse/

It's all in the progenitor cells - which are UNTOUCHED by Velcade. This also highlights a curative pathforward. Kill those fu$%*ng progenitor cells.

Cancer researchers discover root cause of multiple myeloma relapse

Clinical researchers at Princess Margaret Cancer Centre have discovered why multiple myeloma, an incurable cancer of the bone marrow, persistently escapes cure by an initially effective treatment that can keep the disease at bay for up to several years.

The reason, explains research published online today in Cancer Cell, is intrinsic resistance found in immature progenitor cells that are the root cause of the disease – and relapse – says principal investigator Dr. Rodger Tiedemann, a hematologist specializing in multiple myeloma and lymphoma at the Princess Margaret, University Health Network (UHN). Dr. Tiedemann is also an Assistant Professor in the Faculty of Medicine, University of Toronto.

The research demonstrates that the progenitor cells are untouched by mainstay therapy that uses a proteasome inhibitor drug ("Velcade") to kill the plasma cells that make up most of the tumour. The progenitor cells then proliferate and mature to reboot the disease process, even in patients who appeared to be in complete remission.

"Our findings reveal a way forward toward a cure for multiple myeloma, which involves targeting both the progenitor cells and the plasma cells at the same time," says Dr. Tiedemann. "Now that we know that progenitor cells persist and lead to relapse after treatment, we can move quickly into clinical trials, measure this residual disease in patients, and attempt to target it with new drugs or with drugs that may already exist. Dr. Tiedemann talks about his findings in this video:

In tackling the dilemma of treatment failure, the researchers identified a cancer cell maturation hierarchy within multiple myeloma tumors and demonstrated the critical role of myeloma cell maturation in proteasome inhibitor sensitivity. The implication is clear for current drug research focused on developing new proteasome inhibitors: targeting this route alone will never cure multiple myeloma.

Dr. Tiedemann says: "If you think of multiple myeloma as a weed, then proteasome inhibitors such as Velcade are like a persnickety goat that eats the mature foliage above ground, producing a remission, but doesn't eat the roots, so that one day the weed returns."

The research team initially analyzed high-throughput screening assays of 7,500 genes in multiple myeloma cells to identify effectors of drug response, and then studied bone marrow biopsies from patients to further understand their results. The process identified two genes (IRE1 and XBP1) that modulate response to the proteasome inhibitor Velcade and the mechanism underlying the drug resistance that is the barrier to cure.

Dr. Tiedemann is part of the latest generation of cancer researchers at UHN building on the international legacy of Drs. James Till and the late Ernest McCulloch, who pioneered a new field of science in 1961 with their discovery that some cells ("stem cells") can self-renew repeatedly.

The science has continued to advance unabated ever since, and notably with key discoveries by Dr. John Dick of cancer stem cells first in leukemia and next in colon cancer. Dr. Tiedemann's new findings underscore the clinical importance of understanding how cells are organized in the disease process. ...

Dan D

Re: Big news (not unexpected): myeloma relapse cause discove

by Nancy Shamanna on Mon Sep 09, 2013 2:54 pm

Thanks for posting this press release and video, Dan D. It's so interesting that research can now focus on thousands of patients' genetic profiles. That was probably done by 'DNA' sequencing.
Are the 'progenitor cells' the same as stem cells? I couldn't quite follow all of the logic here, but luckily, will get a chance to hear Dr. Tiedmann speak at our upcoming patient seminar in Calgary, on Sept 21. Our support group is putting this together in conjunction with the Tom Baker Cancer center.

Dr. Tiedmann only mentions proteasome inhibitors in this excerpt. Perhaps this is why another type of drug, the IMID's, of which Revlimid is a type, are used in 'maintenance' therapy'. Perhaps the fewer no. of progenitor cells left in one's system after treatments, the longer to relapse?

Nancy Shamanna
Name: Nancy Shamanna
Who do you know with myeloma?: Self and others too
When were you/they diagnosed?: July 2009

Re: Big news (not unexpected): myeloma relapse cause discove

by Mark on Mon Sep 09, 2013 3:07 pm

Hi Dan D,

I was just about to post this link. I was going to post it in the old thread here on the Beacon Forum that Dr. Guido Tricot made a similar point about the novel agents and the myeloma stem cell/progenitor cell(s):

https://myelomabeacon.org/forum/interesting-interview-with-dr-guido-tricot-t2075.html

"We used to think that every cancer cell was the same – and had the same possibility of causing the cancer to come back. Now we know that there are two different sets of myeloma cells. There’s the large majority of the cells are what we call more mature myeloma cells and those cells cannot cause the disease to come back, while there’s a small fraction of cells (usually less than 1% of the cells) that we call myeloma stem cells which have the capacity to have the disease come back if you don’t eradicate them. Most of the treatments, especially the newer treatments such as Velcade, Thalidome, and Revlimid, have good effects on the more mature cells but do not have any effect on the myeloma stem cells. If you cannot eradicate myeloma stem cells, you cannot cure this disease."

Mark

Mark

Re: Big news (not unexpected): myeloma relapse cause discove

by Dan D on Mon Sep 09, 2013 4:38 pm

So the question is what are the clinically relevant targets or markers on these progenitor cells? Notably this article - published in one of THE BEST journals - suggests that CD20 is found on the surface of such progenitor cells. What's notable is that CD20 is the target of the approved Ab drug Rituximab. That said, apparently studies using Rituximab in multiple myeloma patients have met with mixed results - at least in terms of eliminating such cells - but I am no expert on this work (which I think is limited). So maybe these studies need to be revisited or reworked with this drug.

Dan D

Re: Big news (not unexpected): myeloma relapse cause discove

by DanaH on Mon Sep 09, 2013 6:49 pm

Hey Dan D and Mark,

Please bear with me as I don't understand any of the science behind the multiple myeloma monster..but I wondered which cells are harvested for a Stem Cell Transplant?? Sorry if this seems like a simple minded question, as it most certainly is, so thanks if either of you find it in your heart to respond to someone who even struggles with the layman's explanations of all of this.
All the best to both of you.
Dana

DanaH
Who do you know with myeloma?: Myself, SMM as of 1/2012
When were you/they diagnosed?: 1/2012
Age at diagnosis: 54

Re: Big news (not unexpected): myeloma relapse cause discove

by WendyB on Mon Sep 09, 2013 8:44 pm

Dana,
The stem cells that are harvested before a transplant are the most basic of stem cells...those that normally live in the bone marrow and lead to the formation of all other stem cells and eventually the production of red blood cells, white blood cells and platelets. The Melphalan given prior to the transplant kills the bone marrow and along with it not only the bad myeloma cells but all of the good stem cells.
By the way...the Plasma cell that becomes cancerous (our monster Myeloma cells) is one of the white blood cells responsible for producing antibodies.

Hope this helps...

Wendy

WendyB
Name: Wendy B
Who do you know with myeloma?: myself
When were you/they diagnosed?: October 2006
Age at diagnosis: 41

Re: Big news (not unexpected): myeloma relapse cause discove

by DanaH on Mon Sep 09, 2013 8:55 pm

Thanks Wendy,
that does help. I wondered if they collected these "progenitor cells" that were the problem and re-infused these, but it sounds like they collect just the stem cells that eventually can turn into the problem cells.
Best to you,
Dana

DanaH
Who do you know with myeloma?: Myself, SMM as of 1/2012
When were you/they diagnosed?: 1/2012
Age at diagnosis: 54

Re: Big news (not unexpected): myeloma relapse cause discove

by DanaH on Mon Sep 09, 2013 11:57 pm

@ Nancy Shamanna,
I have a friend who doesn't live too far from Calgary and would very much like to attend your support group patient seminar on Sept 21 in conjunction with the Tom Baker Cancer center. Would this be possible or must one be a member to attend? Any details would be most appreciated. Many thanks in advance for whatever information you can share.
All the best to you Nancy,
Dana H

DanaH
Who do you know with myeloma?: Myself, SMM as of 1/2012
When were you/they diagnosed?: 1/2012
Age at diagnosis: 54

Re: Big news (not unexpected): myeloma relapse cause discove

by starmanjones on Tue Sep 10, 2013 8:40 am

This is OLD NEWS. Dr. William Matsui published this in "Blood" over 8 years ago. Shocked credit wasn't given to him by the Canadian researchers.

The article referenced above, that CD20 is expressed on the progenitor cells, comes from Matsui.

A real disappointment drug companies aren't targeting the cure by going after these cells.

starmanjones

Re: Big news (not unexpected): myeloma relapse cause discove

by Nancy Shamanna on Tue Sep 10, 2013 9:06 am

Hi Dana, re; 'yOU, Me and Myeloma Conference 2013

The conference is posted on the website of the Southern Alberta Myeloma Patients Soc. (SAMPS) You can click up a registration form and email it in to us. There is a limit of 200 on the conference so your friend should do this soon! There is a small fee to cover lunch. Hope that helps !

Nancy Shamanna
Name: Nancy Shamanna
Who do you know with myeloma?: Self and others too
When were you/they diagnosed?: July 2009

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