[suzierose]

B Cell Agents...response vs. survival

by suzierose on Mon Sep 19, 2011 3:38 pm

Hi,

Continuing to explore the new innovative agents and the paradigm shift for the Cancer Model where the Cancer Stem Cells (CSC) are recognized/designated as "tumorgenic" or "tumor initiating" vs the plasma cells which are the targets in conventional chemotherapeutic regimens.

I had been focusing on response rates (RR) as they do decrease side effects and increase quality of life (QOL) for the disease. I am now beginning to wonder if disease response is the appropriate surrogate market for survival. i.e. does response predict survival? The studies seem to say that for multiple myeloma neither the magnitude nor kinectics of clinical response impact survival. Is that the correct deduction? Based on studies read, the most intensive therapy for multiple myeloma, SCT or marrow ablation provide no overall survive in the national intergroup trial (Barlogie 2006) nor in 2 meta analyses (Levy 2005/Koreth2007).

Additional based on the CSC paradigm while bortezomib and lenalidomide have significant activity vs multiple myeloma plasma cells they exhibit little activity vs multiple myeloma CSC and now I am reading about secondary malignicies with lenalidomide in newly diagnosed patients as maintenance therapy.
Which makes me ponder, are the benefits (PFS)greater than the associated toxicities when you consider cancer cell resistance?

All of which is leading me to look at the monoclonal antibodies out there like I-131Tositumomab and rituximab which have no activity vs multiple myeloma plasma cells but do have activity against CSC. The other agent of interest is elotuzumab, as all of these agents are attacking the B cells vs. plasma cells, if I am understanding the studies.

Which test would I look at that would indicate if I am in the 25% of multiple myeloma pts that have the CD20 antigen? Would that be the FISH test?

I would like to have feedback regarding the monoclonal antibodies and their safety profiles along with any other agents that multiple myeloma specialists have seen as having efficacy against B cells in multiple myeloma. Also the I-131 Tositumomab study was started in 2005 at U of MI and I was unable to find updates at ASCO, ASH or IMF in 2008 or 2010..were updates provided?

Lastly, what are the opportunities in terms of cytogenetics for patients to have their own plasma cells tested to determine what drugs demonstrate efficacy against them in order to select the best chemotherapeutic regimens.

I really appreciate the time given to respond as this process just calls for a lot of evaluation and input from clinicians as opposed to just clinical studie results, in terms of what they are actually seeing in the populations they have treated.

[Dr. Edward Libby]

Re: B Cell Agents...response vs. survival

by Dr. Edward Libby on Wed Sep 21, 2011 12:37 pm

Flow cytometry of the bone marrow will let your physician know if the plasma cells express CD20. Unfortunately, even in patients whose myeloma cells express CD20 studies have seen only minimal response to the anti-CD20 drug Rituximab. Therefore, rituximab is not felt to have significant activity in patients with myeloma.

Other antibodies are in development and we are still learning about their risks and benefits.
In 2011 treatment is individualized (or personalized) according to the cytogenetics etc of a single individuals myeloma. All patients are benefiting from the rapid increase in understanding of the impact of myeloma cytogenetics. We now classify and treat patients according to their cytogenetic risk profile ( see msmart.org).

[suzierose]

Re: B Cell Agents...response vs. survival

by suzierose on Wed Sep 21, 2011 8:22 pm

Thank you Sooo much for your reply !!!

I REALLY appreciate your taking the time out of your busy day with multiple tasks and patient load that you have. You can't begin to know how much I appreciate your taking your time to respond.

When we speak of individualized treatment, I hear cytogenetics in the lab. Where just like antibiotics they do a culture and see what those cells response to and are resistant to..is that correct? We determine MICS for bacteria, can we do that with multiple myeloma plasma cells? If so, who and where and how can I demand that? How can I get the test that shows in the lab what my plasma cells are already resistant to when it comes to conventional therapy?

To me that is critical because it diminishes relapse..and my becoming a refractory patient.

Secondly,what were the outcomes of the study done at U of MI with MCAB like 131 tositumomab that was targeted at B cells?

I very much appreciate your repsonses.

They are extremely helpful.

thank you for your time

[Dr. Edward Libby]

Re: B Cell Agents...response vs. survival

by Dr. Edward Libby on Thu Sep 22, 2011 12:58 pm

Good question but.......I am not aware of any myeloma center performing the type of testing you are describing (exposing indivdual patients myeloma cells to different chemotherapies to determine which is best) at this time. This technique is being used to find new drugs that myeloma could respond to but not to guide therapy for individual patients yet. I did not find the results of the study you mentioned but tositumomab would have little/no effect in myeloma because it is targeted against CD20. As I mentioned earlier anti CD20 therapy has not shown promise in myeloma. Radioimmunoconjugates like tositumomab are effective in lymphoma however. Researchers are looking at other surface antigens on myeloma cells like CD66 to target antibodies against . Antibody therapies for myeloma currently under investigation include elotuzomab (anti-CS1), BT-062 (anti-CD138), SGN40 (anti-CD40), CNTO328 (anti-IL6).
My best recommendation for you in terms of your own therapy is to seek care at a myeloma center that has a large number of studies so that when/if your myeloma relapses you will have many trials to consider.

[suzierose]

Re: B Cell Agents...response vs. survival

by suzierose on Thu Oct 06, 2011 10:12 pm

Thanks so much Dr. Libby!!

Looks like I have to leave B cell agents until I am refractory...hopeful by then we will have found a monoclonal antibody that is effective in multiple myeloma.

I also would like to see the testing done on individual plasma cells to determine what is effective.
My thinking is that they already test plasma cells, so all they would need to do is use some of the patients plasma cells from the bone marrow aspirate to test them in-vitro and learn prior to therapy what the cells are resistant to and what they response to.

I don't know it just doesn't seem to be a very complex concept anymore so than a bacterial culture.
Perhaps, there is something I am missing though in thinking about this.

I am headed to NIH...I think they will have lots of studies, lol.

Thanks so much for your feedback. I appreciate the information and suggestions.

[Mark]

Re: B Cell Agents...response vs. survival

by Mark on Thu Dec 22, 2011 8:26 pm

Suzierose,

I saw this article about Cancer Stem Cell theory and its relationship to Myeloma. Not sure if you had seen it yet. It does discuss the possibility that it is BCells that cause multiple myeloma to relapse.

"The scepticism about her B-cell results forced her to do a more rigorous molecular analysis. In 2008, Pilarski, Belch and Julia Kirshner, then a postdoctoral fellow in Pilarski's lab, showed that a self-renewing population of B cells can give rise to myeloma plasma cells in their three-dimensional bone-marrow tissue model3. “We think these B-cell precursors really were cancer stem cells,” she says, “and that this will be a useful therapeutic model.”

Pilarski's next aim is to find a way of destroying the tumorigenic B cells. She is also investigating whether myeloma patients with higher levels of these cells relapse earlier. The preliminary evidence suggests that they do. “That tells you these early cells are very important, and very bad for the patient,” she says."

http://www.nature.com/nature/journal/v480/n7377_supp/full/480S43a.html

I have seen some references suggesting use of the drug Fludarabine in order to test if that would extend patients PFS in Myeloma. Fludarabine has effects on rapidly dividing and resting B Cells. I used a high dose of Fludarabine at my Allo. Obviously the immunotherapy is what can make the Allo work so well, but if I am getting some help from the Fludarabine I will take it!

Mark

[suzierose]

Re: B Cell Agents...response vs. survival

by suzierose on Wed Dec 28, 2011 12:49 am

Hi Mark,

Thanks for the excellent article ( I had not seen it) on stem cells as the culprit vs plasma cells when it comes to relapse in multiple myeloma.

I kinda refer to this is the 'weed' theory..where the plasma cells represent the top of the plant above the soil, and the stem cells are the root. All gardeners know what happens when you chop off the top of the weed and leave the root. ..your lawn looks good for a short time (PFS) but then low and behold ...it's baaaack.

I first became aware of Matsui, about a week after I was diagnosed, when I saw his webcasts from ASH 2010.
http://myeloma.org/ArticlePage.action?tabId=17&menuId=61&articleId=3146&aTab=-4&gParentType=link&gParentId=5269&parentIndexPageId=305&parentCategoryId=540

I thought his ideas were very exciting, innovative and the type of out of the box thinking we need to change what has been a stagnate landscape for cancer over the last 50 years. I am very hopeful about B cell agents and believe this can be a turning point.

I also really liked how Pilarski scientifically challenged the results from the Epstein/Yacoby at UA, Little Rock. thank goodness for bright minds. like hers, that continue to question the status quo, that have created standards of therapy where multiple myeloma remains incurable. If it is multiple myeloma is Vegas and therapy is Black Jack, I am putting my chips on Pilarski and Matsui.

Interesting that Fludarabine is effective against resting B cells, that sounds promising. Do you have a link to any of the studies? seems it has been available for awhile..so that is positive as it generally means fewer unknowns than knowns when it comes to therapy.

Mark, I am with you all the way...if it helps and you are improving...whoooPEE!!

Bring on the B cell agents....or should I say...just pull the damn weed out from the root?!

thanks again for the article.