[suzierose]

Reason to LOWER DEX dose...less Dex is better

by suzierose on Sun Jul 08, 2012 6:36 pm

Less Dex is more effective when given concurrent with lenalidomide...
This should be reassuring for multiple myeloma patients who think lower doses of dex are not effective.

Lenalidomide needs IL-2 to enhance NK-cells that kill multiple myeloma cells...dexamethasone suppresses IL-2 and stops that therapeutic effect of lenalidomide. The effect of dex is long-lasting and continues even when it is discontinued:

"....recently identified that dexamethasone results in suppressive alterations of NK cell receptor expression, preventing the lenalidomide-induced expression of the critical NK cell activating receptors NKG2D and NKp4 (unpublished data), resulting in further abrogation of NK cell function. Our observations have recently been confirmed by others, in clinical observations when dexamethasone was used at > 160 mg per cycle.7 We have recently extended these observations via our ongoing analysis of the immunology in patients with newly diagnosed multiple myeloma enrolled on a range of lenalidomide and dexamethasone dose combinations. We have been able to compare the NK cell function in patients who have yet to be exposed to any therapy and following exposure to either Lenalidomide alone or Lenalidomide in combination with very low dose dexamethasone of 60 mg per cycle. In these comparative analyses we have found, somewhat reassuringly, that if the dexamethasone is used at these very low doses (< 60 mg / cycle) it did not adversely alter the expression NK cell activating receptors (except for DNAM-1) in patients with multiple myeloma (Fig. 1) indicating that NK cell function may well be preserved in vivo.

snip...Overall, our findings indicate that the immunostimulatory capacity of IMiDs in clinical practice are lost when used in combination with dexamethasone, potentially denying patients the full benefits of immunological control of multiple myeloma."

We would conclude that the future design of clinical trials to examine immunologically mediated mechanisms of action must limit the exposure of patients to immunosuppressive agents such as corticosteroids and similarly must incorporate prospectively immunological biomarkers to ensure that the intended immuno-stimulatory effects are actually delivered."

http://www.landesbioscience.com/journals/oncoimmunology/article/18963/?show_full_text=true

[Nancy Shamanna]

Re: Reason to LOWER DEX dose...less Dex is better

by Nancy Shamanna on Sun Jul 08, 2012 8:20 pm

Hi Suzierose..Thanks for posting the really interesting paper by the three Australian scientists. Truly it would seem to be a 'win win' situation if a low dose of Dex was found to be more effective with IMID's than a high dose. Interesting that the preliminary research was done 'in vitro' (outside the human body), and then advanced to the 'in vivo' situation.

OK, you must excuse my rusty immunology knowledge, and of course with some of these papers it would really be of help to have post-graduate degrees in the subject at hand. Why is it important that T-cells (cell immunological response I think) are encouraged...is it the lenalidomide that is stimulating that? What is an 'immumodulatory' response anyhow? I guess that with the bortezomib type drugs we are getting 'angiogenesis', and with the IMID's it is a different type of medicine?

I met my husband Dilip back in the 70's, while studying microbiology, and at one point I was taking a class in immunology for which he was a teaching assistant! If you don't mind me sharing this...it is our 35th wedding anniversary today! My theory is, if we can make it to 35, we can make it to 40 years. (With the help we have had from medical science of course!) The whole 'myeloma' problem has made me appreciate cell biology research even more than ever!

But anyhow, thanks for sharing that vital bit of info, and maybe more studies will corroborate that indeed 'less is more' in the realm of 'dex' treatment. I doubt that anyone would really mind that!

[suzierose]

Re: Reason to LOWER DEX dose...less Dex is better

by suzierose on Wed Jul 11, 2012 1:14 am

Hi Nancy!

I hope you had a lovely anniversary!!

My 32nd anniversary is on the 12th. We met in college both studying as science majors. Science majors have such limited time vs. other more liberal arts majors. I still recall being in lab for entire afternoons when others were out enjoying the wonderful weather, could see them from the window in the lab, as we labored.

You asked:
Why is it important that T-cells (cell immunological response I think) are encouraged...is it the lenalidomide that is stimulating that?

Our T-cells produce Killer cells, lenalidomide stimulates them to produce killer cells via IL-2. Which attack cancer cells.
http://www.nobelprize.org/educational/medicine/immunity//immune-detail.html

You also asked:
What is an 'immumodulatory' response anyhow? I guess that with the bortezomib type drugs we are getting 'angiogenesis', and with the IMID's it is a different type of medicine?

Bortezomib has another mechanism of action, not an anti-angiogenesis effect.

Lenalidomide is an immunomodulatory means that they modulate the immune system. Myeloma changes how our normal immune system function. IMIDS intervene in that dysfunction and helps the system do what it normal does. One of the ways it does that is by modulating the production of angiogenesis (production of new blood vessels) cancer cells need a blood supply to survive. Lenalidomide inhibits the production of new blood vessels for their survival.
That is one way it modulates the immune system.

"The immune system is comprised of cellular (macrophages, dendritic cells, NK cells, T cells and B cells), and humoral components (antibodies, cytokines). The immune system can prevent development of cancers by eliminating or suppressing oncogenic viral infections, altering the inflammatory milieu conducive to tumor genesis, and by immune surveillance by identifying and destroying transformed cells before they can cause harm[5].

Lenalidomide has been shown to modulate different components of the immune system by altering cytokine production, regulating T cell co stimulation and augmenting the NK cell cytotoxicity. Immunomodulatory properties of Lenalidomide are implicated in its clinical efficacy in multiple myeloma, CLL and myelodysplastic syndromes; where the disease pathogenesis involves in part a deregulated immune system in the form of altered cytokine networks in tumor microenvironment, defective T cell regulation of host-tumor immune interactions, and diminished NK cell activity."
http://www.jhoonline.org/content/2/1/36/

What this article is saying is that, lenalidomide needs IL-2 to potentiate NK cells that kill the myeloma cells, but it does not do that withOUT IL-2. However, dexamethasone, suppresses IL-2 which means that lenalidomides effect is diminished since there is less IL-2 when on dex. That means that lower doses of dex, decrease IL-2 suppression that lenalidomide needs to increase NK-cell activity.

Makes you wonder if we need dex at all, when on lenalidomide....clinical trials though show increase response with dex plus lenalidomide vs. lenalidomide alone. I think the increase was 4% though...so it begs the question..do we need dex at all? While it has been a traditional mainstay, perhaps now..it does more harm than good...along with it's 'steroid mania" that we ALL would prefer to do without...not to mention the muscle loss and risk of diabetes along with lipodystrophy ( fat belly, moon face etc).

Hope this helps in providing answers to your questions!

Celebrating our anniversary after yours!! Hope ours is as great as your..ahhh romance!!

suzierose

[Nancy Shamanna]

Re: Reason to LOWER DEX dose...less Dex is better

by Nancy Shamanna on Wed Jul 11, 2012 9:56 am

Thanks Suzierose, for the nice reply! I should know more about immunology, and it's sad that it takes a life-threatening illness for one to get more interested in that again, but that is true in my case. I am re-reading 'How the Immune System Works' by Lauren Sompayrac, which we bought three years ago when trying to puzzle out everything 'myeloma'.

Well, and this is just my experience, with a low level of lenalidomide which I took for 'maintenance' or in another sense, to completely put me into remission after my ASCT, I wasn't prescribed any dex at that time. Having already taken 'dex' with my induction chemo with bortezomib, I was relieved not to have to take it again, since it just added another strange dimension to the psychological stresses I was already having to endure. But that is not to say that I would not have had it were Revlimid given to me as a first treatment Of course Revlimid was not available in Canada at that time, so that wasn't an option. In the last few years, treatments have been changing almost yearly it seems, so what one was given three years ago probably wouldn't be the same now.

Have a very nice anniversary yourself, and enjoy your upcoming year together too! We loved our trip 'up north'..it was so interesting. We will go again sometime and explore some more.