16 Comments »

Gary said:
I read an article in the WSJ yesterday which seemed to question the utility of your top journal article. Scientists have discovered that for kidney cancer the mutations for an individual different dramatically between locations on the tumor and at different metastasized locations in the body. In other words, a single personalized genetic signature against which to treat the cancer did not exist. This seems to cast uncertainty on the usefulness of the whole area of personalized medicine. I suspect that it is a long way from kidney cancer to MM but it would not surprise me if the gene array work performed on my bone marrow biopsies expressed similar hetrogeneities.
I am hoping that you and your experts can dispel my fears. Gary
# 9 March 2012 at 4:50 pm

Gary said:
I must be having a bad day. Contributions 2 and 4 seem to be totally inconsistent. If the protein Celebron is necessary for the immunomodulatory drugs revlamid and pomalidomide to be effective (article 2) than how is it possible for pomalidomide to be effective in patients who no longer respond to revlamid? What am I missing?
# 9 March 2012 at 5:07 pm

suzierose said:
Why does pomalidamide work in relapsed lenalidomide treated patients? They are in the same class of agents. If celebron is essential for lenalidomide to work and mutation makes it resistant, why then would pomalidamide work in that patient population?
Are we really talking about a group of relapsed patients that are not resistant to lenalidomide to begin with?
# 9 March 2012 at 8:37 pm

TerryH said:
Thanks for the excellent article. I found it very interesting.
Gary and suzierose - Just because cereblon is necessary for Revlimid to be effective, doesn't mean it's sufficient. There probably are other factors that also determine whether Revlimid can be effective in a myeloma patients.
The same is probably true for pomalidomide. For it to work, cereblon levels have to be at a certain level or higher, but other factors also are probably necessary.
Now, as long as there are differences in the "other factors" between Revlimid and pomalidomide -- as there appear to be based on the clinical trial data -- then pomalidomide can be effective in some myeloma patients who have stopped responding to Revlimid.
Gary - I think the story you are referring to is one that I also posted about in the forum on Thursday. Here is the link:
http://www.myelomabeacon.com/forum/cancer-varies-even-within-a-single-tumor-t923.html
What I don't understand is why you see a conflict between the result of this new research and the gene sequencing that was done for the research paper mentioned in this article.
The research paper mentioned here doesn't say that all myeloma patients have exactly the same disease with the same genetic mutations, or that the disease is everywhere the same within the body.
All the article reports is that researchers have gotten a much broader and deeper picture of the genetic mutations common in multiple myeloma. This will help them to identify potential new treatments for the disease, and -- possibly -- tests to determine if patients may respond to those treatments.
# 10 March 2012 at 12:24 am

Julie Shilane (author) said:
Hi Gary,
In response to your first comment, Dr. Ravi Vij said, "It is true that with the initial sequencing of tumor genomes, we are finding heterogeneity in tumors. There is data to suggest that this is true even in the case of multiple myeloma.
"However, this knowledge [from the genome mapping study] is extremely important as it could mean that combination therapy with multiple drugs is perhaps needed for best results.
"Also, some of the emerging data suggests that at different times, different clones predominate and it is possible that drugs that one may have been deemed resistant to in the past may again be effective again in case of a subsequent relapse.
"The insights in biology gained by this technology will be invaluable and will almost certainly lead to better therapy in the future."
# 10 March 2012 at 12:09 am

Jan Stafl said:
Thank you for a great review of the most promising recent Myeloma research. It seems to me that prior to Revlimid maintenance therapy after an ASCT, checking the Celebron level to see if it is adequate for efficacy of this approach is wise. Do you know where this test can be run, and how to arrange it?
I agree that genome sequencing at this point is unlikely to be clinically useful in MM. However, elotuzumab combination therapy in refractory cases seems very promising, and is now available at 200 various worldwide sites in level 3 trials. Do you have any news on this treatment option? Keep up the good work! Jan
# 10 March 2012 at 10:32 am

suzierose said:
Hi Terry,
Sorry, but the direct quote is inconsistent with what you are postulating regarding 'sufficiency" as the article states cereblon is essential to resistance development.
Dr. Vesole explains the mechanism of resistance that develops in the MM cells, how they mutate and result in resistance for both pomalidomide and lenalidomide. He states:
“Cereblon, a common cellular protein, is necessary for immunomodulatory drugs (Revlimid and pomalidomide) to destroy myeloma cells. As the myeloma cells mutate, they lose their ability to generate cereblon and, thus, the myeloma cells become resistant to these agents.”
No cereblon being generated in MM cells means resistance to pomalidomide and lenalidomide.
# 11 March 2012 at 12:48 am

TerryH said:
No reason to apologize, suzierose, because I don't think what I said is contradicted by what Dr. Vesole says or what is in the abstract for the cereblon study in Blood.
Dr. Vesole says that cereblon is necessary for Revlimid and pomalidomide activity. The abstract for the the Blood article says that cereblon is "required" for the antimyeloma activity of those drugs. Neither Dr. Vesole nor the Blood article say that cereblon is sufficient for the activity of the two drugs, which is exactly the point that I made.
If, aside from cereblon, there are other factors that determine whether patients respond to Revlimid and pomalidomide, and if there are differences between the two drugs in what those other factors are, there is no reason that pomalidomide can't be active in some patients who have stopped responding to Revlimid.
Obviously, based on the cereblon requirement, pomalidomide won't work in patients who have stopped responding to Revlimid because their cereblon levels have dropped. But it could work in patients who are no longer responding to Revlimid for reasons other than a drop in cereblon production.
Anyway, this is all kind of a moot point, because several clinical trials show that some (not all) patients who have previously stopped responding to Revlimid treatment do, in fact, respond to pomalidomide treatment.
# 11 March 2012 at 2:22 am

suzierose said:
Hi Terry:
you write:
"Dr. Vesole says that cereblon is necessary for Revlimid and pomalidomide activity. The abstract for the the Blood article says that cereblon is “required” for the antimyeloma activity of those drugs. Neither Dr. Vesole nor the Blood article say that cereblon is sufficient for the activity of the two drugs, which is exactly the point that I made."
Ok, perhaps this is about how terms are being used. The quote does say that cereblon must be manufactured by the MM cells in order for pomalidimide and lenalidomide to be effective. It says it is essential. And that the MM cells mutate, no longer produce cereblon, and then neither pomalidimide nor lenalidomide works.
As Dr. Vesole is saying that cereblon is essential for the MM cells to be susceptible to both pomalidimde.
and lenalidomide. And he goes further by saying it is a specific mutation by the MM cells to no longer produce the cereblon so that they are no longer susceptible to lenalidomide/pomalidimde ..i.e. the MM cells are resisistance because the cereblon protein IMIDs need for antimyeloma activity is no longer there.
So it is not clear to me what you are saying 'required' is. Depletion of cereblon in MM cells results in no myeloma activity in that mutated population.
I agree that the immunomodulatory have multiple actions, but the cells were smart enough to mutate to delete the absolutely essential protein to make them no longer susceptible, so they could survive. And that results in the other actions that ensue in a cascade downhill from there no longer are in play either.Which the article also says, immunomodulatory factor, IRF4, is no longer impacted either.
Dr. Vesole is saying that cereblon is essential for the MM cells to be susceptible to both pomalidimde.
and lenalidomide. And he goes further by saying it is a specific mutation by the MM cells to not produce the cereblon so that they are no longer susceptible to lenalidomide/pomalidimde ..i.e. the MM cells are now resisistance because the cereblon protein they need for antimyeloma activity is no longer there.
Point of fact, the Blood article makes it clear, that because cereblon is absolutely essential for efficacy it can be used as a biomarker for antimyeloma activity of the drugs, just like we measure free light chains to see it the drug is working, we can measure to see if the cells have cereblon or are depleted. If they are depleted of cereblon they are resistant, and particularly the remaining cells without cereblon, they are stable and 'happy' myeloma cells again much to our chagrin.
What do you mean by required?
http://bloodjournal.hematologylibrary.org/content/118/18/4771.short
I can see why you think it is moot.
However, the initial query I posed was about that discrepancy.
How can the cells that are resistant to lenalidomide due to cereblon depletion, now that we know that is the mutation, how then are they susceptible to pomalidomide.?
Now, what I suspect is that there is a mixed population of cells and while there is a stable population resistant to lenalidomide, with depleted cereblon.. there are still some cells that aren't depleted. IOW's there is a REDUCED production of cereblon sensitive MM cells. . So, what happens, is that those cells not only no longer respond to lenalidomide due to receptor binding cells but that different receptor binding of pomalidomide targets those remaining cells that are still producing some cereblon...however, pomalidomide is not able to exert anti-myeloma vs the stable resistant cereblon depletion population that lenalidomide has created.
Perhaps, what we need to explore is just how much efficacy we are getting in lenalidomide relapsed/refractory patients to when they are put on pomalidomide. How many respond and for how long? How effective is the anti-myeloma impact in cells with reduced cereblon production which are evolving to the mutation? IOW's how large is the mutated population, which no longer responds to lenalidomide?
# 11 March 2012 at 8:54 am

Julie Shilane (author) said:
Great discussion.
At the time the physicians were surveyed for this article, Dr. Peter Voorhees said, "A target for the IMiDs has been elusive for years. Now we know that cereblon expression and binding is required for the activity of thalidomide, Revlimid, and pomalidomide and that subsequent downregulation of IRF-4 is an important mediator of IMiD-based myeloma activity. The stage is now set to see if we can use cereblon expression in myeloma cells to predict response to IMiD-based therapy in patients and to better understand the basis of IMiD resistance in cases where cereblon expression is preserved."
I have followed up with Dr. Voorhees, and he has agreed to address some of the questions in the above comments. As in his quote above, he indicated that there are multiple pathways to resistance.
Jan, there are a number of recent Beacon articles about elotuzumab:
http://www.myelomabeacon.com/tag/elotuzumab/
In particular, you may be interested in the following two articles:
http://bit.ly/yqTxbx and http://bit.ly/zZSPtV
# 11 March 2012 at 12:59 pm

suzierose said:
Hi Terry!
Sorry for that message not being edited better due to cutting and pasting as well as no edit button
However, I did find an outcomes chart for heavily pre-treated lenalidomide/bortezemib patients.
If you scroll down to the outcome chart you will see that the responses in the refractory/relapsed group is not robust at all. Which would be consistant due to cellular resistance of the MM cells depletion of cereblon.
http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Hematology%202011/Tracks/Multiple%20Myeloma/Capsules/634.aspx
Thanks Julie!! Looking forward to hearing the feedback from Dr.Voorhees.
# 11 March 2012 at 5:22 pm

Dr. Peter Voorhees said:
Dear all,
This is a terrific discussion. Let me make two points:
1) Myeloma is a varied disease, not just from patient to patient, but within the individual patient as well. In a single patient, there are going to be mutations found in the majority of the myeloma cells and other mutations found in select "sub-clones." There will be mutations that are irrelevant to the behavior of the disease and those that are critical to driving the disease process. The first step is to see what mutations are out there, and then sort out which ones are driving disease behavior, what proportion of patients harbor those mutations, and, at the individual level, what proportion of the myeloma cells harbor the mutation. The Nature article is a first but important step. For example, mutations in a gene called BRAF were identified in ~5% of cases. BRAF mutations are frequently seen in melanoma and drugs that inhibit BRAF have shown promise in this chemotherapy resistant disease. So now we can start to address whether BRAF inhibitors will have activity in myeloma patients whose disease harbors this particular mutation. A ways to go, but a fruitful avenue of research!
2) Lenalidomide and pomalidomide bind cereblon inside myeloma cells, which is important for their activity against the disease. As such, one would expect that absent or low expression of cereblon would impart resistance to both drugs. However, when Dr. Stewart and colleagues looked at a variety of different lenalidomide resistant myeloma cell lines and patient myeloma samples, they found that cereblon was not reduced in all cases of lenalidomide resistance, which suggests that there are other pathways to lenalidomide resistance. It may be that in instances of lenalidomide resistance that are not due to cereblon being absent or reduced, pomalidomide may have activity (I am conjecturing here). At the end of the day, these data are highly provocative but still preliminary. Most of the data generated thus far has been in myeloma cell lines -- only a few patient samples have been tested. We need to determine the best way to measure cereblon levels. We need to sort out what degree of reduction in cereblon expression is necessary to produce resistance. We need to find out if this is the dominant pathway to resistance in patients. Lastly, we need to understand the mechanism of resistance in cases where cereblon expression is preserved. There is no commercially available test for measuring cereblon levels in myeloma cells at present, but I strongly expect one is forthcoming!
I hope this helps.
Take care!
Pete V.
# 12 March 2012 at 9:20 am

suzierose said:
Re: Genome Sequencing and the Underlying Causes of MM:
The Nature link states:
"About 40% of cases harbour chromosome translocations resulting in overexpression of genes (including CCND1, CCND3, MAF, MAFB, WHSC1 (also called MMSET) and FGFR3) via their juxtaposition to the immunoglobulin heavy chain (IgH) locus1. Other cases exhibit hyperdiploidy. However, these abnormalities are probably insufficient for malignant transformation because they are also observed in the pre-malignant syndrome known as monoclonal gammopathy of uncertain significance. Malignant progression events include activation of MYC, FGFR3, KRAS and NRAS and activation of the NF-κB pathway1, 2, 3."
I was very relieved to read this as I have not been able to connect how a so called 'high risk cytogenetic" MM patient is considered to have advanced/aggressive disease yet classified as Intl Stage One. I have been pondering that question since diagnosis, as the prevailing wisdom was that the genetic mutations occur/evolve with long standing disease. Just could not make sense of that. It is wonderful to learn that these same mutations are seen with MGUS, when patients have NO CRAB symptoms nor are even considered for therapy. It reminds me once again how medicine says, you are borderline diabetic or hypertensive and does not recommend therapy until you become diabetic or hypertensive..while this may be prudent if therapy is toxic..is it prudent in terms of intervening prior to the disease is firmly established. Particularly, when you consider that the tests used to determine 'borderline/smoldering' may not have a cellular sensitivity level to truly diagnose whether your cellular evolvement can be halted if treated earlier than later.
Also from the Nature article it looks like NF-kappaB is a powerful pathway to target in terms of drug therapy as it is overly abundant in MM patients, according to Dr. Siegal:
http://www.myelomabeacon.com/news/2011/03/23/genome-sequencing-reveals-clues-about-the-underlying-causes-of-multiple-myeloma/
Many folks have also posted in the forums on natural products that impact NF-kB pathway.
"A large number of compounds are currently known as NF-kappaB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development"
http://www.ncbi.nlm.nih.gov/pubmed/11999122
I recall Ninja's recipe was quite a success for him and the Beacon also had articles:
http://www.myelomabeacon.com/news/2010/02/17/curcumin-and-multiple-myeloma-preclinical-and-early-clinical-studies-are-promising-still-awaiting-more-clinical-evidence/
# 17 March 2012 at 12:53 pm

suzierose said:
Article #4 Pomalidomide/Dex in Lenalidomide/Bortezomib refractory patients:
Data results:
"Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%"
Wonder what accounts for the higher 4mg dose not being anymore effective than 2mg dose of pomalidamide. What is going on there?
Interesting how numbers for overall response rate of 49% can be deceptive to a patient.
Because ....49% of patients did NOT respond,
Rather the highest response rate in patients was a minor response of 23%...for patients on 2mg and that number drops to 14% in patients on 4mg.
Hmmmm, and just how was Minor Response defined in terms of labs:
Minor response (MR) was defined as ≥ 25% but < 49% reduction of serum M protein and reduction in 24-hour urine M protein by 50%-89%, which still exceeds 200 mg per 24 hours.
Now why did they not include FLCA...to give us a more precise view of efficacy? Oh, that's right the goal was compare two different doses in relapsed patients (lenalidomide/bortezomib).
So overall what the trial shows, that is considered the 4th biggest MM story, is that 2 mg pomalidomide with dex shows a less than 50% reduction in M spike in less than a third (23%) of MM patients refractory to both lenalidomide and bortizomib in this trial.
If you are in that 23% you are a happy camper though!!
# 18 March 2012 at 12:00 pm

Myeloma Beacon Staff said:
Hello suzierose,
The important thing to recognize when looking at the pomalidomide study that you mention is that patients in both cohorts had a median of 6 (yes, six) previous lines of therapy. In other words, these were very heavily pre-treated patients -- patients with few other options.
When it comes to efficacy results for relaped/refractory patients, it's always important to look at the median number of previous therapies. Otherwise, you can end up making apples to oranges comparisons. Results for patients who have had just 2 previous lines of therapy can't be compared to results for patients who have had 6, 7, or 8 previous lines of therapy.
On the issue of response rates ... As you know, authors adopt different conventions when it comes to the reporting of "overall" or "total" response rates. Here at The Beacon, we try to be as consistent as possible and use the terminology "overall response" to mean partial response or better.
But, if you're reading an article or abstract somewhere else, it is important to look at exactly what the authors are including in their definition of "overall" or "total" response. Sometimes, minimal response may also be included, and some authors go so far as to include patients with stable disease. (That may be okay, by the way, if you're talking about heavily pre-treated patients, who might otherwise be expected to have disease that progresses quite quickly. In that case, achieving a minimal response, or keeping a patient's disease stable, may legitimately be considered a positive outcome.)
# 18 March 2012 at 1:55 pm

suzierose said:
Thanks MBS!!
# 18 March 2012 at 4:04 pm

Get new Myeloma Beacon articles by email.