[mikeb]

MLL trisomy, Revlimid, and secondary cancer risk?

by mikeb on Mon Mar 16, 2015 12:40 pm

The recent Beacon research review article on chromosomal abnormality differences between African-Americans and whites got me thinking a little more about my own FISH results. I've gone down a chain of thinking that has led to the question I'll ask here.

I have an 11q trisomy. That includes the MLL (aka KMT2A) gene. Like other trisomies, this tri­somy is considered to be a slightly positive prognostic indicator for multiple myeloma. How­ever, it is a negative prognostic indicator for certain forms of leukemia, such as aggressive acute lymphoblastic leukemia (ALL) and aggressive myeloid leukemia (AML) (see, for ex­am­ple, this journal article on "Global and Hox-specific roles for the MLL1 methyl­trans­fer­ase").

AML is one of the secondary cancers that has been associated with Revlimid (see, for ex­am­ple, this Beacon article from 2011, "Myeloma Experts Present Additional Data On Revlimid And Secondary Cancers (ASCO 2011)").

Putting 2 and 2 together (and probably getting 22 instead of 4!), I started wondering whether having the 11q / MLL trisomy might put a multiple myeloma patient at higher risk than normal for developing AML as a secondary cancer if they have been treated with Revlimid (as I have). I have done a little searching on the internet, but have not found anything about this.

I'm wondering if anyone has looked into this and possibly found any connection (or not). It sounds like something Dr. Antonio Palumbo from the University of Turin in Italy might have some information about, since he has looked at chromosomal abnormalities and Revlimid secondary cancers, as mentioned in the Beacon article cited in the previous paragraph.

Mike

[Christa's Mom]

Re: MLL trisomy, Revlimid, and secondary cancer risk?

by Christa's Mom on Mon Mar 16, 2015 6:54 pm

Hi Mike,

I don't know if this helps, but I remembered that the Beacon published this article a while back.

"Revlimid And Secondary Cancers: Melphalan May Be The Culprit," The Myeloma Beacon, March 7, 2014.

The secondary cancers from Revlimid seem to occur mostly when you take Revlimid in con­junc­tion with melphalan. I'm under the impression that this is / was a treatment protocol for people who are transplant ineligible.

Lyn

[mikeb]

Re: MLL trisomy, Revlimid, and secondary cancer risk?

by mikeb on Tue Mar 17, 2015 4:49 pm

Hi Lyn,

Thanks for the pointer to the Beacon article. That's important information, for sure.

My question is a little different, though. What if, instead of looking at the interaction of melphalan with Revlimid (as in the study you pointed to did), we looked at the interaction of someone's chromosomal abnormalities (particularly the 11q trisomy) with Revlimid?

My hypothesis is that we might see a higher rate of secondary cancers, especially AML, in people with the 11q trisomy than in people with other chromosomal abnormalities when both groups are treated with Revlimid.

But maybe that's completely wrong. And maybe, instead, people with the "high risk" chromosomal abnormalities in multiple myeloma would be the ones at higher risk for secondary cancers too. Or maybe there's no difference.

So another way of saying it is that I'm interested in understanding what role (if any) different chromosomal abnormalities play in increasing or decreasing someone's risk of developing a secondary cancer if they've been treated with Revlimid.

Thanks,
Mike

[Multibilly]

Re: MLL trisomy, Revlimid, and secondary cancer risk?

by Multibilly on Tue Mar 17, 2015 5:29 pm

Hey Mike,

Interesting question. From the article below, I am gathering that the medical industry doesn't currently know the role that cytogenetics may play in predisposing a multiple myeloma patient to secondary cancers. Note point (ii) below:

Non-treatment-related factors are less well understood but may play significant roles [in the development of secondary cancers]. Potential disease-related risk factors include baseline complex cytogenetics and the subtype of myeloma. The MM-015 study noted that 3 of the patients who ultimately developed MDS / AML in the lena­lido­mide arm were part of a small group of 11 patients who had complex cyto­genetics at baseline. IgG and IgA isotype MGUS patients have been reported to have an increased risk of MDS/AML. Host factors, such as genetic poly­mor­phisms , environ­mental factors, and behavioral factors have also been postulated as risk factors.

Clinical and preclinical research is needed to better elucidate lenalidomide’s mechanism of action and its potential role in secondary cancers. The following is a partial list of important questions to be resolved:

1. Is there a relationship between the amount of lenalidomide exposure (dose, duration, or schedule) and the risk of SPMs?
2. Do baseline cytogenetic abnormalities increase risk of developing SPMs?
3. Is patient age or previous history of malignancy a risk factor for the devel­op­ment of SPMs?
4. Are there other treatment (e.g., type of chemotherapy), host (e.g., SNPs), or disease (e.g., genetic aberrations) related risk factors or biomarkers for the development of SPMs?
5. What are the characteristics, prognosis, and natural history of these SPMs? What is the time to development? For t-MDS/AML, what types of cytogenetic and molecular changes are seen and are they different than the pattern already established in cases due to cytotoxic chemotherapy or radiation?"

Reference:

J Yang et al, "Secondary Primary Malignancies in Multiple Myeloma: An Old Nemesis Revisited," Advances in Hematology, 2012 (link to full text article)

[JimNY]

Re: MLL trisomy, Revlimid, and secondary cancer risk?

by JimNY on Tue Mar 17, 2015 7:04 pm

Hi Mike,

Can you explain more about the potential connection between the chromosomal area where you have a trisomy and ALL and AML?

The reason I ask is that, when I quickly skimmed the reference on that topic in your first posting, I had the impression that the researchers were talking about the role of that chromosomal area in all cells in the body.

When you talk about chromosomal abnormalities in multiple myeloma, however, you are talking about chromosomal abnormalities found in the mutated plasma cells (myeloma cells). I don't think there is any reason to assume that those mutations would be present in other cells in the body, although I guess they could be.

This makes me wonder if looking at characteristics of a patient's myeloma cells when you are considering their likelihood of developing a secondary cancer may be a bit like the proverbial "looking for your keys under the lamp post because there's light there -- not because you think you dropped them there."

It's probably the person's genome as found in all the body's cells, not just their myeloma cells, that affects how likely they are to get a secondary cancer from, say, Revlimid -- right?

Also, even though AML is a blood cancer like myeloma, it involves a totally different group of blood cells (myeloid cells) than the group of blood cells that plasma cells belong to (lymphoid cells). See, for example, this diagram for a quick refresher on that topic:

http://upload.wikimedia.org/wikipedia/commons/thumb/f/f0/Hematopoiesis_simple.svg/1024px-Hematopoiesis_simple.svg.png

(You probably are familiar with diagrams like that one, but I thought I would include it, just in case.)

Hope this helps a bit. I'm not an expert on this topic by any means ...

[mikeb]

Re: MLL trisomy, Revlimid, and secondary cancer risk?

by mikeb on Wed Mar 18, 2015 2:18 pm

Hi Multibilly and JimNY – Thanks a lot to both of you for your replies. I've learned some important things from both of them.

Multibilly:

Thanks for the quote and the link to the paper. That does, at least, make it sound like some researchers are thinking along the same line as I am, even if the research to answer the ques­tion has not been done yet.

JimNY:

You made a really important point:

"When you talk about chromosomal abnormalities in multiple myeloma, however, you are talking about chromosomal abnormalities found in the mutated plasma cells (myeloma cells). I don't think there is any reason to assume that those mutations would be present in other cells in the body, although I guess they could be."

In my little MLL hypothesis, somehow I forgot about that important distinction. That was pretty dumb of me.

Thanks also for your link to the diagram. I had not seen that before, and it was helpful to me.

Based on what JimNY has said, I think my original fear / hypothesis about a possible link be­tween 11q trisomy and Revlimid secondary cancers (especially AML) is unfounded. I had not thought through the possible pathways or anything like that.

But now I'm wondering more about the broader question of any baseline chromosomal abnor­mal­ities (maybe in the bone marrow microenvironment) and secondary cancers related to Rev­limid, (question 2 in Multibilly's research paper quote).

Mike