[Beacon Staff]

Clonal heterogeneity & evolution in multiple myeloma

by Beacon Staff on Wed Mar 04, 2015 7:15 pm

Many regular Beacon readers are familiar with the column that Dr. Gareth Morgan wrote for The Beacon last year titled "Evolution, Intra-Clonal Heterogeneity, And Multiple Myeloma" (Nov 3, 2014). The column was popular and sparked a lot of interesting.

As there regularly are new articles published on this topic, and many interesting articles that have been published in the past, we thought we would create a single thread here in the forum for discussion of the topic and research related to it.

We know this is a topic than can get quite technical, and it won't appeal to each and every Beacon reader. At the same time, it's a topic that is likely to grow in importance as more myeloma therapies become available, and questions of "Which therapy is best for which patient" become more and more important.

To kick off the thread, we thought we would point out a new article that was recently published on the topic. The complete text is freely available, and the article is a good review of how what we know about clonal heterogeneity and evolution in myeloma has developed – dare we say "evolved" – over time.

Here is the article citation:

G Bianchi & IM Ghobrial, "Biological and Clinical Implications of Clonal Heterogeneity and Clonal Evolution in Multiple Myeloma," Current Cancer Therapy Reviews, 2014 (abstract with link to free full text PDF, full text at PubMed)

and here is the article abstract:

Clonal heterogeneity and clonal evolution have emerged as critical concepts in the field of oncology over the past four decades, largely thanks to the implementation of novel technologies such as comparative genomic hybridization, whole genome/exome sequencing and epigenetic analysis. Along with the identification of cancer stem cells in the majority of neoplasia, the recognition of intertumor and intratumor variability has provided a novel perspective to understand the mechanisms behind tumor evolution and its implication in terms of treatment failure and cancer relapse or recurrence.

First hypothesized over two decades ago, clonal heterogeneity and clonal evolution have been confirmed in multiple myeloma (multiple myeloma), an incurable cancer of plasma cells, almost universally preceded by a pre-malignant conditioned named monoclonal gammopathy of undetermined significance (MGUS). The genetic events and molecular mechanisms underlying such evolution have been difficult to dissect. Moreover, while a role for the bone marrow microenvironment in supporting multiple myeloma cell survival, proliferation and drug-resistance has been well established, whether it is directly involved in driving evolution from MGUS to multiple myeloma is at present unclear.

We present in this review a historical excursus on the concepts of clonal heterogeneity and clonal evolution in multiple myeloma with a special emphasis on their role in the progression from MGUS to multiple myeloma; the contribution of the microenvironment; and the clinical implications in terms of resistance to treatment and disease relapse/recurrence.

We'll be interested to here what people think about the article and what the key things were they found interesting in it.

[mikeb]

Re: Clonal heterogeneity & evolution in multiple myeloma

by mikeb on Thu Mar 05, 2015 10:03 pm

Beacon Staff,

Thanks for starting this thread. I'm no expert on this stuff, but I find the parts I can understand very interesting. And my gut feeling is that you're right - this topic is going to be increasingly important.

I'm looking forward to reading the Bianchi & Ghobrial paper. Thanks for the link.

Since clonal heterogeneity is closely tied to DNA replication, folks who are interested in this Beacon forum topic might also be interested in an upcoming free MOOC (Massive Open Online Course) being offered by EdX, "Molecular Biology: DNA Replication and Repair" from MIT. The course begins March 10.

Mike

[JimNY]

Re: Clonal heterogeneity & evolution in multiple myeloma

by JimNY on Fri Mar 06, 2015 5:28 pm

I agree with Mike. Glad to see this topic here in the forum. Should be interesting to see how it develops.

There's a paragraph in the article that's been recommended that mentions a case of a patient who had genetic testing done on their myeloma cells at multiple points during their treatment. This case is frequently mentioned in the literature, as far as I can tell, so it's worth sharing some of what the authors say about it.

The previously discussed report on the longitudinal follow up of a newly diagnosed patients with t(4;14), revealed several important information. The disappearance and dominance of different clones in this patient appeared to be clearly determined by selective pressure from treatment. For instance, the first relapse of the patient after a partial remission with lenalidomide and low dose dexamethasone (Rd) was attributed to the emergence of a previously minor clone, which became progressively dominant as the founder clone declined under the pressure of treatment. Both this clone and a related one that appeared at this time harbored mutations in the BIRC2/3 gene, a positive regulator of the NF-κB pathway, suggesting a role for NF-κB in mediating Rd resistance. This data suggest that partial response can be the consequence of lack of suppression of a non-dominant clone rather than to partial suppression of the whole tumor population and provide a strong biologic rationale for using combinatory chemotherapy in an attempt to eradicate all clones and avoid selection of aggressive ones. Interestingly, at the time of the fourth relapse after receiving melphalan, prednisone and bortezomib (MPV) therapy, the dominant clone was profoundly different from the founding clone and characterized by complex genomic abnormalities, raising the possibility that melphalan, an alkylating agent, could potentially select for highly genomically unstable and aggressive clones."

There's a lot to chew on in just that one (long!) paragraph. Some key points:

• At relapse, the "progressively dominant" myeloma clone was one that was just a minor clone originally.
• This suggests that a partial response to treatment may not be as much due to partial reduction of all myeloma cells, but perhaps reduction in some, but not all, clones
• After treatment with a melphalan-containing regimen, the new dominant clone was very different from previous clones, suggesting melphalan may "select for" (not eliminate, or perhaps cause?) unstable and/or aggressive clones.

For what it's worth, I think Dr. Morgan spoke about many of these points in his Beacon column.

[mikeb]

Re: Clonal heterogeneity & evolution in multiple myeloma

by mikeb on Sun Mar 08, 2015 12:31 pm

Yes, JimNY, lots to chew on in that paragraph! And in the entire paper.

A couple of other things that were particularly interesting to me, assuming I understood these parts of the paper correctly:

• Because the bone marrow microenvironment supports clonal evolution, another possible way to fight multiple myeloma might be to modify the bone marrow microenvironment, rather than attacking myeloma cells directly. For example, they noted that the onco-suppressor, miR-15a, is down-regulated in bone marrow with myeloma cells in it, compared to normal bone marrow. So maybe there is a way to block that down-regulation.
   
• Only 3% of overall mutated genes overlapped between the high-risk patients [t(4:14)] and standard-risk patients [t(11:14)] in the Walker et al. study. I would have assumed much more over­lap would occur. This finding seems to me to strongly support the argument that multiple myeloma should be considered to be several very different diseases genetically, rather than one single disease. The different diseases just happen to have the same target - bone marrow plasma cells.

The main takeaway that I got from the paper is that mutliple myeloma is an incredibly complex disease. But I guess we already knew that.

Mike

[bluebell]

Re: Clonal heterogeneity & evolution in multiple myeloma

by bluebell on Mon Mar 09, 2015 8:28 pm

Thanks Beacon Staff for starting this thread. I look forward to reading the paper.

Maybe this is addressed in the paper, but I was wondering if clonal heterogeneity and clonal evolution occur in other cancers as well. I know other cancers can become resistant to drugs over time.

[mikeb]

Re: Clonal heterogeneity & evolution in multiple myeloma

by mikeb on Tue Mar 10, 2015 5:35 pm

Great question, bluebell. That's something I wondered about too.

The paper does address it and talks about a now-famous paper in the journal "Science" back in 1979 hypothesizing that "cancer originates from one founder cell, which progressively accumulates random somatic genetic mutations, thus giving rise to a series of subclonal populations existing in equilibrium." That hypothesis has since been supported by lots of research.

The current paper goes on to point out that most hematologic cancers usually have only a "limited number" of genetic alterations. However, multiple myeloma cells have a "significant number of karyotipic aberrations."

So, from this paper, it sounds like other cancers do have clonal heterogeneity and evolution, but there's more of it in multiple myeloma. Aren't we lucky?

Mike

[Sentinel]

Re: Clonal heterogeneity & evolution in multiple myeloma

by Sentinel on Thu Apr 02, 2015 5:44 pm

I am surprised at the dates on this thread. This is recent news, apparently.

For me, clonal heterogeneity in multiple meyloma is a given. My current opinion is that MGUS is the actual illness. It is the initial stage when chromosomal damage allows clonal evolution and diversification to progress.

Once the clonal evolution begins, in my opinion, something happens that allows the chromo­somal stability to weaken and diversification to expand.

From then on, it can be seen as a computational problem. When a population of rapidly di­versi­fying clones search a space of possibilities, their chances of finding a solution to a given prob­lem increase as their ability to diversify does.

It is for this reason that I feel it is unethical for clinical trials with multiple myeloma to focus on one drug, and especially if supplemented with alkylating agents, as the combination of focus on a particular drug (selective pressure) and alkylating agents (increase in mutation rate) will result in selection for clones that are tolerant to the anti-cancer treatment. Should relapse occur, it will be more aggressive.

For the same reason, it is perfectly understandable that one doctor treating multiple myeloma with a cocktail of drugs claims success – the doctor is presenting the diverse heterogeneous population of clones with such a ring-fence of attacks that the population is less likely to find a route out.

I would go further and augment this treatment with anti-mutagens such as a Mediterranean diet, e.g., olive oil, specific foods, and hope that the rate of diversification in clones reduces.

I believe it is important for those with multiple myeloma to insist on MGUS treatment. Multiple myeloma is nothing more, in my opinion, than a gravy-train for drug developers unwilling or unable to justify treating the root cause (MGUS).

I would like to know of any data or opinion about MGUS genetic anticipation (when successive generations exhibiting MGUS are younger) or any data about MGUS inheritance patterns.

I will watch this thread.