Rafael Fonseca, MD is the Chair of Myeloma at the Mayo Clinic in Scottsdale and recently shared a Twitter thread (of 26 tweets) that asked the question “What is the Risk Classification of the t(11;14) in multiple myeloma? He then told the story with examples and data of venetoclax – the first drug to show specific utility for myeloma patients with the 11;14 translocation.
The information that followed was so valuable, we want to share it here because many patients are not on Twitter. Twitter can be a little cryptic, so we’ve added some comments to help clarify certain points. Get ready for a great read, especially if you have 11;14 myeloma!
WHAT IS THE RISK CLASSIFICATION OF THE t(11;14) in MM? This has been a long-debated question and probably asked in the wrong way. I have always had a special interest in the t(11;14) and want to tell a story and how it relates to venetoclax. #mmsm #ASH19
In 1998 we reported the t(11;14) was a poor prognostic marker (only translocation visible in karyotypes). We were seeing the effect of abnormal karyotypes- more growth and tumor burden. @VincentRK onlinelibrary.wiley.com/doi/full/10.10ncbi.nlm.nih.gov/pubmed/10459351
- The first link is a 2001 article showing that out of 13 patients with 11;14 at the Mayo Clinic, the median survival for these patients was 8.1 months and these patients had many circulating plasma cells in the blood. Also, patients with primary plasma cell leukemia frequently have this translocation (2 out of 13 in this patient sample).
- The second link is a 1999 article showing that patients vary in their responses when genetic features are taken into account. This was a relatively new concept at that point in time.
That year I convinced M Gertz to send me to Leiden, Netherlands to study t(11;14) via fiber-FISH- most elegant FISH assay. Only achievable by the great Dutch masters. At my return M Kuehl said “stop wasting your time & start doing interphase FISH.” Best advice! @MorieGertz
- The fluorescence in situ hybridization in situ hybridization (FISH) test was not always well understood or utilized in the characterization of myeloma. Today, every myeloma patient should receive a FISH test so they understand what type of myeloma they have.
With interphase FISH we reported a prevalence of 15% of MM. It was associated with better outcomes (2003) and subsequently confirmed by others. KEY POINT: Most of the trials where it was tested had a backbone of alkylators and not any novel agents. ncbi.nlm.nih.gov/pubmed/12576322
- There are 15% of myeloma patients with the 11;14 translocation.
- The article referenced shared the fact that when compared to the other genetic mutations (such as the t(14;16), t(14;20) or deletion of 17), the 11;14 patients had better outcomes.
- Most of the trials where it was tested was using chemotherapy such as melphalan or cytoxan and not “new” agents like proteasome inhibitors (like Velcade) or immunomodulators (like Revlimid)
THIS IS AN IMPORTANT POINT: The t(11;14) is known to be associated with lymphoplasmacytic morphology and CD20 expression. Often hyposecretory or (non-secretory) and IgG lambda type. AGAIN KEY POINT: MM with t(11;14) often has scant cytoplasm (more later).
- Many times patients with the 11;14 translocation do not secrete a monoclonal protein (this is called non-secretory myeloma). This makes it harder to track the disease because it can no longer be detected in the blood, only through bone marrow biopsies or the use of imaging.
- Many patients with t(11;14) have IgG lambda myeloma.
- Cytoplasm is the material in a cell that does not include the cell nucleus. So in t(11;14) patients, there is not much cytoplasm in each myeloma cell. In the picture below, the cell nucleus is larger than normal.
We had this theory called the “Donor Chromosome Theory.” It postulated all MM would have 14q32 translocations. This came after Kuehl, Chesi & Bergsagel had identified translocations as ubiquitous in cell lines & discovered the t(4;14) and t(14;16) pnas.org/content/93/24/
- In doing more genetic testing, myeloma researchers found that many myeloma types include some sort of relationship with the 14 chromosome.
- Chromosome 14 contains 800-900 genes that provide instructions for making proteins. It represents 3.5% of the total DNA in cells.
- Each translocation involving chromosome 14 affects a different gene. For example, the t(11;14) affects the CyclinD1 gene and the t(14;16) affects the C-MAF gene
In 2001 Dr. Sue Hayman first reported a 50% prevalence in pts with light chain amyloidosis. It was also associated with strong nuclear positivity for cyclin D1. In 2003 H. Avet-Loiseau reported at a high frequency in IgM MM. ashpublications.org/blood/article-ncbi.nlm.nih.gov/pubmed/12393502
- The first article suggests that translocations with chromosome 14 can be early events in both MGUS and myeloma. And in 29 amyloidosis patients, over 72% of them had chromosome 14 involvement. A total of 55% of patients with light chain amyloidosis in the study had the t(11;14). Light chain amyloidosis can also be found in myeloma patients and it creates organ damage such as congestive heart failure or kidney failure.
- The second article shares that t(11;14) myeloma is 5 times as likely to be IgM, IgE, and non-secretory myeloma (but not IgD myeloma compared to IgG and IgA myeloma.
In 2008 we reported the t(11;14) in 50% of cases with primary plasma cell leukemia, not so in sPCL. Others had also reported similar findings. If you “tickle” a MM cell with a t(11;14) it can behave badly! ncbi.nlm.nih.gov/pubmed/18216867
- The article shares that primary plasma cell leukemia (pPCL) is an original diagnosis and the majority of these patients have the t(11;14)
- Secondary plasma cell leukemia (sPCL) is really an evolution or worsening of multiple myeloma and is associated with more genetic mutations.
- The article states that the two diseases (primary and secondary PCL) are different disorders with different genetics and survival. (they probably should have named them something else because this is super confusing for myeloma patients!)
In 2005 Bergsagel and Kuehl proposed the TC classification of MM via gene expression, showed the GEP signature of t(11;14) was identical to that of the t(6;14). Venetoclax? Also, UAMS showed two subtypes of t(11;14): CD1 and CD2. CD1 is better! ncbi.nlm.nih.gov/pubmed/16155016
As time went by its prognostic significance seemed to worsen. Could this be related to the Rx used? While all MM outcomes improved it appeared the t(11;14) had stagnated. Lakshman showed inferior ORR, PFS, and OS compared with standard risk pts. ncbi.nlm.nih.gov/pubmed/28655925
- More research showed that t(11;14) patients did worse than patients without a translocation. Other multiple myeloma patients were living longer with the newer therapies, but why wasn’t this group living longer too?
In a seminal observation in 2014 Boise proposed the “Tao of myeloma.” Hypothesis; effective treatments against MM could be built targeting NORMAL PLASMA CELL DIFFERENTIATION, not the genetic changes of the cells, but rather natural vulnerabilities. ashpublications.org/blood/article-
- Myeloma researchers were learning more both about the genetics of myeloma but also the biology of the actual plasma cell as well as its dependence on the bone marrow microenvironment. So maybe the ying (the genetics) and the yang (the plasma cell biology) were both involved but perhaps it was enough to create treatments to target how the cells had become different without trying to create genetic-specific medication.
This explained why drugs like proteasome inhibitors are predominantly useful in the clinic for late B cells – myeloma and Waldenström, and to some extent in other B cells tumors – not much else. Dr. Tiedeman did some elegant studies in this regard. ncbi.nlm.nih.gov/pmc/articles/P
- To create a plasma cell, the cell has to go through a maturation process. It starts out as a B-cell and then matures into a plasma cell. In the referenced article, Dr. Roger Tiedeman of Princess Margaret Cancer Center in Canada shows that proteasome inhibitors like Velcade don’t actually kill the b-cells, just the plasma cells. This is why proteasome inhibitors can reduce the myeloma tumor burden but aren’t curing myeloma.
But what about IMIDs? While IMIDS have pleiotropic effects not until recently it was shown that the protein context matters. The group of Florian Basserman showed the chaperon effect of IMIDs & effects on lactate metabolism. ncbi.nlm.nih.gov/pubmed/27294876ashpublications.org/blood/article/
- Immunomodulators (IMiDs) are drugs like lenalidomide, thalidomide or pomalidomide.
- We recently learned why they work in myeloma – they impact the Cereblon protein.
- Pleiotropy is when one gene influences two or more seemingly unrelated phenotypic traits.
- IMiDs act like a chaperone, linking Cereblon to other pathways to help regulate cell death, cell invasion and cell metabolism by governing how lactate levels are regulated in the body.
During protein folding lots of ROS are produced, and our group showed that IMIDs inhibit detoxifying mechanisms (TrxR). In this case the cells “self-poison.” But to be effective there needs to be abundant protein folding. ncbi.nlm.nih.gov/pubmed/27294876
- ROS means “reactive oxygen species” ROS play important roles in cell signaling and cell balance.
Again IMIDs primarily work in MM, WM, some lymphomas and the only other disease is the 5q- MDS. Again the protein context is essential. Remember MM with t(11;14) is lymphoplasmacytic with scant cytoplasm. nature.com/articles/24030
- lymphoplasmacytic = related to lymphocytes and plasma cells (both are white blood cells)
How is this related to the t(11;14)? If the cells have less cytoplasm, due to less proteins = less ER stress potential, and thus lower effect of PIs and IMIDs. Thus these drugs work better in “plump” mature plasma cells like in hyperdiploid MM, rather than in t(11;14).
And then came venetoclax! Investigators showed that venetoclax showed great promise in MM with the t(11;14) as this genetic subset depends more on anti-apoptotic signaling (pro-survival to avoid the double negative) of bcl-2. ncbi.nlm.nih.gov/pubmed/29018077
- Bcl-2 (B-cell lymphoma 2) is in the family of regulator proteins that starts or stops cell death.
Again, the work of Drs. Boise, Bahlis and Neri has shown that both t(11;14), and perhaps also elevated level of expression of bcl-2 predict a better response to venetoclax. This is truly the first targeted Rx for a specific genetic subset of MM. twitter.com/Rfonsi1/status
- Here’s a link to the recent ASH 2019 results for the Phase 1/2 study of venetoclax with daratumumab and dex with or without bortezomib
- While much “precision medicine” has not worked well for genetic targets, this is the first time that a targeted therapy IS working for one group of t(11;14) myeloma patients
So what happened with the BELLINI trial? In hindsight this trial had a major flaw- venetoclax was tested without selection for t(11;14). Given increased mortality, the trial was stopped, and the FDA paused venetoclax development. fda.gov/drugs/drug-saf
- The BELLINI trial included all relapsed or refractory myeloma patients, not just those with t(11;14).
- The FDA paused the BELLINI trial in March 2019 because it was found that there were more deaths on the venetoclax arm than the control arm.
So the theory of the Tao of myeloma holds and we have now a targeted therapy for MM with t(11;14). If you do not have enough proteins the PI/IMID combination will work, but “not as well.” We urgently need FDA approval for this indication.
First, IMHO (in my humble opinion) SCT (stem cell transplant) should not be delayed in pts with t(11;14). The benefit was presented at ASH. Another study conducted by the IMWG suggests patients can do well if properly treated. twitter.com/Rfonsi1/statustwitter.com/Rfonsi1/status
- The first chart below shows overall survival by type of therapy for t(11;14) patients. (so using a proteasome inhibitor plus and IMiD is the best idea instead of one of those alone.)
- The second chart below shows t(11;14) outcomes compared to other genetics in myeloma with stem cell transplant. Another Tweet from Dr. Fonseca: “Dr Sobejano and colleagues reporting on the role of SCT in patients with the t(11;14). It seem to be important and if possible a modality not to miss for this patient population ativsoftware.com/appinfo.php?pa
How about Rx of AL? Indeed, in AL the presence of this translocation is a negative prognostic marker for CyBORD treatment. In AL it is particularly important to achieve very deep responses (CR, nFLC). So clinical trials are urgently needed and ongoing for venetoclax in AL.
- What impact does this have on the treatment of AL amyloidosis? Dr. Fonseca urges the use of venetoclax in this disease in clinical trials.
The same is true in pPCL (primary plasma cell leukemia). In patients with t(11;14) the addition of venetoclax is being tested in trials. Again another instance where very deep responses are needed.
In the setting of RR MM venetoclax is being tested in combinations. L Boise tells me that at a minimum it always should be started in combination with dexamethasone, but I think more is needed. Trials testing combos with bortezomib, carfilzomib and daratumumab are ongoing.
- Myeloma drugs are almost always used in combination. So what is the best combination with venetoclax for relapsed or refractory myeloma? Perhaps first with dexamethasone and then other “standard of care” myeloma drugs. Some are now in clinical trials that include venetoclax.
What about SMM with t(11;14). I submit to you (not a recommendation for now) that it will be better to treat SMM with t(11;14) with venetoclax (combinations) than with IMIDs. Trials ongoing.
- Genetic markers can be seen even in smoldering myeloma patients. A smoldering myeloma patient could know if they have t(11;14) or not and join a clinical trial if they have this marker.
What about maintenance for post SCT t(11;14) patients?
So in the end it is not about risk status. It is about a different biology and the correct treatment. Much like having a student who does not do well in school and you only later realize he needs glasses. The end!