What We Know About the Myeloma Translocation 11;14

Rafael Fonseca, MD, is in the Division of Hematology and Medical Oncology, a Professor of Medicine, and the Chief Innovation Officer at Mayo Clinic. He recently answered the question: What is the Risk Classification of the t(11;14) in multiple myeloma? The following information groups provide insight into this translocation.

Risk Classification of t(11;14)

In 1998, it was reported that t(11;14) was a poor prognostic marker (the only translocation visible in karyotypes). It was also associated with more growth and tumor burden.

• HERE 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).
• HERE is a 1999 article showing that patients vary in their responses when genetic features are taken into account. 

Interphase FISH Study

Interphase Chromosome Flow-FISH (IC Flow-FISH) is a method developed to detect chromosome number abnormalities in peripheral blood cells.

• The fluorescence (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 testing, the following was discovered:

• There are 15% of myeloma patients with the 11;14 translocation. 
• 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 testing trials used chemotherapy such as: melphalan or cytoxan and proteasome inhibitors (like bortezomib) or immunomodulators (like lenalidomide).

T(11;14) is Associated with Lymphoplasmacytic Morphology and CD20 Expression

Often, hyposecretory (when the amount of hormones released is too low) or non-secretory and IgG lambda types occur.  

• 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. In t(11;14) patients, there is not much cytoplasm in each myeloma cell.

The “Donor Chromosome Theory” 

This theory considers that MM may have 14q32 translocations. 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

Light Chain Amyloidosis

In 2001, Dr. Sue Hayman first reported a 50% prevalence of t(11;14) in patients with light chain amyloidosis. It was also associated with strong nuclear positivity for cyclin D1. In 2003, H. Avet-Loiseau reported a high frequency in IgM MM.

• Translocations with chromosome 14 can be early events in both MGUS and myeloma. Over 72% of 29 amyloidosis patients 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.  
• T(11;14) myeloma is five times more likely to be IgM, IgE, and non-secretory myeloma (but not IgD myeloma, compared to IgG and IgA myeloma).

Primary Plasma Cell Leukemia

In 2008, t(11;14) was found in 50% of cases of primary plasma cell leukemia (PCL) but not so in secondary PCL. Primary PCL is an original diagnosis, and the majority of these patients have the t(11;14).

• Secondary PCL is really an evolution or worsening of multiple myeloma and is associated with more genetic mutations.
• These two diseases (primary and secondary PCL)  are different disorders with different genetics and survival.

TC Classification

In 2005, Bergsagel and Kuehl proposed the TC classification of myeloma based on gene expression, showing that the GEP signature of t(11;14) was identical to that of t(16;14). Also, UAMS showed two subtypes of t(11;14): CD1 and CD2.

As time went by, the prognostic significance seemed to worsen. While all myeloma outcomes improved, it appeared the t(11;14) didn't. Lakshman showed declining ORR, PFS, and OS compared with standard-risk patients.

• More research showed that t(11;14) patients did worse than patients without translocation. Other multiple myeloma patients were living longer with the newer therapies.

Targeting Normal Plasma Cell Differentiation

In 2014, Boise proposed the “Tao of myeloma” Hypothesis–that effective treatments against myeloma could be developed targeting NORMAL PLASMA CELL DIFFERENTIATION, not the genetic changes of the cells, but rather natural vulnerabilities.

• Myeloma researchers learned more about the genetics of myeloma and also the biology of the actual plasma cell (as well as its dependence on the bone marrow microenvironment). Genetics and plasma cell biology were both involved and could target the differentiation of the cells without trying to create genetic-specific medication.   
• This explained why drugs like proteasome inhibitors are predominantly useful in the clinic for late B cell malignancies, such as myeloma and Waldenström, and to some extent in other B cell tumors.
• 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. Dr. Roger Tiedeman of Princess Margaret Cancer Center in Canada, shows that proteasome inhibitors like bortezomib (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. 

Immunomodulators (IMIDs)

IMIDS produce more than one effect. Immunomodulators (IMIDs) are drugs like: lenalidomide, thalidomide or pomalidomide.

• They work in myeloma because 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 (reactive oxygen species) are produced, and IMIDs inhibit detoxifying mechanisms (TrxR). In this case the cells “self-poison.” But to be effective there needs to be abundant protein folding.

Again, IMIDs primarily work in myeloma and Waldenström, some lymphomas, and the only other disease is the 5q- MDS. The protein context is essential. Remember, multiple myeloma with t(11;14) is lymphoplasmacytic (related to lymphocytes and plasma cells, both are white blood cells) with scant cytoplasm.

The Introduction Of Venetoclax

Investigators have shown that venetoclax might be more effective against myeloma 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.

Venetoclax is a BCL-2 (B-cell lymphoma 2) inhibitor. It is in the family of regulator proteins that starts or stops cell death. 

The work of Drs. Boise, Bahlis, and Neri have shown that both t(11;14) and perhaps elevated levels of expression of BCL-l and -2 predict a better response to venetoclax. This is the first targeted medication for a specific genetic subset of myeloma.

• 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. At ASH 2019, results for the Phase 1/2 study of venetoclax with daratumumab and dex with or without bortezomib were presented.
• Subsequent analyses have shown that venetoclax is particularly beneficial for patients with t(11;14).

Stem Cell Transplant

SCT (stem cell transplant) should not be delayed in patients with t(11;14).  

• Overall survival can be determined by the type of therapy for t(11;14) patients. For example: using a proteasome inhibitor plus an IMID is more effective than one of these alone.
• T(11;14) outcomes compared to other genetics in myeloma with stem cell transplant can be a vital treatment option.

Relapsed or Refractory Multiple Myeloma 

Venetoclax-based combinations are being used in relapsed and refractory multiple myeloma. Most commonly, it is used with dexamethasone, bortezomib, carfilzomib, and daratumumab. Clinical trials are ongoing to identify the most effective combinations.

Smoldering multiple myeloma (SMM) 

Smoldering multiple myeloma (SMM) with t(11:14) might also be treated with venetoclax and with IMIDs.

• 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. 

If you have t(11;14) myeloma or plasma cell leukemia, join HealthTree Cure Hub for multiple myeloma. Here, you will be able to connect with others with the same genetic features using our Twin Machine technology and find clinical trials designed specifically for your condition.

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