A blood test for MRD monitoring?
Through the IMF Black Swan Research Initiative® projects, several myeloma teams have been investigating different blood tests for monitoring low levels of myeloma (MRD: minimal residual disease). One such collaboration has just reported results. The study’s co-principal author, BSRI team member Dr. Bruno Paiva, has been instrumental in developing the NGF test in the bone marrow, and now is involved in studies of circulating plasma cells (CTCs: circulating tumor cells identified as part of a “liquid biopsy”).
Several important points about blood testing are becoming clear:
- Myeloma cells are routinely present in the blood of patients with active myeloma and frequently present in patients with smoldering myeloma (SMM).
- The genetic mutations found in myeloma cells in the blood are very similar to the mutations in matched bone-marrow myeloma cells. The myeloma cells are definitely part of the same clone, although there may be some “sub-clone” variations.
- A much larger comparison is required to evaluate if a blood-sampling “liquid biopsy” can be used versus bone marrow sampling.
Using both methods
An emerging approach is to establish MRD negativity in the bone marrow using NGF testing with sensitivity at 10-6 level, giving a negative result: 0 out of a million cells. Thereafter, serial monitoring can rely upon the evaluation of the number, plus special features, of any myeloma cells found in the blood.
There has been skepticism about simple blood testing to detect and/or monitor cancer. However, in the case of myeloma, the very precise research by the Spanish team in developing the NGF method is making blood testing a reality. This will definitely make MRD monitoring much, much more manageable for patients and doctors alike.
Understanding causes of myeloma
There is a 2- to 4-fold increased risk of myeloma or related diseases among first-degree family members of patients with MGUS, SMM, or active multiple myeloma (MM). This means that 2 to 5% of patients can have an affected relative. But what causes this increased risk? A recent paper shows that about one-third of the family cases occur because multiple genes which predispose to myeloma can all be found in the affected families.
In technical terms, this is called “polygenic etiology,” or multiple genes contributing to the development of myeloma at once. So, what are these multiple genes that predispose to myeloma? There are at least 16 to17 DNA regions involved on (as of now) 10 different chromosomes: 3(p22.1); 5(q15); 6(p22.3; q21); 7(q36.1); 8(q24.21); 9(p21.3); 10(p12.1); 16(q23.1); 20(q13.13) and 22(q13). Each of these regions may contribute to the genesis of myeloma in different ways by affecting immunoglobulin levels, susceptibility to infection, and activation of cancer-causing genes such as MYC or anti-oncogenes like p53, which is involved in 17-p high-risk myeloma. The p53 target is especially important, since this is where chemical products such as benzene can attack “mutational hotspots” to either trigger cancer or increase its aggressiveness.
There is much more to be learned here. It will take time to work out how all the different factors lead to increased risk of MGUS or MM. In addition, there are clearly other important so-called “driving” mutations—those that occur in the majority of myeloma cases, which are not familial—that may be much more affected by environmental factors.
Further family studies
The IMF Black Swan Research Initiative supported the German contribution to this recent publication as well as another, much larger German project, which will reveal many more details about what is causing myeloma within families. In addition, the population-based study of Iceland, iStopMM, will allow researchers to establish decisive causal correlations because of the large number of MGUS patients who will be studied there (more than 4,000 patients with MGUS will be identified).
So, stay tuned for ongoing updates from both Germany and Iceland, and further news about blood testing for MRD!
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