Multiple Myeloma an incurable disease, but I have spent the last 25 years in remission using a blend of conventional oncology and evidence-based nutrition, supplementation, and lifestyle therapies from peer-reviewed studies that your oncologist probably hasn't told you about.
Click the orange button to the right to learn more about what you can start doing today.
Make no mistake. Genetic abnormalities in Multiple Myeloma (MM) are an important diagnostic indicator. However, as complicated as the study linked below is, it only lists how “high risk” MM patient will respond to induction therapy. NOT how long that newly diagnosed multiple myeloma (NDMM) patient will live.
My point here is simple. Conventional oncology has made great strides at stabilizing the average NDMM patient. According to research, the average patient is a 69 year old with stage 2,3 MM. Helping this patient heal and reach some stage of remission (not always complete but very good or partial) is fantastic.
However, research and experience since my diagnosis in early 1994 has taught me two things.
First, that the majority of MM research is based on progression-free survival (PFS). This is your first remission, not how long you live (overall survival OS). And certainly PFS says nothing about your short, long-term and late stage side effects. Nothing about your quality-of-life.
Second, while diagnosing your genetic abnormalities is important, this indicator is no more important than say your CRAB symptoms, FLC or immunoglobulin levels.
The NDMM patient must look at his/her diagnostic information as a whole package. Then make the best decisions you can to form your therapy plans.
If you have any questions about genetic abnormalities, CRAB symptoms, FLC’s, etc. scroll down the page, post a question or comment and I will reply to you ASAP.
To Learn More About Diagnostic Criteria for Multiple Myeloma Click Now
“Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response…
The use of interphase fluorescence in situ hybridization (FISH), which has greater sensitivity than conventional cytogenetics to detect aberrations given the low proliferative rate of plasma cells, has revealed abnormalities in the majority of patients2,3.
Translocations involving the immunoglobulin heavy chain gene (IgH) locus and trisomies of odd numbered chromosomes are considered primary cytogenetic abnormalities, occurring at the early premalignant stages and potentially involved in disease pathogenesis4.
Amongst all prognostic factors described in MM, FISH abnormalities have been found to be the most predictive of outcomes5. Translocation
have been associated with poor prognosis, and their presence identifies high-risk (HR) disease.
On the other hand, patients with
and/or trisomies are considered to have standard-risk (SR) disease3,6…
Furthermore, poor outcomes associated with HR cytogenetic groups, have led to efforts to identify treatments and combinations with the potential to improve prognosis of patients with these abnormalities…
An IgH translocation was identified in 46%, and trisomies were found in 57%.
Overall, 40% had trisomies without IgH translocation, 30% had an IgH translocation without trisomies, and 16% had both trisomies and IgH translocation.
Primary IgH translocations to partner genes CCND1, CCND3, MAF, MAFB, and FGFR3/MMSET were mutually exclusive. The most frequently observed primary IgH translocation was
t(11;14), found in 16% of patients in the absence of trisomies,
and in 3% in the presence of trisomies.
t(4;14) was found in 6% in the absence of trisomies,
and in 3% in the presence of trisomies.
t(14;16) was found in 3% in the absence of trisomies, and in 1% in the presence of trisomies.
t(6;14) and t(14;20) were each found in ~1% of patients.
IgH variable region deletions or translocations involving partners other than the 5 recurrent partners were seen in 4% and 8% in the absence and presence of trisomies, respectively (Supplementary Fig. 1)…
Consistent with previous studies, IgH translocations and trisomies were detected in a large subset of patients (46% and 57%, respectively) with newly diagnosed MM12,15,16, and IgH translocations were more frequent in non-hyperdiploid myeloma17.
Among recurrent translocations, t(11;14) has been the most commonly detected, followed by t(4;14) and t(14;16)5,12, which is also consistent with our findings. In this study, 6% of patients had no cytogenetic abnormalities detected by FISH.
However a subset of these patients had insufficient cells to allow testing using all probes, and thus the prevalence of “normal cytogenetics” in our sample is likely lower; in a previous study by our group, 3% of patients had normal cytogenetics12.
Few studies have previously shown that certain primary cytogenetic abnormalities are associated with unique clinical and immunological disease features. t(11;14) translocation has been found to be associated with IgE and IgM heavy chain isotypes18, non-secretory MM7,18, LC MM5, lower serum monoclonal protein levels (<1 g/dL), and lower PCLI19.
In this study, we found that t(11;14) was associated with lower B2M levels, monoclonal protein concentration and PCLI, LC MM and lower stage disease.
However, 62% of patients with t(11;14) had ≥50% BMPCs compared to 54% in the entire cohort.
In contrast, t(4;14) translocation has been associated with ISS stage III disease7, IgA isotype7,9, higher serum monoclonal protein5 and B2M > 37,9, which is consistent with our findings.
t(4;14) was also associated with non-secretory MM in one study7. In a previous study from our group, PCLI was higher among patients with t(14;16), and similar to our findings, t(14;16) was associated with the lambda LC isotype5. In another study by Avet-Loiseau et al., there was no association between t(11;14) or t(4;14) and LC isotype or with degree of renal dysfunction9.
In this study, we found a higher proportion of renal dysfunction (Cr ≥ 2) among patients with t(14;16), t(6;14) and t(14;20) translocations.
Greenberg et al. studied the association between cytogenetic subtypes and clinical presentation of end-organ damage.
Patients with t(14;16) were more likely to have renal failure as the predominant myeloma-defining event on presentation, whereas t(11;14) and t(6;14) patients were more likely to present with bone disease8.
There is also evidence that cytogenetic abnormalities confer unique biologic features; t(11;14) was found to be associated with lymphoplasmacytoid morphology, while t(4;14) was associated with immature plasma cell morphology7.
In addition to their clinical and biologic significance, we sought to assess if primary cytogenetic abnormalities were associated with differences in response to induction treatment with novel agents. Interestingly, we found that patients with IgH translocation had higher response to PI-based first-line induction treatment compared to patients with trisomies without IgH translocations; however there was no difference in TTNT. Conversely, patients with trisomies had a higher response to an IMiD-based induction regimen and longer TTNT compared to those with IgH translocation.
Use of PI-based induction has been associated with improved complete response rates in high-risk cytogenetic groups, specifically with t(4;14). However, these results have not been consistent in all studies20,21,22. In our study, the patients with HR IgH translocations achieved a higher rate of ≥VGPR compared to those with SR IgH translocations when treated with a PI + IMiD based combination.
However, the rates of ≥VGPR did not differ between the two groups when the induction treatment was PI-based or IMiD-based. Despite evidence that PI + IMiD based combinations improve the prognosis of patients with high-risk cytogenetics, particularly t(4;14) translocation23, there has not been previous evidence of superior responses in patients with high-risk translocations compared to those with standard-risk disease for various PI + IMiD based combinations24,25.
Variables outcomes with treatment have been reported even within individual cytogenetic groups26. This may reflect heterogeneity in patient and disease characteristics within individual cytogenetic groups including the presence of specific secondary cytogenetic abnormalities.
|Primary abnormalities||Tested N||Abnormality N (%)|
|IgH translocation with trisomies||1959||312 (16)|
|Unknown partner/del of IgH region||1959||156 (8)|
|IgH translocation without trisomies||1959||581 (30)|
|Unknown partner/del of IgH region||1959||71 (4)|
|Trisomies without IgH translocation||1959||791 (40)|