Acquired Chromosomal Abnormalities t(14;16), Del(17p) or Del(13q) after Receiving Chemotherapies Predict the Poor Prognosis of Multiple Myeloma

Introduction:

Multiple myeloma (MM) is known as heterogeneous disease characterized by the clonal proliferation of tumor plasma cells. Recently, the prognosis of MM is classified depending on the appearance of cytogenetic abnormalities. However, no publication to date have investigated the best therapy to MM patients with these abnormalities. The chromosomal abnormalities such as t(14;16), del(17p) and del(13q) are known to be a poor prognosis in patients with untreated MM. In some cases, the appearance of these mutations change after receiving several chemotherapies. However, it has been unclear whether the changes of chromosomal abnormalities during receiving chemotherapies influence the prognosis of MM or not. In this study, we investigated the changes of chromosomal abnormalities and analyzed the prognosis in patients with MM.

Methods:

We studied 159 newly diagnosed MM patients who were treated in our hospital from July 2011 to March 2017, retrospectively. In 37 patients, using the samples acquired from bone marrow biopsy, the presence of t(14;16), del(17p) and del(13q) were tested by fluorescence in-situ hybridization (FISH) before induction and salvage therapy. Based on the analysis for the samples of healthy volunteers, the positive level of FISH was set at 2% or more, 3% or more and 6% or more for t(14;16), del(17p) and del(13q), respectively. The survival probabilities were analyzed using the Kaplan-Meier method and were compared using the log-rank test. P value was calculated by the Bonferroni method, to compare the three groups.

Results:

In 37 patients with MM, the median age was 63 years old (range 45-80), and males were 21 (56.7%). The International Staging System (ISS) scores were respectively 54.1%, 32.4% and 13.5% for stage I, stage II and stage III. At diagnosis, t(14;16) positive case was one (2.7%), del(17p) positive was six (16.2%) and del(13q) positive was 13 (35.1%). These results contained three double positive cases both del(17p) and del(13q) (8.1%). Median follow up time was 73 months (range 6-189). In 37 patients with MM, 4-year overall survival (OS) was 79.9% (95% CI, 62.3-89.9%, median OS: 73 months). We divided these 37 patients into three groups. The first group had disappearance of one of t(14;16), del(17p) or del(13q) chromosomal abnormalities during the clinical courses (n=9), the second group had no changes of those chromosomal abnormalities (n=23) and the third group had the addition of acquired chromosomal abnormalities (n=5). Five cases were in the third group; one case acquired t(14;16), three cases acquired del(17p) and one case acquired del(13q). There were two cases where del(13q) existed at diagnosis, then disappeared at the first disease progression and reacquired it at the second progression. We assigned these two cases into the group with no changes. 4-year OS of the groups with disappearance of one of those abnormalities, that with no changes of abnormalities and that with addition of acquired one of those abnormalities were 87.5% (95% CI, 38.7-98.1%, median OS: 101 months), 81.3% (95% CI, 57.4-92.6%, median OS: 73 months) and 60.0% (95% CI, 12.6-88.2%, median OS: 53 months), respectively (P=0.00689).

Discussion & Conclusions:

In our study, the group with the addition of acquired t(14;16), del(17p) or del(13q) showed the poorest prognosis. The group with disappearance of those chromosomal abnormalities during clinical courses exhibited the best prognosis among those three groups with a statistically significant difference. The acquired chromosomal abnormalities might have existed at the diagnosis as a minor population in heterogeneous myeloma cells and obtained predominance during the treatments as a resistant clone. Acquired chromosomal abnormalities t(14;16), del(17p), or del(13q) after receiving chemotherapy predict the poor prognosis of MM. It is important that testing chromosomal abnormalities occur before not only induction therapy but also salvage therapies.

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