Beyond FISH: CMA detects 8p-, xq+, and y- as markers of early post-transplant progression in myeloma Free

Background:

Multiple myeloma (MM) encompasses a broad clinical spectrum from indolent to aggressive disease. Recurrent cytogenetic abnormalities play an important role in biology and prognosis of MM, and accurate detection of those abnormalities defines risk stratification and may guide therapeutic approach. Low proliferative rate of myeloma cells limits utility of conventional karyotyping. Fluorescent in-situ hybridization analysis (FISH) performed on CD138 enriched sample is the current standard for the detection of clinically significant cytogenetic abnormalities, however findings are limited by using a pre-defined set of probes. Cytogenomic microarray (CMA) allows detection of copy number changes and loss of heterozygosity (LOH) (but not balanced translocations) across the entire genome with high resolution, thus potentially allowing to identify novel prognostically significant cytogenetic changes.

Aims:

To identify cytogenetic abnormalities detected by CMA post-induction that are associated with early post-transplant progression in MM.

Methods:

We analyzed post-induction bone marrow samples of patients with newly diagnosed MM who underwent autologous SCT at our center. Only patients treated with one line of induction therapy were included. CMA was performed on CD138-enriched samples using ThermoFisher CytoScan HD microarrays for copy number and heterozygosity alterations. Fisher exact test was used to compare frequency of cytogenetic abnormalities between groups.

Results:

Of 316 pts who met the inclusion criteria, 202 (63.9%) pts were progression free at 18m (late progressors) and 51 pts had progressive disease (PD) before 18 m (early progressors). Patients who were either lost to follow up or started a new line of therapy before 18m without PD were excluded from the analysis.

Mean age (62.2y vs 62.7y) and induction regimens (most common RVD in 54.9% vs 54.5%, Dara RVd in 25.5% vs 25.7%, CyBorD in 5.9% vs 7.4%) were very similar between the late and early progressors. Presence of ≥5% plasma cells or presence of abnormal CMA findings in the post-induction bone marrow sample did not differ between the late and early progressors (56.9% vs 47.5%, p 0.273 and 41% vs 37%, p 0.629 respectively).

Recurrent abnormalities with frequency cutoff ≥10% in at least one group included 1q+, 8p-, 9+, 13-, 15+, Xq+, and Y-. Comparing the groups of early and late progressors, 8p- was found almost exclusively in early progressors (13.7% vs 0.5%, p 0.0001). Among male patients, Y- was found almost exclusively in early progressors (19.4% vs 2.6%, p 0.003) and was not associated with older age. Other abnormalities significantly more prevalent in early progressors were 13- (21.6% vs 8.4%, p 0.012) and Xq+(11.8% vs 4%, p 0.04).

Discussion:

Early post-transplant progression in MM patients is associated with inferior survival. While some of those patients have known predictors of inferior PFS at diagnosis, others do not, and fall under the category of functionally high-risk disease. CMA is a sensitive tool that allows detection of chromosomal abnormalities across the entire genome, including ones that are not covered by the standard FISH panels, and therefore may allow detection of additional chromosomal aberrations predictive of high-risk disease.

We identified 4 abnormalities that were significantly more prevalent in our cohort of early progressors. One of those, monosomy 13, is a very common abnormality in newly diagnosed MM and is not considered an independent adverse prognostic factor. In our analysis of post-induction marrow samples, detection of monosomy 13 may be associated with early progression by indicating persistence of a resistant clone, or by association with other abnormalities. Strikingly, deletion of 8p was noted almost exclusively in early progressors. It was shown that 8p- may contribute to resistance to bortezomib through loss of TRAIL pathway, but effects of 8p- on transplant outcomes are unknown. Other interesting findings were high incidence of loss of Y in the early progressors, that was independent of age, and gain of Xq, significance of which is unknown.

In conclusion, CMA may help to identify novel chromosomal abnormalities associated with high-risk myeloma. Our findings of association of 8p-, Xq+, and Y- with early progression warrant further investigation. Detection of novel predictors of early progression on post-induction assessment may help tailor post-transplant strategies.