Amp(1q) and tetraploidy are commonly acquired chromosomal abnormalities in relapsed multiple myeloma.

Long-term disease control in multiple myeloma (MM) is typically an unmet medical need, and most patients experience multiple relapses. Fluorescence in situ hybridization (FISH) is the standard technique to detect chromosomal abnormalities (CAs), which are important to estimate the prognosis of MM and the allocation of risk adapted therapies. In advanced stages, the importance of CAs needs further investigation. From 148 MM patients, two or more paired samples, at least one of which was collected at relapse, were analyzed by FISH. Using targeted next-generation sequencing, we molecularly investigated samples harboring relapse-associated CAs. Sixty-one percent of the patients showed a change in the cytogenetic profile during the disease course, including 10% who acquired high-risk cytogenetics. Amp(1q) (≥4 copies of 1q21), driven by an additional increase in copy number in patients who already had 3 copies of 1q21, was the most common acquired CA with 16% affected patients. Tetraploidy, found in 10% of the samples collected at the last time-point, was unstable over the course of the disease and was associated with TP53 lesions. Our results indicate that cytogenetic progression is common in relapsed patients. The relatively high frequency of amp(1q) suggests an active role for this CA in disease progression.

Clonal dynamics in a composite chronic lymphocytic leukemia and hairy cell leukemia-variant.

Composite lymphoma is the rare simultaneous manifestation of two distinct lymphomas. Chronic lymphocytic leukemia (CLL) has a propensity for occurring in composite lymphomas, a phenomenon that remains to be elucidated. We applied cytogenetics, droplet digital polymerase chain reaction, and massively parallel sequencing to analyze longitudinally a patient with CLL, who 3 years later showed transformation to a hairy cell leukemia-variant (HCL-V). Outgrowth of the IGHV4-34-positive HCL-V clone at the expense of the initially dominant CLL clone with trisomy 12 and MED12 mutation started before CLL-guided treatment and was accompanied by a TP53 mutation, which was already detectable at diagnosis of CLL. Furthermore, deep sequencing of IGH showed a composite lymphoma with presence of both disease components at all analyzed timepoints (down to a minor clone: major clone ratio of ~1:1000). Overall, our analyses showed a disease course that resembled clonal dynamics reported for malignancies with intratumoral heterogeneity and illustrate the utility of deep sequencing of IGH to detect distinct clonal populations at diagnosis, monitor clonal response to therapy, and possibly improve clinical outcomes.

The prognostic value of additional copies of 1q21 in multiple myeloma depends on the primary genetic event.

Hyperdiploidy (HRD) and specific immunoglobulin heavy locus (IGH) translocations are primary chromosomal abnormalities (CA) in multiple myeloma (MM). In this retrospective study of 794 MM patients we aimed to investigate clinical features and common CA including gain(1q) in separate subgroups defined by primary CA. In the entire group, we confirmed that gain(1q) was associated with short time to next treatment and adverse overall survival (OS). The impact was worse for four or more copies of 1q21 as compared to three copies. However, in a subgroup of patients with clonal gain(11q) and without known primary IGH translocations (CG11q), already three copies of 1q21 were associated with a poor outcome; in the absence of gain(1q), patients in this subgroup had a remarkably long median OS of more than nine years. These cases were associated with HRD, coexpression of CD56 and CD117, male gender, and IgG subtype. In non-CG11q patients, four or more copies of 1q21 (but not three copies) had a significant adverse impact on outcome. Several associations with CA and clinical findings were observed for the defined subgroups. As an example, we found a predominance of early tetraploidy, plasma cell leukemia, and female gender in the t(14;16) subgroup. Our results underscore the importance of subgrouping in MM.