(PA-318) Precision Medicine in a Patient with Multiple Myeloma Presenting with t(2;11) and CCND1 Overexpression

Cytogenetic (CG) abnormalities are common in multiple myeloma (MM) and frequently involve the IGH locus (14q32.33). IGH rearrangements lead to specific oncogenes falling under control of the IGH enhancer. One such translocation, t(11;14) [IGH::CCND1], is associated with increased expression of CCND1 (11q13) and B-cell leukemia/lymphoma 2 (BCL-2) protein. Venetoclax, a BCL-2 inhibitor, is used in the treatment of this subset of MM patients. Translocations involving IGK (2p11.2), the light chain locus, and CCND1 are rarely described in MM and its functional significance is relatively obscure. Here, we present a unique case of newly diagnosed MM, with an unusual t(2;11)(p11.2;q13) that was refractory to multiple lines of therapy then demonstrated a rapid and durable response to a venetoclax-based treatment.

Methods:   n/a

Results:   

A 71y/o female was diagnosed IgG lambda MM. Labs were notable for M-spike 2.11 g/dL, IgG 2,727 mg/dL, lambda free light chain 5,238.0 mg/L, kappa-lambda ratio 0.0, (R-ISS stage 1). PET/CT showed numerous hypermetabolic lytic lesions. Bone marrow biopsy (BMBx) showed 40% plasma cells (PC), with CG and FISH demonstrating a hypodiploid karyotype (6/20 of metaphase cells) and a balanced translocation of chromosomes 2 and 11. Due to t(2;11)(p11.2;q13), further FISH studies using IGK break-apart and IGH::CCND1 fusion probes were performed, with 85% of interphase cells exhibiting an IGK rearrangement and 82% with a gain of CCND1 without a detectable IGH::CCND1. BCL-2 (3+) and Cyclin D1 were positive by IHC.

First line bortezomib, lenalidomide and dexamethasone was started with a partial response. On progression, repeat BMBx was sent for NGS, which confirmed IgK::CCND1. She received two additional lines of therapy with rapid progression. On subsequent BMBx, whole exome sequencing showed that the IGK::CCND1 rearrangement resulted in the fusion of exon 4 of IGK to the 3’ UTR of CCND1. The decision was made to transition to venetoclax, carfilzomib and dexamethasone. 6 months later, workup showed a stringent complete response (sCR) with normal CG studies. The patient has remained in a sCR with persistent Measurable Residual Disease by NGS exceeding 3 years.

Conclusions:   

Here we describe a rare case of t(2;11)(p11.2;q13) identified by a gain of CCND1 without IGH::CCND1 in the background hypodiploidy. Cyclin D1 overexpression suggests that the proximity of the IGK enhancer to the 3’ region of CCND1 may be sufficient to upregulate CCND1 transcription. As overexpression of BCL-2 was seen, venetoclax was considered for treatment. This patient represents the only case described of t(2;11)(p11.2;q13) in MM treated with venetoclax. This case highlights the power of molecular diagnostics in identifying rare rearrangements, such as those involving IGK, or when a gain of CCND1 is identified without hyperdiploidy or IGH::CCND1. This approach identified biomarkers that allowed for tailored treatment that was more effective and better tolerated than standard therapy for the patient.