Unusual Co‐Occurrence of Multiple Myeloma and AML in a Patient With Germline CEBPA Variant. Expanding the Spectrum of Hereditary Hematologic Malignancies

Timeline and genetic analysis of a 55-year-old female with a family history of gastric cancer and multiple myeloma, who was diagnosed with AML and a germline CEBPA variant. The advent of precision genomics has brought hereditary predisposition syndromes (HPS) into the spotlight, emphasizing genetic factors in hematopoietic neoplasms, especially myeloid malignancies. Among these, CEBPA variants are well-recognized drivers in acute myeloid leukemia (AML) [1]; however, their role in plasma-cell malignancies such as multiple myeloma (MM) remains underexplored. We report an unusual case of a 55-year-old female harboring a germline CEBPA variant who developed MM followed by therapy-related-AML (t-AML), highlighting potential broader oncogenic implications of CEBPA variants. Her family history included gastric cancer in her mother at 36 years and MM in her maternal uncle, both deceased (Figure 1A). The patient's severe psychiatric condition complicated medical management. Diagnosed with IgA kappa MM in December 2016, she presented with osteolytic lesions and hypercalcemia. Treatment with six cycles of bortezomib, thalidomide, dexamethasone from December-2016 to July-2017 led to complete remission. Autologous hematopoietic stem cell transplantation was not feasible due to her psychiatric status, so maintenance therapy with thalidomide continued until 2018 but was halted due to side effects. Relapses in 2019 and 2021 were managed with lenalidomide and dexamethasone, followed by third-line treatment involving melphalan, prednisone, and bortezomib, with subsequent thalidomide maintenance. In 2023, she developed cytopenias. A complete blood count showed a WBC 5.9 × 109 L−1 (60% myeloblasts), hemoglobin 11.2 g/dL, MCV 95 fL, and platelet 220 × 109 L−1. Bone marrow aspirate revealed 80% myeloblasts, consistent with AML-M2. The blast immunophenotype was CD34+, HLA-DR+, CD117+, MPO+, CD13+/−, with no aberrant expressions or evidence of monocytic, erythroid, or megakaryocytic differentiation. BM cytogenetics showed 45,XX [10], and the AML FISH panel was negative. A myeloid NGS targeted panel on the bone marrow identified three pathogenic variants: two in CEBPA (c.161del, p.(Gly54Alafs*106) VAF 41.7% and c.493dup, p.(Arg165Profs*5) 47.2%, respectively) and one in WT1 (c.1090_1093dup, p.(Ala365Valfs*4) VAF 42.3%). Both CEBPA variants were frameshift variants in the N-terminal region, not involving the bZIP domain. The presence of these CEBPA variants, both with a VAF greater than 30%, suggesting a germline origin. To confirm the germline origin, the patient's two living relatives (sister and daughter) were tested. Peripheral blood DNA was extracted and PCR followed by Sanger sequencing was performed. These studies confirmed the germline origin of the CEBPA variants (Figure 1B). Two additional siblings declined genetic testing. Due to her psychiatric condition, intensive chemotherapy was declined. She started treatment with azacitidine monotherapy, completing nine cycles and achieving complete remission. However, the AML relapsed, and Venetoclax was added. Despite this treatment, the disease progressed, and the patient ultimately passed away. Written informed consent for publication was obtained from the patient's family. This case highlights a germline CEBPA variant in a patient with MM followed by AML, a rare clinical scenario suggesting broader oncogenic implications of CEBPA beyond AML. Evidence linking CEBPA variants to MM is scarce; one study identified CEBPA variants in 2/39 MM cases (5.1%) among various hematologic malignancies [2]. MM typically involves genetic abnormalities like IgH translocations, hyperdiploidy, and KRAS, NRAS, and TP53 mutations [3]. The coexistence of a germline CEBPA variant in a patient with MM suggests complex genetic interactions impacting hematologic neoplasm development beyond the myeloid lineage. The potential link between CEBPA and a family history of MM is intriguing, but unconfirmed. Further research is needed to clarify whether CEBPA contributes to MM pathogenesis or if other genetic factors better explain the familial occurrence. Therapies for MM, including alkylating agents, proteasome inhibitors, and immunomodulators, are known risk factors t-AML [4]. This case suggests possible synergy between cytotoxic treatments and germline predispositions, emphasizing the importance of identifying CEBPA variants for genetic counseling and familial risk assessment. Further research on germline CEBPA variants in non-myeloid malignancies may reveal new oncogenic mechanisms. Investigating the interaction between cytotoxic therapies and genetic predispositions could clarify AML progression pathways. Sincerely, The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/cge.14693. The data that support the findings of this study are available from the corresponding author upon reasonable request.