Case presentation
Although some reviewers postulated that secondary AML occurs during complete remission of MM after chemotherapy, other scholars hypothesized that myeloma cells can stimulate bone marrow during cell proliferation, this phenomenon may result in subsequent development of a second hematological malignancy, particularly in cases with Rb-1 deletion [5]. Reports showed that the underlying monoclonal gammopathy of undetermined significance (MGUS) progresses to MM, resulting in the co-existence of MGUS and AML, particularly in elderly patients [9]. The simultaneous development of AML and MM in a patient without previous exposure to chemotherapy is a rare event. The possibility that these two malignancies may originate from common stem cells has not been supported with evidence. Malhotra et al. [11–13] reported 15 cases diagnosed with both Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and MGUS or multiple myeloma (MM) at their institute over a period of 5 years (January 2008 to December 2012). Eleven patients with MGUS and two patients with MM had received prior radiation treatment or chemotherapy and then developed MPNs. The two other patients with MM who did not received any cytotoxic treatment developed myelofibrosis. MGUS (Monoclonal gammapathies) denotes the presence of a monoclonal protein without manifesting MM features or other related malignant plasma-cell disorders, such as Waldenstrom macroglobulinemia, primary amyloidosis, B-cell lymphoma, and chronic lymphocytic leukemia [14].
The vast majority of MGUS patients did not present any symptoms. Clinical observations regarding the development from MGUS to MM indicated the absence of symptoms such as anemia, bone destruction, hypercalcemia, and renal function damage; only the serum M protein and the number of bone marrow plasma cells showed changes [15]. In the current study, we report a patient who underwent regular physical examination annually for 5 years and did not manifest any clinical symptoms, such as anemia, bone destruction, hypercalcemia, renal function damage, and abnormal immunoglobulin items, through routine clinical laboratory examinations. The present case was demonstrated myeloid cell malignancy and atypical plasma cells on cytology based on the immune markers of bone marrow myeloid cells and bone marrow plasma cells were determined by flow cytometry. The results showed that the CD138 positive expression of bone marrow plasma cells,and the CD38 strong expresion, the CD117, CD33, CD34 and LHA-DR positive expression, and CD15,CD56, CD17 and MPO part or weak positive expression of bone marrow myeloid cells and FISH analyses of magnetically separated plasma cells. The presence of the M protein in immune fixation electrophoresis supported the diagnosis of concurrent AML and MM without history of chemotherapy except ultraviolet irradiation.
The mechanism of the simultaneous occurrence of AML and MM without exposure to chemotherapy remains unclear. The deletion of RB-1, TP53, and lP32 was associated with the simultaneous occurrence of AML and MM. We speculate that multiple gene mutation or some susceptible genes may be involved in the simultaneous occurrence of both malignancies. Nevertheless, the mechanism underlying the simultaneous occurrence of AML and MM must be further investigated.
Studies have reported that disease management in patients who developed MM focuses on myeloma treatment. Anti-cancer agents, such as thalidomide, lenalidomide, and pomalidomide, demonstrated evident activity in MPN and MM and should be considered in the treatment regimen [16].
The concurrent prognosis of AML and MM remains very poor, and a standard treatment regimen has not been established. Murukutla et al. [10] summarized the therapy experiences of patients in prior reports, which included the use of drugs, such as bortezomib, tipifarnib, cyclophosphamide, vincristine, cytarabine, idarubicin, melphalan, and prednisone. Recently, Kim et al. [8] reported a 51-year-old man who had no past medical history but presented with simultaneous diagnosis of myeloma and AML, which were successfully treated with allogeneic stem cell transplantation. However, these therapy experiences are insufficient to construct a model protocol. The combination of bortezomib with CAG exhibits evident curative effects on elderly patients who are not suitable for allogeneic stem cell transplantation. In the present case, the patient achieved and maintained remission for more than 6 months. This finding may benefit the selection of optimum treatment options for this specific group of patients.
UV radiation is a complete carcinogen, especially for long-term management of children and young adults and in combination with topical or systemic immunosuppressants [17]. We suspect the patient’s malignancy may be related to exposure to the UV radiation, but that no data to proof this hypothesis can be given.
The genetic and molecular biomarkers of a case with simultaneous AML and MM have made considerable progress with the technological developments of flow cytometry and FISH. Before 2003, all case reports of simultaneous presentation of AML and MM performed a type of serum immunofixation test that revealed the types of paraproteins in patients, including IgA, IgA/k, IgG, IgG/k, and IgG/λ; however, few cases conducted the chromosome type test, and the results displayed 46XY and hypodiploidy, as well as chromosomal abnormalities [3, 10]. Luca DC and Almanaseer IY (2003) [1] performed an immunohistochemical test (flow cytometric analysis), which demonstrated myeloblasts with positive expression of Cd14, CD33, and HLA-DR, and a negative expression of CD45 for plasma cells; cytogenetic test showed that the karyotype was monosomy 13. Kim et al. [8] reported a case of simultaneous presentation of AML and MM with k-type paraprotein; immunohistochemical test of the case revealed plasma cells to be positive for CD138 with kappa light chain restriction and myeloblasts to be positive for CD34 and CD117; flow cytometric test confirmed the presence of two distinct neoplastic populations of plasma cells and myeloblasts; fluorescence in situ hybridization (FISH) test revealed a complex chromosomal pattern, with +5, +7, +8, +8q22, +11q23, −13q14, −16q22, +17q13.1, +20q12, and +21q22, and immunoglobulin heavy chain (IgH) rearrangement. The present study showed that the new biomarkers included the abnormal expression levels of the amplified RB-1, TP53, and CDKN2C (1p32) for plasma cells by FISH, as well as the positive or partial expression of CD33, CD15, CD56, CD7, CD17, and MPO for myeloblasts via flow cytometric test.
In the present study, the hybridized probes of FISH test included RB-1, TP53, Bcr/abL, PML/RARA, AML1/ETO, MLL, FGFR1, CBFB, TET/AML, Bcl-2, MYC, and CCND1/JgH. However, gene mutation was not detected for the negative biomarkers by FISH analysis. Some recent reports showed that FLT3 ITD, NPM1, or CEBPA mutation is associated with AML [18–20]. Testing the gene mutation for the negative biomarkers of FISH analysis is the most feasible idea. However, the limitation of this study was the failure to perform the gene mutation test for the negative molecules of FISH test, such as FLT3, ITD, NPM1, and CEBPA.