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Journal of Hematology

Case Report

Volume 13, Number 3, June 2024, pages 94-98

Non-Secretory Multiple Myeloma Associated With High-Risk Phenotype and Complex Cytogenetics Including t(8;22)

Multiple myeloma (MM) is a hematologic malignancy defined by clonal proliferation of plasma cells within the bone marrow and constitutes 1-2% of all new cancer diagnoses in the United States each year [1]. In addition to proliferation of monoclonal plasma cells within the bone marrow, MM is typically characterized by the presence of monoclonal immunoglobulins in the serum and/or urine. Either the secreted proteins or the malignant plasma cells can lead to the end-organ damage seen in MM [2]. Quantifiable serum and/or urine monoclonal proteins and/or light chains are used to monitor disease activity and response to treatment. However, approximately 3% of MM patients have malignant cells that do not make or secrete immunoglobulins, lack evidence of immunoglobulin in serum or urine, and are diagnosed as non-secretory multiple myeloma (NSM) [3]. NSM patients may have slightly reduced overall survival (OS) compared to MM patients with secretory disease [4]. Providers must rely on advanced imaging and frequent bone marrow biopsies to determine treatment response, and this would require a restructuring of commonly accepted treatment response criteria. Due to this, there is a scarcity of randomized controlled data describing how NSM patients respond to novel therapeutic options [5]. Certain cytogenetic abnormalities have been identified as harboring a worse prognosis with a more aggressive disease course [6]. The fusion product t(8;22) - rarely seen in MM - may also be related to poor prognosis.

A 60-year-old male with no significant past medical history presented to his primary care physician with gradually worsening left-sided chest pain over multiple weeks. Physical exam was significant for point tenderness over the left anterior lower ribs and was managed with over-the-counter analgesic medications.

Due to lack of improvement, a chest radiograph was obtained 2 months later which showed a 2.1 × 1.9 cm lytic lesion in the lateral left seventh rib with a small left-sided pleural effusion. Computed tomography (CT) imaging revealed lytic lesions throughout the spine as well as on the left seventh rib and in the upper sternum. Additionally, a bone survey revealed further osseous disease in the proximal left humerus and re-demonstrated known lesions in the axial skeleton. Given the high suspicion for MM, serum and urine free light chain assays and serum protein electrophoresis with immunofixation were obtained which showed no evidence of a monoclonal protein. A 24-h urine electrophoresis and immunofixation was also negative for monoclonal protein. Chemistry panels including calcium, renal and liver function testing were all within normal limits. Complete blood counts showed mild normocytic normochromic anemia with a hemoglobin of 13.1 g/dL.

As the clinical suspicion for MM remained high due to lack of explanation of lytic lesions, a bone marrow biopsy was performed which revealed diffuse involvement by non-light chain restricted atypical plasma cells (Fig. 1).

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Figure 1. Bone marrow biopsy (H&E stain). (a) Bone marrow intertrabecular space diffusely infiltrated by sheets of non-cohesive cells. Residual bone marrow elements are scattered (• megakaryocyte; ○ adipocytes) (H&E, × 100 optical magnification). (b) Sheet of atypical plasma cells infiltrating with residual bone marrow elements. The plasma cells have eccentric nuclei with mild atypia and moderate eosinophilic cytoplasm with perinuclear hofs (H&E, × 400). H&E: hematoxylin and eosin.

Flow cytometry revealed a population of CD38 and CD138 positive atypical plasma cells with aberrant expression of CD20 and CD117, without expression of CD19 or CD56. The plasma cells were negative for both surface and cytoplasmic light chain expression, supporting the diagnosis of NSM (Fig. 2).

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Figure 2. Bone marrow biopsy (IHC and ISH). (a) Plasma cells show strong membranous staining (CD138, IHC, × 100). (b) Few scattered positive cells (blue) represent residual uninvolved plasma cells; the atypical plasma cells appear negative (kappa light chain, ISH, × 100). (c) Few scattered positive cells (blue) represent residual uninvolved plasma cells; the atypical plasma cells appear negative (lambda light chain, ISH, × 100). IHC: immunohistochemical; ISH: in situ hybridization.

Chromosome analysis revealed a complex karyotype in 6/20 cells characterized by deletions of chromosomes 7p and 20q, reciprocal translocations t(8;22) and t(10;22), and an unbalanced translocation between chromosomes 1 and 16 resulting in a der(16). In addition, fluorescence in situ hybridization (FISH) analysis confirmed the involvement of the MYC locus in the t(8;22)(q24.2;q11.2) translocation, as evidenced by MYC break apart probe (Fig. 3).

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Figure 3. MYC break apart probe: t(8;22)(q24.2;q11.2) detected using dual color dual fusion FISH probe. FISH: fluorescence in situ hybridization.

Serology at time of diagnosis revealed a β2-microglobulin of 5.5 mg/L (1 - 2 mg/L), serum albumin of 4.3 g/dL (3.2 - 4.6 g/dL), and lactate dehydrogenase (LDH) of 349 U/L (110 - 216 U/L). Findings were consistent with a stage III disease based on revised International Staging System (R-ISS).

The patient was treated with lenalidomide, bortezomib, and dexamethasone induction therapy with daratumumab added after cycle 1. The addition of anti-CD38 monoclonal antibodies to standard triplet regimens has become the standard of care for high-risk transplant eligible MM patients [7]. Lenalidomide was discontinued after cycle 3 due to ocular toxicity. After four cycles of treatment, bone marrow biopsy showed a decrease in malignant plasma cell burden from almost 100% to 5% and he underwent an autologous peripheral blood stem cell transplant. Post-transplant, he was maintained on single agent bortezomib due to his inability to tolerate lenalidomide and the unclear role of daratumumab in the post-transplant maintenance setting [8]. Furthermore, bortezomib maintenance appears to improve survival in the post-transplant setting for high-risk MM patients when compared to thalidomide maintenance [9].

As his disease cannot be monitored with serology, he has been followed with periodic bone marrow biopsies in addition to history, physical exam, laboratory evaluation and serial positron emission tomography CT (PET-CT) scans. Most recent PET-CT showed gross stability of all osseous lesions with no new or enlarging lesions. He is currently 29 months post-transplant and last bone marrow biopsy showed no morphologic increase in plasma cells with resolution of previously seen cytogenetic changes.

The diagnosis of NSM first requires the diagnosis of MM, which is made more difficult due to the lack of light chain expression. MM can be established by various criteria, including: 1) ≥ 60% clonal plasma cell population in the bone marrow; and 2) ≥ 10% clonal plasma cells in the bone marrow or an extramedullary plasmacytoma with evidence of myeloma defining events including end-organ damage attributable to the neoplastic population. MM can then be subtyped, with NSM also requiring the absence of monoclonal protein in the serum and urine as well as negative serum free light chain study [2].

NSM constitutes around 3% of all cases of MM and can be further categorized into four subgroups: “non-producers”, “true non-secretors”, “oligosecretors” and “false non-secretors”. The non-producer subgroup is characterized by MM cells that are unable to synthesize any immunoglobulins whatsoever, while the non-secretor subgroup is characterized by MM cells that can produce protein but have defects in secreting immunoglobulins [3]. Oligosecretors or FLC-restricted MM is seen when MM cells only produce FLC in the absence of a heavy chain and the false non-secretor subgroup refers to MM cases where there are measurable intracellular immunoglobulins by immunofluorescence without measurable extracellular component by conventional testing. As our patient had no intracellular immunoglobulin detected nor any monoclonal heavy or light chains detected in serum, he would be classified as a non-producer [5].

While large, randomized studies evaluating the prognosis and optimal treatment for NSM are lacking, the few studies comparing outcomes between non-secretory and secretory myeloma generally show similar outcomes between the two groups [10, 11], while at least one retrospective review found OS to be slightly worse in NSM patients [4]. However, when compared to other NSM patients, the non-producer subtype has been identified as having a markedly reduced progression-free survival (PFS) and decreased sensitivity to MM therapies [12]. A retrospective review of 30 patients with a new diagnosis of NSM over a 10-year period at the Mayo Clinic identified half the cohort of patients to have ISS stage III disease [4]. First-line therapy did not generally differ from age-matched controls with secretory MM. There was an increased propensity for these patients to harbor t(11;14) which is most commonly identified in mantle cell lymphoma [13]. This finding has clinical relevance due to high bcl-2 expression in MM patients with t(11;14) and the therapeutic benefit of bcl-2 inhibition in this subset of patients [4]. Further studies are needed to evaluate the efficacy of frontline MM therapies as well as the frequency and potential therapeutic implications of t(11;14) in newly diagnosed NSM patients.

Identifying patients with higher-risk disease is of utmost importance to determine the appropriate induction regimen. High-risk disease has been associated with increased risk of relapse, decreased PFS and OS. Prognostication and risk stratification of MM patients is typically performed using R-ISS which is based on cytogenetic profile using interphase FISH, and disease markers including β2-microglobulin, LDH, and albumin.

Our patient was diagnosed with R-ISS III disease based on elevated levels of β2-microglobulin and serum LDH, even without the presence of any high-risk cytogenetic abnormalities. Patients with stage III disease based on R-ISS have an estimated median PFS of 29 months [14].

Cytogenetic abnormalities play a significant role in prognostication systems for MM patients. The International Myeloma Work Group identified translocations t(4;14), t(14;16), t(14;20), del(17/17p), any non-hyperdiploid karyotype, del(13), gain of 1q and high-risk gene expression profiling as high-risk cytogenetic abnormalities. The presence of ≥ 3 cytogenetic abnormalities is considered complex cytogenetics and is associated with ultrahigh risk with an expected OS of < 2 years [6].

Translocations involving c-MYC on chromosome 8 and IGL on chromosome 22, in particular t(8;22)(q24.2;q11.2) is seen in approximately 5-10% of Burkitt lymphoma cases but is rare in MM [15]. Only 19 cases have been reported in literature of patients with this translocation. In all previously reported patients, t(8;22) was identified as a component of complex cytogenetic karyotype [16-24]. To our knowledge, this is the first reported case of a patient with t(8;22) with NSM.

NSM is a rare subtype of MM which has four distinct phenotypic subgroups, one of which is the “non-producers”. We report a case of NSM with a non-producing phenotype and with t(8;22) as a part of complex cytogenetics. Despite R-ISS staging considering the patient to have stage III disease, the patient has multiple additional negative prognostic features including complex cytogenetics and the non-producing phenotype of NSM, suggesting a more inferior prognosis. Our patient has sustained complete response which may be attributed to aggressive frontline treatment and continued maintenance therapy. While complex cytogenetic abnormalities have been associated with worse outcomes in patients with MM, it remains unclear whether the presence of t(8;22) independently affects the prognosis of those patients. This case highlights the need for appropriate risk stratification of patients by identifying clinically higher risk phenotypes and incorporating all cytogenetic information.

Acknowledgments

The authors would like to thank Allegheny Health Network and NeoGenomics.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Informed consent was obtained from the patient.

Author Contributions

RAJ and JRL wrote, edited and finalized the manuscript. AA, KA and MK conceptualized and performed background research. RM, KF and JRM provided formal analysis and writing regarding genetics. JCA wrote and edited the manuscript. PN and NRJ wrote and provided pathology images and analysis. SS and PM wrote, finalized and provided supervision for the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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