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Multiple myeloma (MM) is a common hematologic malignancy with an annual incidence of 0.53 to 5 per 100,000 populations.[1] It arises from post germinal center B cells and shares many biologic characteristics with other B cell lymphoproliferative disorders. It can rarely occur synchronously with several indolent B cell lymphomas, providing insights into shared disease-initiating events and genetic alterations.[2] Approximately 50 cases of myeloma with synchronous chronic lymphocytic leukemia (CLL) have been reported in the literature so far, each contributing to the understanding of this rare phenomenon. Pragmatically, arriving at the correct diagnosis still remains the most important aspect. We present a patient with simultaneous presentation of MM and CLL and provide an overview of hematopathology findings, diagnostic pitfalls, and approach to the treatment of the same.
A 57-year-old lady with no earlier co-morbidities presented with a generalized weakness for 3 weeks and was evaluated elsewhere. Initial evaluation revealed multiple enlarged cervical lymph nodes and peripheral blood leukocytosis with lymphocyte predominance (white blood cell [WBC] count 16,000/μL, N 4%, L 94%). Other investigations were significant for elevated total protein concentration (13 g/dL) with reversal of the albumin: globulin ratio. Peripheral blood flow cytometry was performed, which showed a gated population of 86% by CD45/SSC, FSC/SSC, and CD19/SSC gating and was positive for CD19, CD20, CD23, CD5, CD200 expression and negative for CD34, CD38, CD10, CD25, CD103, CD123, kappa, lambda, ZAP-70, CD11c, and FMC-7 expression. Due to elevated total protein concentration, a serum protein electrophoresis was performed, which revealed an IgG lambda paraprotein. On telephonic consultation, we requested her to get a bone marrow aspiration and biopsy, which showed a hypercellular marrow with 74% plasma cells interspersed with small lymphocytes, casting suspicion of lymphoplasmacytic lymphoma (LPL) or indolent B cell lymphoma with plasmacytoid morphology. As the presence of IgG paraprotein and CD5 positivity on lymphoid cells are rare events in LPL, we requested her for a repeat bone marrow examination at our center.
At our center, clinical and peripheral blood findings were concurrent with findings noted elsewhere. A repeat bone marrow aspiration and biopsy were performed, which revealed a hypercellular marrow with nodular infiltrates of atypical small lymphoid cells. Adjacent marrow was significant for the presence of plasma cells with typical morphology. No other abnormal cells or increase in fibrosis was noted [composite [Figure 1] shows the above features.]
Figure 1: (a) Low power view showing focal nodular lymphoid aggregates in the bone marrow, Nodular lymphoid infiltrate (40x; H&E), (b) Nodular lymphoid infiltrate (100x; H&E), (c) Atypical small lymphocytes(left) and plasma cells (right) (H&E; 100x), (d) Adjacent marrow with increase in plasma cells (H&E; 100x)Immunohistochemistry on the lymphoid nodules demonstrated positive staining for CD5, CD20, CD23, and kappa (weak). Plasma cell infiltrates were positive for CD138 and lambda light chain staining. Lymphoid nodules were negative for CD138 and cyclin D1 staining. [composite [Figure 2] shows details of findings on immunohistochemistry.]
Figure 2: (a) CD20 positive nodular atypical lymphoid infiltrate (40x), (b) CD5 positivity within the atypical lymphoid infiltrate (40x), (c) Weak kappa staining within the atypical small lymphoid cells, (d) CD23 positivity within the atypical lymphoid infiltrate (40x), (e) CD138 highlighting the increase in plasma cells adjacent to nodules. (100x), and (f) Lambda light chain restriction within the plasma cells. (100x)Peripheral blood showed an IgG—lambda monoclonal protein (5.9 g/dL) and an absence of MYD88 mutation. She did not have any other evidence of end-organ damage in the form of skeletal or renal involvement. Therefore, a final diagnosis of MM with concomitant CLL was made and she was managed accordingly. She was initiated on therapy with a triple combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD). Disease reassessment was planned after four cycles, which was consistent with a very good partial response (VGPR). She did not give consent for a repeat bone marrow examination. She is currently asymptomatic and planned for autologous stem cell transplantation followed by maintenance therapy.
Simultaneous occurrence of MM and CLL is a rare phenomenon that was first reported in 1960, following which approximately 50 patients have been reported in the literature so far.[3] This phenomenon presents a significant diagnostic challenge, and the collation of data from a few small case series provides guidance about diagnostic pitfalls and a suggested approach to management.[4],[5]
The finding of increased lymphoid and plasmacytoid cells in the same bone marrow specimen can be noted in several diseases with overlapping characteristics. The most important differential diagnosis is lymphoplasmacytic leukemia (LPL), which can present with a spectrum of morphological features, including lymphocytes, plasma cells, and plasmacytoid lymphocytes.[6] LPL is characterized by the expression of IgM paraprotein and the presence of an MYD88 L256P mutation in up to 90% of patients.[7] Additionally, LPL is usually negative for CD5 expression, which is positive in patients with CLL. Non–IgM-secreting LPL is rare, and reported patients have demonstrated the MYD88 mutation, allowing distinction from other low-grade lymphomas.[8] Our patient had an IgG paraprotein and an absence of CD5 expression and MYD88 mutation, making LPL unlikely.
Similar diagnostic overlap may also be noted with other low-grade lymphomas, notably marginal zone lymphoma. These disorders can present with plasmacytoid morphology and may show light chain restriction and a small monoclonal band on electrophoresis. In this case, demonstration of a separate lymphoid clone must be done by a combination of findings on morphology, flow cytometry, and cytogenetic abnormalities on Fluorescence in situ hybridization (FISH).[9] Although the CD5 expression is usually seen, IgG expression is uncommon, differentiating from typical patients with LPL.[10] Lymphocytosis and plasmacytosis may be seen as reactive phenomena due to viral or autoimmune factors, and usually demonstrate a polyclonal gammopathy. A concise review by Alley et al.[11] provides a summary of salient findings to enable the above differential diagnoses.
CLL is noted to present with several other hematologic and solid organ cancers, likely due to a combination of genetic or immunological features. The presentation of CLL and myeloma simultaneously raises questions about a common cell of origin. An unknown immunological stimulus is well known to be an initial event in CLL, and shared genetic susceptibility, chronic immunologic stimulation, and autoimmunity have been noted to play a role in the pathogenesis of myeloma as well.[12],[13]
While presenting simultaneously, most available data point toward a biclonal origin of these two malignancies. A case series including 11 patients published in 1985 was able to define distinct origins of the two malignancies based on differential Ig light chain expression and anti-idiotype antibodies.[4] Importantly, it indicated that both lymphoid and plasma cells may express similar immunoglobulin chains irrespective of the cell of origin. Subsequently, a biclonal origin was demonstrated using differential FISH findings in lymphoid and plasma cells.[14] This has been reasserted by the demonstration of differential findings on single-nucleotide polymorphism (SNP) mapping array and FISH analyses on bone marrow (BM) samples of five patients.[15] Our patient also demonstrated differential light chain staining in lymphoid and plasma cells, possibly indicating a biclonal origin.
Most patients reported in the literature were treated with myeloma-directed therapy as the CLL component is usually indolent and regresses after treatment for myeloma. Myeloma-based regimens followed by autologous stem cell transplantation are the most commonly described.[5],[16] In addition, lenalidomide has shown efficacy in both myeloma and CLL, and has been used as a single agent to produce clinically important responses.[17] Compared to patients with myeloma alone, patients with CLL and myeloma appear to have slightly inferior responses but need validation in larger cohorts. In a study from Mayo Clinic describing 28 patients, patients with CLL + MM were shown to have similar baseline characteristics and responses to initial therapy. There was a non-statistically significant reduction in the overall survival with CLL and MM (58 vs. 84 months, P = 0.61).[5] Our patient achieved a VGPR after four cycles of CyBorD and is planned for an autologous stem cell transplantation followed by maintenance therapy.
To summarize, the simultaneous occurrence of CLL and myeloma is a rare phenomenon and presents a diagnostic challenge. A combination of morphological, immunohistochemical, and cytogenetic features can be used to differentiate two separate clones. Treatment with myeloma-directed chemotherapy followed by autologous stem cell transplantation appears to be an effective strategy for this rare phenomenon.
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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Author contributions
SS and RS wrote the manuscript and managed the patient; SR and MTM provided and reviewed histopathological images; MTM, KJ, and SS finalized the manuscript
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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CheckDOI: 10.4103/ijpm.ijpm_606_21
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