Rare case of non-producer variant of plasma cell dyscrasias with circulating plasma cells

Abstract

Non-producing variant of plasma cell disorders with circulating plasma cells is an aggressive variant of plasma cell dyscrasias with relatively poor outcomes. A 75-year-old man was admitted due to anaemia (90 g/L) and thrombocytopenia (9×10⁹/L). Comprehensive metabolic panel showed creatinine of 1.34 mg/dL, total protein of 6 g/dL, and corrected calcium was normal. Peripheral smear review showed 8% circulating atypical plasmacytoid cells. Bone marrow biopsy (BMB) confirmed plasma cell myeloma involving 90%–95% of bone marrow cellularity. Serum protein electrophoresis showed no monoclonal protein. Due to aggressive biology of non-producer variant and outcomes based on circulating plasma cells, he was started on VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) chemotherapy. BMB after cycle 1 chemotherapy showed no morphologic, immunophenotypic, or flow cytometric features of a plasma cell neoplasm. Given excellent treatment response cycle 2 was changed to VRD (bortezomib, lenalidomide and dexamethasone). Following two cycles of VRD, he underwent autologous haematopoietic cell transplantation. Day 80 BMB suggested stringent complete response.

Background

Multiple myeloma (MM) is a malignancy of plasma cells defined by infiltration of bone marrow and presence of CRAB feature (hypercalcaemia, renal insufficiency, anaemia and lytic bone lesions) as well as three specific biomarkers: clonal bone marrow plasma cells ≥60%, serum free light chain (FLC) ratio ≥100 (provided involved FLC level is ≥100 mg/L), and more than one focal lesion on MRI.^{1 2} In the USA, MM is the second most common haematologic neoplasm and accounts for approximately 10% and is more common in African-Americans compared with whites.^{1 2} Non-secretory MM (NSMM) is characterised by typical morphological and pathological MM characteristics and the absence of an M-protein on immunofixation electrophoresis with estimated incidence of 3%–5%.^3–5 Among the NSMM cases, there is a subset in which no cytoplasmic immunoglobulin synthesis is detected, and this entity is called ‘non-producing’ MM (NPMM).⁶ Plasma cell dyscrasias (PCL) is an aggressive form of MM characterised by presence of a monoclonal population of plasma cells with an absolute plasma cell count exceeding 2000/μL or 20% of the peripheral blood white cells circulating in the peripheral blood.⁷

Case presentation

A 75-year-old man with a medical history of dyslipidaemia was admitted due to bicytopenia. The patient had persistent cough and symptoms of upper respiratory tract infection for several weeks prior to presentation. Complete blood count (CBC) showed white blood cell count (WBC) of 7.9×10⁹/L, haemoglobin 90 g/L, platelet count 9×10⁹/L. Complete metabolic panel showed creatinine of 1.34 mg/dL, total bilirubin of 1.34 mg/dL (normal 0.2–1.1 mg/dL), serum calcium 9.6 mg/dL, albumin 3.6 g/dL and total protein of 6 g/dL. IgG direct antiglobin and complement test were negative. Haptoglobin was high, ruling out any autoimmune haemolytic process. Peripheral smear review showed normochromic, normocytic anaemia with sparse nucleated precursors (1%), thrombocytopenia, few atypical plasmacytoid cells (8%) and some damaged cells, which were difficult to classify (figure 1). Subsequently, bone marrow biopsy (BMB) with aspirate showed marked hypercellularity (>95%) with decreased trilineage haematopoiesis (figure 2). The plasma cells show morphologic heterogeneity with prominent immature, plasmablastic and pleomorphic morphology (figure 3). Flow cytometry demonstrated a dominant abnormal CD45-dim population with expression of CD38, CD138, CD56 and CD117 (partial). The abnormal cells were negative for cytoplasmic kappa and lambda immunoglobulin light chains and negative for myeloid and lymphoid markers (by flow cytometry and immunohistochemical stains). Immunohistochemical staining was positive for CD138 in sheets of plasma cells essentially replacing the marrow cellularity (figure 4). Fluorescence in situ hybridization (FISH) was positive for t(11;14) and showed complex karyotype on cytogenetic analysis. Serum protein electrophoresis and immunofixation showed no monoclonal proteins. Serum immunoglobulin IgA was normal, and IgM/IgG were low (<20 mg/dL and 315 mg/dL, respectively). Beta 2 microglobulin was 5.5 (normal 1.1–2.4 mg/L). FLC assay showed kappa light chain was low (0.15, 0.33–1.94 mg/dL), and lambda light chain and ratio were normal. Skeletal survey showed possible lytic lesion in right femoral neck and subtrochanteric portion of the left femur. Our patient was diagnosed with non-producing variant of plasma cell dyscrasias with circulating plasma cells (CPCs).

Figure 1.

Peripheral smear showing atypical plasmacytoid cell.

Figure 2.

High power view of bone marrow aspirate showing marked hypercellularity.

Figure 3.

Bone marrow aspirate shows morphologic heterogeneity with prominent immature, plasmablastic cells.

Figure 4.

Positive CD 138 shows sheets of plasma cells essentially replacing the marrow cellularity.

Treatment

Given aggressive biology, chemotherapy with VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) was planned. Due to financial reasons, thalidomide could not be started. After completion of cycle 1 VD-PACE chemotherapy, repeat BMB showed no morphological, immunophenotypic or flow cytometric features of a plasma cell neoplasm. Given excellent treatment response and discussion with transplant centre, subsequent cycle 2 was changed to bortezomib, lenalidomide and low-dose dexamethasone (VRD).

Outcome and follow-up

Patient subsequently completed two cycles of VRD chemotherapy and later successfully underwent autologous hematopoietic stem cell transplantation (AHCT) with melphalan conditioning. Day 80 posttransplant, repeat BMB normal immunophenotype with no evidence of involvement by plasma cell neoplasm conferring stringent complete response (sCR) based on standard International Myeloma Working Group response criteria.⁸ He was started on dual maintenance with lenalidomide 10 mg orally days 1–21 every 28 days and ixazomib 3 mg orally days 1, 8 and 15 every 28 days.⁹ The patient remains in sCR at 4 months post-AHCT.

Discussion

MM is the second most common haematologic neoplasm in the USA, with estimated new cases of 32 119 (1.8% of all new cancer cases) and deaths of 12 960 (2.1% of all cancer deaths) in 2019.¹⁰ Non-secretory myeloma is a rare myeloma subtype, until a few years ago, was established by demonstration of monoclonal plasma cells ≥10% in the bone marrow and by negative results on serum and urine electrophoresis and immunofixation studies with estimated incidence of 3%–5%.^3–5 With advances in the detection of FLC, the proportion of true NSMM is closer to 1%–2% of all MMs.¹¹ Given the rarity of NSMM in the overall MM population, its clinical course and prognosis are not thoroughly characterised. Among the NSMM cases, there is a subset with loss of FLC secretion by MM clones in which no cytoplasmic immunoglobulin synthesis is detected, and this entity is called NPMM with estimated incidence of 0.15%. MM patients can usually be risk stratified based on cytogenetic abnormalities, lactate dehydrogenase, beta 2 microglobulin, bone marrow plasma cell immunophenotype, monoclonal protein quantity, presence of CPCs, serum FLC ratio, plasma cell proliferative rate and gene expression profiling.^12–19

CPCs usually confers poor prognosis. Plasma cell leukaemia is an uncommon but aggressive malignancy and has been defined as the presence of ≥20% CPCs on conventional WBC differential count and an absolute plasma cell count of ≥2×10⁹/L in the peripheral blood.^{20 21} PCL accounts for 1%–2% of all plasma cell dyscrasias, which includes both primary PCL (pPCL) arising de novo, in the absence of antecedent MM and secondary PCL (sPCL), which describes leukaemic transformation of MM. The most extensive data on the epidemiology of PCL come from a series of 291 patients identified in the Surveillance, Epidemiology and End Results (SEER) database between 1973 and 2004 with a relative incidence of 0.6% for 49 000 patients with MM identified.²² This SEER study did not distinguish between pPCL and sPCL. There is no single cytogenetic abnormality that is typical or diagnostic of PCL. Studies have since shown that MM patients with ≥5% to 20% CPCs, as measured on a peripheral smear, have similar outcomes to patients with ≥ 20% CPCs and suggested a lower threshold of CPCs be used to define PCL.¹⁹ Given 8% atypical plasmacytoid cells circulating in peripheral blood, loss of FLC secretion, no cytoplasmic immunoglobulin synthesis and without antecedent MM, our patient was diagnosed with non-producer variant of plasma cell dyscrasias with CPCs.

There have been no prospective randomised trials to suggest treatment of PCL. Available data are primarily based on data from small retrospective series, case reports and extrapolation of data from patients with MM. Although the treatment of PCL has borrowed much from MM, with bortezomib-based induction therapy followed by autologous transplantation in eligible patients, outcomes are often poor, even in the era of novel agents. Median OS of patients with ≥5% CPCs was 1.1 years.¹⁹ In general, patients younger than 65 years with good performance status are treated with aggressive induction therapy, such as VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) followed by transplantation.^{23 24} Other regimens for elderly and unfit patients include VTD (bortezomib, thalidomide and dexamethasone), VRD (bortezomib, lenalidomide and dexamethasone) and VCD (bortezomib, cyclophosphamide and dexamethasone).²⁵

Given the aggressive biology, multiagent chemotherapy with VD-PACE was administered to our patient. Due to financial reasons, thalidomide could not be started. Monitoring response of non-producer variant is a challenge. Serial BMB could be the gold standard, but frequent BMB can be time consuming and costly, and patient discomfort makes them less feasible in real life. After completion of cycle 1 VD-PACE chemotherapy, repeat BMB was done for our patient and showed no morphological, immunophenotypic or flow cytometric features of a plasma cell neoplasm.

Patients with MM have increasing treatment options. Progress in medical research has enhanced our understanding of tumour biology, and this is particularly true for MM with introduction of drugs targeting the tumour in its microenvironment. Proteasome inhibitors, immunomodulatory drugs and the monoclonal antibodies have already been used in clinical practice as preferred first-line treatment choices. Recently, the Food and Drug Administration granted accelerated approval to selinexor for relapsed or refractory MM, which reversibly inhibits nuclear export of tumour suppressor proteins, growth regulators and messenger RNAs of oncogenic proteins via blockage of exportin 1.²⁶ Studies are underway to evaluate the use of minimal residual disease on treatment decisions (NCT03224507), next-generation cereblon E3 ligase modulators as well as cellular therapies such as chimeric antigen receptor T-cells and bispecific T-cell engagers.^{27 28}

The outcomes of aggressive form of the plasma cell dyscrasias have slightly improved with the introduction of autologous stem cell transplantation and combination approaches with modern therapies, including bortezomib and immunomodulatory drugs, such as lenalidomide. MM remains an incurable illness however with increasing therapeutic options hopefully a curative option will be available in the future. This case highlights the challenges in diagnosis of non-producer variant of plasma cell dyscrasias with successful management.

Learning points.

• Non-secretory multiple myeloma (NSMM) is characterised by typical morphological and pathological MM characteristics and the absence of an M-protein on immunofixation electrophoresis.

• Among the NSMM cases, there is a subset with loss of serum free light chain secretion by MM clones in which no cytoplasmic immunoglobulin synthesis is detected, and this entity is called ‘non-producing’ MM.

• Plasma cell leukaemia is an aggressive form of MM characterised by high levels of abnormal plasma cells circulating in the peripheral blood.

• Studies have shown that MM patients with ≥5% to 20% circulating plasma cells, as measured on a peripheral smear, have similar outcomes to patients with ≥20% circulating plasma cells.