A Clinical and Laboratory Profile of Multiple Myeloma

Background: Myeloma, the most common malignant disease of bone, is incurable and occurring with increasing frequency in elderly population. Typical clinical features are weakness, fatigability, bone pain, anemia, renal insufficiency and hypercalcemia. Incidental discovery on comprehensive laboratory panels is common. Serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis help the diagnosis of multiple myeloma. Objective: The aim of this study was to define and evaluate the clinico-laboratory features of newly diagnosed adult multiple myeloma (MM) patients in the context of Bangladesh. Materials and Methods: This study was carried out in two centers, from October 2005 to January 2010 in Bangabandhu Sheikh Mujib Medical University (BSMMU) and July 2012 to June 2017 in Enam Medical College and Hospital (EMCH). Thirty two diagnosed valid cases of multiple myeloma were included in this study. Clinical history, physical and relevant laboratory findings were carefully recorded and analyzed. Results: In this study among 32 patients, 29 were males and 3 were females with mean age 51.94 ± 10.09 years. The common complaints were bone pain, weakness and fatigue. The common clinical findings were bone tenderness, pallor and high ESR (ESR of all the study patients was more than 100 mm in 1st hour). Hemoglobin level was <8.5 gm/dL in 13 patients, serum creatinine ≥2 mg/dL in seven patients, serum albumin <30 mg/L in 14 patients and serum β2 microglobulin >5.5 mg/L in 15 patients. Three patients were hypercalcemic. Lytic lesions were the most common radiological finding in the study. Conclusion: This study showed that multiple myeloma is a disease of the middle and elderly aged population with male preponderance, with high male female ratio. Multivenued studies are needed to view the real picture of multiple myeloma in the context of Bangladesh.


Introduction
Multiple myeloma (plasma cell myeloma or plasmacytic myeloma or myelomatosis or Kahler disease) is a hematological neoplasm characterized by proliferation of a single clone of plasma cells derived from B cells. This clone of plasma cells proliferates in the bone marrow and frequently invades the adjacent bone, producing skeletal destruction that results in bone pain and fractures. Occasionally, plasma cells infiltrate multiple organs and produce other symptoms. The excessive production of a monoclonal protein (M-protein) may lead to renal failure from Bence Jones protein or hyperviscosity from excessive amounts of M-protein in the blood. The diagnosis depends on identification of abnormal monoclonal plasma cells in the bone marrow, M-protein in the serum or urine, osteolytic lesions, and a clinical picture consistent with multiple myeloma. 1 Multiple myeloma accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. In Western countries, the annual age-adjusted incidence is 5.6 cases per 100,000 persons. The median age at diagnosis is approximately 70 years; 37% of patients are younger than 65 years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older. 2,3 In India, the incidence varies from 0.3−1.9/100000 for male and 0.04−1.3/100000 for female. 4 In most patients with this disease no clear risk factor can be identified. Exposure to ionizing radiation, farming pesticides, or possibly petrochemicals increase the risk. There is an increased incidence of multiple myeloma in persons with rheumatoid arthritis or obesity (body mass index of more than 30 kg per m 2 ). 5 Myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma cells that are derived from post-germinal center B cells. Multistep genetic and microenvironmental changes lead to the transformation of these cells into a malignant neoplasm. Myeloma is thought to evolve most commonly from a monoclonal gammopathy of undetermined clinical significance (usually known as MGUS) that progresses to smoldering myeloma and, finally, to symptomatic myeloma. Several genetic abnormalities that occur in tumor plasma cells play major roles in the pathogenesis of myeloma. 6,7 The adhesion of myeloma cells to hematopoietic and stromal cells induces the secretion of cytokines and growth factors, including interleukin-6, vascular endothelial growth factor (VEGF), insulin-like growth factor 1, members of the superfamily of tumor necrosis factor, transforming growth factor β1, and interleukin-10. 8 These cytokines play an important role in myeloma cell proliferation.
Myeloma is classified as asymptomatic or symptomatic, depending on the absence or presence of myeloma-related organ or tissue dysfunction, including hypercalcemia, renal insufficiency, anemia, and bone disease. 9 It is important to note that 34% of patients are asymptomatic at presentation with incidental abnormalities on total protein, creatinine, calcium or hemoglobin laboratory panels. 10 Anemia, which is present in about 73% of patients at diagnosis, is generally related to myeloma marrow infiltration or renal dysfunction. 11 Bony lesions develop in almost 80% of patients with newly diagnosed disease; in one study, 58% of patients reported bone pain. 1 Renal impairment occurs in 20 to 40% of patients with newly diagnosed disease 1,12 mainly as a result of direct tubular damage from excess protein load, dehydration, hypercalcemia, and the use of nephrotoxic medications. 13 The risk of infection is increased with active disease but decreases with response to therapy. 14 Hypercalcemia is uncommon. 1 Serum β2-microglobulin and albumin are two most important prognostic factors. The International Staging System defines three risk groups on the basis of these two. 15 Myeloma is usually incurable. In recent years, the introduction of autologous stemcell transplantation and the availability of agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival. In patients presenting at an age under 60 years, 10-year survival is approximately 30%. 16 Therefore, the purpose of this study which determines the spectrum of clinical, hematological and biochemical changes in the patients of multiple myeloma in the context of Bangladesh is obviously appropriate and timely as there was no such study conducted in our country previously.

Materials and Methods
This study was carried out in two centers ─ from October 2005 to January 2010 in Bangabandhu Sheikh Mujib Medical University and from July 2012 to June 2017 in Enam Medical College and Hospital. In this study the total number of cases was 32. Diagnosis was based on serum protein electrophoresis, bone marrow examination and FNAC from plasmacytoma. Relevant clinical history, physical findings, complete blood count and ESR, bio-chemical tests like serum albumin, serum calcium, serum creatinine, serum β2 microglobulin and radiological survey were recorded for further analyses.

Results
Total 32 patients diagnosed as multiple myeloma were included in this study. Out of them 29 (90.63%) were males and 3 (9.27%) were females with male female ratio 9.67:1. Age range of patients was 36−71 years with mean 51.94 ± 10.09 years and median 53 years.    18 Bone tenderness was in 47% cases observed by Kaushik et al. 21 It was lower than the findings in this study possibly due to late stage of presentation in our study.
Anemia in myeloma is caused due to replacement of marrow by myeloma cells and decreased production of erythropoietin due to accompanying renal involvement. In some cases it may be associated with cytokine mediated bone marrow suppression.
Hemoglobin value ≤10 gm/dL was seen in 63.9% of the patients in Sultan et al 18  ESR is high in multiple myeloma due to increased paraproteins and anemia. ESR >100 mm in 1 st hour was reported in different series from 33−100%. 1,17,22,23 This is similar to the present study (100%).
Leukopenia and leucocytosis were found in 15.63% and 12.5% in patients of the present study. In the study of Kyle et al 1 these were 20% and 8%. Low platelet count is uncommon in early phases of myeloma. Thrombocytopenia may be due to infiltration of the marrow by plasma cells or intravascular destruction of platelets or thrombopoietic activity of IL-6. In our study thrombocytopenia was in 18.75% cases, but in the study of Kaur et al 17  Multiple myeloma is a disease of middle age and elderly with male preponderance. The presentation of multiple myeloma can range from asymptomatic to severely symptomatic with complications. Our clinico-laboratory findings were comparable to other studies with some variations. It may be due to small number of patients included in this study. Our study can be considered as an important step towards studying multiple myeloma. Nonetheless, further such multicenter studies would enrich our views to determine the actual picture of multiple myeloma in the context of Bangladesh.