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Clinical profile of multiple myeloma in a tertiary care center from North East India.

INTRODUCTION

Multiple Myeloma has most likely been present for thousands of years, but first well-documented case was a patient, Sarah Newbury, described by Samuel Solly in 1844. (1) This 39-year-old women developed fatigue and bone pain from multiple fractures. The best known case of MM was that of Thomas Alexander McBean, "a highly respectable tradesman," 45 years of age. He developed fatigue and had noted that his "body linen was stiffened by his urine."

For two years nerore his death on January 1, 1846, he complained of severe recurrent bone pains on multiple occasions. (2)

Multiple Myeloma is a neoplastic disease of the plasma cells characterized by clonal proliferation of terminally differentiated B lymphoid cells, which accumulate in bone marrow and produce a monoclonal protein (Immunoglobulin), usually IgG or IgA, often referred to as M or myeloma protein. Multiple Myeloma comprises 10% of all haematological malignancies and 1% of all neoplastic disorders with usual age of presentation in 6th and 7th decade of life. Exact incidence in India is not known, but data from 6 population based cancer registries (Covering <0.3%) shows 0.3 to 1.9 per 1,00,000 men and 0.4 to 1.3 per 1,00,000 women, highest in Delhi. (3)

AIMS AND OBJECTIVES

In India clinical study of Multiple myeloma is very much limited, especially in North East India.

Our study aims to describe the common clinical and laboratory features, stages and outcome of patients with Multiple Myeloma coming to a tertiary care center in North East India.

MATERIALS AND METHODS

Newly diagnosed and previously diagnosed untreated patients of MM coming to Assam Medical College over a period of one year from June 2013 to May 2014 were randomly included in this prospective observational study. Diagnosis was confirmed by the 2009 updated criteria of International Myeloma Working Group. (4) (Table No. 1). Patients with monoclonal gammopathy of undetermined significance, other coexisting malignancy, non-secretory myeloma, solitary plasmacytoma of bone and previously diagnosed case of MM under treatment were excluded from the study. Informed consent and ethical clearance were taken. Patients were evaluated on the basis of proper history, clinical examination and laboratory and imaging investigations. Evidence of end organ damage was assessed by the ROTI criteria. (5) Staging of the cases was done on the basis of International Staging System (ISS).

All the data was entered into Microsoft Excel 2010 spreadsheet and analysed by GraphPad Prism Version 6.05 software. Various data were correlated with ISS stage using the contingency coefficient analysis (Cross tabs procedure). The significance of study parameters between the three ISS stage was assessed using Freeman-Halton extension of Fisher's exact test. Significance was assessed at 5% level of significance (p <0.05).

RESULTS AND OBSERVATIONS

44 MM cases were included in the study with 5 patients from 31 to 40 years, 7 from 41 to 50 years, 16 from 51 to 60 years, 14 from 61 to 70 years and 2 cases above 71 years. The age varied from 38 to 82 with a mean age of 57.7 years (SD 10.29). 27 (61%) patients were male and 17 (39%) were females with a male-to-female ratio of 1.6:1 (Table No. 2).

38 (86%) patients presented with backache and other bone pains which was the most common symptom; 35 (80%) patients had generalized weakness and easy fatigability, 13 (30%) had symptoms of spinal cord compression, 14 (32%) had fever, 10 (23%) had cough, 4 (9%) had burning micturition and urgency, 8 (18%) had bleeding manifestation, 16 (36%) had constipation, 12 (27%) had polydipsia, 6 (14%) had nausea and vomiting, 3 had somnolence and 2 patients had confusion (Table No. 3).

On examination 37 (84%) patients had pallor and 34 (77%) patients had bony tenderness; 14 (32%) patients presented with paraplegia; 6 (14%) patients had oedema.

Splenomegaly and hepatomegaly were seen in 2 and 1 patient respectively; 40 (91%) cases revealed positive M Band by serum protein electrophoresis. In rest of the 4 cases, band was determined by immunofixation method. Urinary Bence-Jones protein was estimated in 28 out of 44 patients and of them 4 (14%) were positive. Immunofixation electrophoresis (IFE) was done on 8 patients of whom 6 had IgG, 1 had IgA and 1 had light chain myeloma.

40 (91%) had radiologically detectable abnormalities; 35 (80%) had lytic lesions, 17 (39%) had pathological fractures, 21 (48%) had generalized osteoporosis and only 4 (9%) had normal skeletal survey. Out of 35 cases of lytic lesions, most frequent area was spine in 25 (71%) followed by skull in 23 (66%), ribs in 15 (43%), long bones in 12 (34%), pelvis in 8 (23%), clavicle in 4 (11%) and scapula in 3 (8.5%) cases. In 24 (69%) cases, lytic lesion were seen in lumbosacral spine and in 12 (34%) they were seen in thoracic spine. Femur was the most common long bone to be involved with 8 (23%) followed by humerus in 3 (8%) and radius in 1 (3%). Out of 17 cases of pathological fractures 14 (87%) were in the vertebra, 7 (44%) were in ribs and 2 (12.5%) were in long bones (Femur).

The mean Hg was 7.12 gm/dL; 18 (41%) has severe anaemia with Hg <7 gm/dL, 23 (52%) had moderate anaemia with Hg between 7 to 10 gm/dL and 3 had mild anaemia with Hg between 10 to 12 gm/dL; 4 cases had leucopenia with total count <4000/cumm and 5 had leucocytosis with total count >12,000/cumm (Mean total count was 8002). The mean platelet count was 1.6 lack and mean ESR 124.8 mm AEFH. Mean serum creatinine was 1.66 mg/dL with 9 (20%) cases having serum creatinine >2 mg/dL. Mean corrected serum calcium was 10.37 mg/dL with 10 (23%) cases having raised serum calcium >11 mg/dL; 29 (66%) had hypoalbuminemia; 26 (59%) had serum globulin >3.5 to 5.5 and 17 (39%) had >5.5 gm/dL; 11 (25%) had serum beta-2 microglobulin level <3.5 mg/L, 16 (36%) from 3.6 to 5.5 mg/L and 17 (39%) had >5.5 mg/L.

Bone marrow study showed that out of 44 cases, 6 (14%) cases had bone marrow plasma cell concentration between <20%, 8 (18%) cases between 20 to <30%, 11 (25%) cases between 30 to <40%, 10 (22%) cases between 40 to <50% and 9 (20%) cases above 50%. The mean bone marrow plasma cell concentration was 37%.

7 (16%) cases were found to be in stage I, 20 (45%) were found to be in stage II and 17 (39%) were in stage III. One (1) out of 7 (14.29%) in stage I, 6 out of 20 (30%) in stage II and 11 out of 17 (64.7%) in stage III were having haemoglobin <7 gm/dL. There was a trend towards higher percentage of cases having CRP >6 mg/L with higher ISS stage, but this correlation was statistically insignificant (p=0.42). A statistically significant (p=0.02) correlation of serum LDH with stage of the disease was found showing serum LDH (>285/IU/L) in 0%, 40%, 58.8% of patients with ISS-I, II and III respectively. Serum creatinine >/= 2 mg/dL was observed in 0%, 10% and 41.2% of cases of ISS-I, II and III respectively (p=0.029). Higher percentage of cases with high ISS stage had serum calcium >11 mg/dL, but it was found to be statistically insignificant (p = 0. 186). Similar results were found with serum uric acid (p=1).

Five (5) (71.43%) cases of stage I, 18 (90%) cases of stage II and 17 (100%) cases of stage III had skeletal lesions, which was statistically significant (p=0.07); 3 (42.86%) of stage I, 16 (80%) of stage II and 16 (94.12%) cases of stage III had lytic lesion which was also statistically significant (p=0.024). Statistically significant correlation also exists between pathological fracture and the ISS stage of disease (p=0.004) as none, 6 (30%) and 11 (64.7%) of stage I, II and III respectively had pathological fractures. Association of generalized osteoporosis with the ISS stage was not statistically significant (p=0.922). There exists significant correlation between the ISS stage and serum beta 2 microglobulin >/= 3.5 (p<0.001).

None, 16 (80%) and 17 (100%) cases of stage I, II and III respectively had serum beta 2 microglobulin >/= 3.5. Similarly, there exists significant correlation between stages and serum albumin <3.5 (p=0.002) as 1 (14.29%) case of stage 1, 13 (65%) cases of stage II and 15 (88.24%) cases of stage III had serum albumin <3.5. A statistically significant correlation also exists between bone marrow plasma cell (BMPC) >/=33% and the ISS stage of the disease (p=0.002). In this study 14.29%, 55% and 88.24% cases in stage I, II and III respectively had BMPC >/= 33%.

DISCUSSION

Diwan AG et al (2014).6 reported that sixth decade is the common age group with a mean of 62 years. Kyle RA et al (2003). (5) reported that the mean age was 66 years with 2% younger than 40 and 38% older than 70 years. Kumar L et al (2006). (7) reported that in India the median age is 55 years; 2 decades earlier than that in USA we found 5 (11.4%) patients from 31 to 40 years and a mean age of 57.7 years. Madu AJ et al (2014). (8) found male:female ratio 1.2:1 and Kumar L et al (5) found 1.5:1. We also found a male:female ratio of 1.5:1.

Bone pain was reported by Diwan AG et al (6) in 85%, Madhu AJ et al (8) in 78.1%, Rahman AAU et al (9) in 78% and Durie BGM et al (10) in 58%. We found them in 86.3%. Riccardi A et al (11) reported symptoms of spinal cord compression in 34%, Dancaster CP et al (12) in 15%, Madu AJ et al (8) in 13.8% and Diwan AG et al (6) in 10%. In our study, symptoms of spinal cord compression was seen in 29.55%.

Diwan AG et al (6) found anaemia in 100% and Rahman AAU et al (9) found mean haemoglobin of 7.56. We found 93% anaemia and mean haemoglobin of 7.12 gm/dL. However, Grepp PR et al (13), Blade J et al (14) and Durie BGM et al (10) showed mean haemoglobin level >8.5 gm/dL.

Madu AJ et al (8), Diwan AG et al (6), Kumar L et al (7) and Bade J et al (14) showed serum creatinine level >2 mg/dL in 13.8%, 30%; 31.3% and 22.3% respectively, which was 20.45% in our study. Dimopoulos MA et al (15), Li SD et al (16), Kyle RA et al (5) and Dancaster CP et al (12) reported hypercalcaemia in 16%, 19.5%, 13% and 22% respectively, whereas we found it in 22.73%. Grepp PR et al (13) and Madu AJ et al (8) found mean serum beta 2 microglobulin of 3.8 and 4 mg/L, whereas we found it to be 4.92 mg/L.

Kyle RA et al (5), Diwan AG et al (6) and Madu AJ et al (8) found positive M band in 82%, 100% and 90.5% respectively and we found in 90.91%. Urine for Bence Jones was found by Dancaster CP et al (12), Kyle RA et al (5) and Madu AJ et al (8) in 38%, 16% and 48%, but we found in only 14.3%.

Kumar L et al (7) found 6.4%, 12% and 81.7% patients in stage I, II and III, whereas Li SD et al (16) found it to be 17.2%, 47.5% and 35.5%. Dimopoulos MA et al (15) found 29%, 38% and 33% in stage I, II and III and we found the same in 15.9%, 45.45% and 38.64% respectively.

Despite the limitation of the study as regards the relatively small sample size and short duration of study, the results obtained in the study were a good indicator in respect to the clinical findings and laboratory profile of multiple myeloma.

CONCLUSION

We conclude that though most patients were in sixth decade, but we got significant involvement in younger age group. Bone pain, mostly low backache was the most common presenting symptom along with fatigue and weakness. Majority of patients were in higher stages (ISS II, III) at the time of diagnosis and severe anaemia, lytic lesions, pathological fractures and renal insufficiency were most observations in these patients in higher stages.

REFERENCES

(1.) Solly S. Remarks on the pathology of mollities ossium with cases. Med Chir Trans 1844;27:435-98.

(2.) Kyle RA. Multiple myeloma: an odyssey of discovery. Br J Haematol 2000;111(4):1035-44.

(3.) National cancer registry program: two year report of the population based cancer registries 1999-2000. New Delhi: ICMR 2005.

(4.) Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046-60.

(5.) Kyle RA, Morie GA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc 2003;78(1):21-33.

(6.) Diwan AG, Gandhi SA, Krishna K, et al. Clinical profile of the spectrum of multiple myeloma in a teaching hospital. Med J DY Patil Univ 2014;7(2):185-8.

(7.) Kumar L, Vikram P, Kochupillai V, et al. Recent advances in the management of multiple myeloma. National Medical journal of India 2006;19(2).

(8.) Madu AJ, Ocheni S, Nwagha TA, et al. Multiple myeloma in Nigeria: an insight to the clinical, laboratory features and outcomes. Niger J Clin Pract 2014;17(2):212-7.

(9.) Rahaman AAU, Shah SZA, Devrajani BR, et al. International staging system: a tool to predict survival in patients with multiple myeloma. World Appl Sci J 2012;16(7):1004-8.

(10.) Durie BMG, Salmon SE. A clinical staging system for multiple myeloma, Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36(3):842-54.

(11.) Riccardi A, Gobbi PG, Ucci G, et al. Changing clinical presentation of multiple myeloma. EUR J Cancer 1991;27(11):1401-5.

(12.) Dancaster CP, Hussain OAN, Jackson WPU. Clinical features of multiple myeloma: a review of clinical manifestations and laboratory investigations in 40 cases. Postgrad Med J 1959;35(410):662-70.

(13.) Greipp P, Miguel SJ, Durie BG, et al. High serum levels of lactic dehydrogenase identify a high-grade lymphoma like myeloma. Ann Intern Med 1989;110(7):521-5.

(14.) Blade J, Rozman C, Cervantes F, et al. A new prognostic system for multiple myeloma based on easily available parameters. Br J Haematol 1989;72(4):507-11.

(15.) Dimopoulos MA, Kastritis E, et al. The International Scoring System (ISS) for multiple myeloma remains a robust prognostic tool independently of patients' renal function. Annals of Oncology 2012;23:722-9.

(16.) Li SD, Wang YF, Qi JY, et al. Indian J Haematol Blood Transfus. Springer 2010;26(3):83-8.

Ajit Kumar Pegu [1], Anupam Dutta [2], Vineet Kumar Todi [3]

[1] Associate Professor, Department of Medicine, Assam Medical College and Hospital.

[2] Assistant Professor, Department of Medicine, Assam Medical College and Hospital.

[3] Post Graduate Trainee, Department of Medicine, Assam Medical College and Hospital.

Financial or Other, Competing Interest: None.

Submission 11-05-2016, Peer Review 07-06-2016, Acceptance 13-06-2016, Published 29-06-2016.

Corresponding Author: Dr. Anupam Dutta, Revti House, Purnananda Road, Shan tipara, Dibrugarh--786001, Assam.

E-mail: dranupamdutta@yahoo.com, dranupamdutta80@gmail.com

DOI: 10.14260/jemds/2016/781
Table 1: Diagnostic Criteria for Symptomatic Multiple Myeloma
Diagnostic criteria for Symptomatic Multiple Myeloma by International
Multiple Myeloma Working Group 2003, Updated in 2009

1      Monoclonal protein present in serum and/or urine
2      Clonal bone marrow plasma cell or plasmacytoma
          Related organ or tissue impairment (ROTI)
    C       Hypercalcaemia (Corrected calcium >2.75 mmol/L)
3   R       Renal insufficiency attributable to myeloma
    A          Anaemia (Haemoglobin <10 g/dL)
    B     Bone lesions (Lytic lesions or osteoporosis with

Table 2: Demographic Profile of Our Patients

Parameters                   Patients (n = 44)    Percentage

Age Wise Distribution
          31-40 years                5               11.4%
          41-50 years                7               15.9%
          51-60 years                16              36.4%
          61-70 years                14              31.8%
           >70 years                 2               4.5%
Sex
              Male                   27               61%
             Female                  17               39%

Table 3: Clinical Presentation

Parameters                                Patients     Percentage
                                          (n = 44)
Symptoms
Backache and other bone pains                38            86%
Generalized weakness                         35            80%
Symptoms of spinal cord compression          13            30%
Fever                                        14            32%
Cough                                        10            23%
Burning micturition and urgency              4             9%
bleeding manifestation                       8             18%
Constipation                                 16            36%
Polydipsia                                   12            27%
Nausea and vomiting                          6             14%
Somnolence                                   3            6.8%
Confusion                                    2            4.5%
Signs
Pallor                                       37            84%
Bony tenderness                              34            77%
Paraplegia                                   14            32%
Oedema                                       6             14%
Splenomegaly                                 2            4.5%
Hepatomegaly                                 1            2.3%
Laboratory results
Positive M Band by serum protein             40            91%
  electrophoresis
Urinary Bence-Jones protein             4 (28 tested)      14%
Skeletal involvement
Radiologically detectable                    40            91%
  abnormalities
Lytic lesions                                35            80%
Spine                                        25            71%
Lumbosacral spine                            24            69%
Thoracic spine                               12            34%
Skull                                        23            66%
Ribs                                         15            43%
Long bones in and                            12            34%
Pelvis in                                    8             23%
Clavicle in                                  4             11%
Scapula                                      3            8.5%
Pathological fractures                       17            39%
Vertebra                                     14            87%
Ribs                                         7             44%
Long bones (Femur)                           2            12.5%
Generalized osteoporosis                     21            48%
Normal skeletal survey                       4             9%

Fig. 1: Stages of Presentation

Stage I      7 (16%)
Stage II    20 (45%)
Stage III   17 (39%)

Note: Table made from pie chart.
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Author:Pegu, Ajit Kumar; Dutta, Anupam; Todi, Vineet Kumar
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Report
Date:Jun 30, 2016
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