In the early phase multiple myeloma may be clinically asymptomatic. Appearance of M components may precede other manifestations by many years [7]. Durie and Salmon analyzed various features of the disease in relation to the total tumor cell mass and correlated them with therapeutic response and survival. They found that the degree of anemia and hypercalcemia, the extent of osteolytic lesions and the serum concentration of M components correlated well with the neoplastic cell mass. Accordingly, they classified multiple myeloma into three stages. It was found that therapeutic response and survival were best in stage I disease and worst in stage III. Thus, discovery of multiple myeloma should ideally be made in stage I [8]. The clinical manifestations do not completely correspond to the staging; however, they give clues as to when to suspect multiple myeloma. Prognosis depends on several factors; one of them is the stage of the disease at diagnosis.

Early attempts to improve on the DS staging system were not widely adopted. But now, Sβ2M is widely recognized as the single most important variable predicting survival. When added to Sβ₂M, serum albumin level was known to add significantly to prognostication. This led to an Sβ₂M and serum albumin staging system, developed by the Southwest Oncology Group. The newly developed and proposed ISS system [5] thus extends and validates these prior observations. Several cases of myeloma go undiagnosed each year, due to the shortage of medical facilities in the rural India. Comparative statistics of biochemical parameters on the various stages of multiple myeloma are rare.

The age of the patients found in our study group ranged from 25 to 78yrs, with a median age of 57yrs, making it necessary for the clinician to keep this in the differential diagnosis, whenever appropriate, for this entire age range. Our median is a little higher than the median age of 55 years reported in National Cancer Registry Programme statistics [9]. On the other hand the mean age in our study was 55.5 years matching with that of Wadhwa et al [10], (55.4 yrs), whereas Advani et al [11], have reported mean age 51 years. In our study, mean age in years were 54.3, 53.9 and 57.7 respectively in stages I, II & III and the difference was not statistically significant.

The male to female ratio was 1.47:1. The male preponderance in our study concurs with previous studies. Tripathy et al [12], reported that the disease manifested in the later ages in females (61 to 70 years) than in the male patients (51 to 60 years). In our stage-wise analysis females presented at younger age in stages I (mean age of females is 50yrs and males is 56.5yrs) & II (F=52.4 and M=55.3yrs), whereas in stage III, females (mean age of 59.5yrs) were older than males (56.4yrs).

We observed that the most common clinical presentation (46%) was bone related such as low backache, bone pain, joint pains and pathological fractures similar to another Indian study [13]. Clinical history taken in our patients showed majority with back ache with bone pain as the chief complaint (30%). Bone pains were chief complaints by the patients in the studies published by Kaur et al [14], (50%), Gupta et al [15], (79%) and Kyle et al [16], (58%). This is followed by generalized weakness and fatigability (22%). Generalized weakness and fatigability were recorded in 46.4% in Kaur et al [14], and in 32% in a study at Mayo clinic [17] and is attributable to anemia. Bony pains and easy fatigability were also the most common symptoms in another study by Subramanian [18]. Pathological fractures, joint pains and fever presented in 8% of patients.

The number of patients diagnosed as ISS III was higher in our study (38.3%) as compared to the data from Jacob LA et al [19], which showed 39%. In Western data (percentage of patients in ISS III was 18%); the maximum numbers of patients were in ISS II [16]. Cytogenetics data are not available for patients, so revised ISS is not used for the classification of patients.

The most commonly occurring paraprotein type is IgG, followed by IgA and light-chain myelomas. Our results showed 79% patients with IgG myeloma, 18% patients with IgA and 9.6% patients with light chain myeloma. Wang et al [20] found IgG myeloma in 56% patients and IgA myeloma in 25% patients. The number of patients with IgG type of myeloma was 72% as per the data from Jacob LA et al [19], and more than 50% from Mayo Clinic [17]. The variation of IgA and light chain myeloma in our series may be due to racial and environmental variations or may be due to small size sample.

We found five different patterns of paraprotein fractions, where IgG κ constituted 70% which was most common, other fraction were IgG λ (10%), IgM κ (10%), IgA κ (5%) and IgA λ (5%).We found 30 (31.9%) cases in stage I with maximum of IgGK (n=19) followed by IgGL (n=4), IgAK (n=3), IgMK (n=2) and 2 cases of Lambda Light chain disease. In stage II maximum cases were of IgGK (n=17) followed by IgGL (n=7), LLC disease (n=3) and IgAK (n=1). In the stage III, the cases were in the order of IgGK (n=16), IgGL (n=11), IgAK (n=5), KLC disease (n=2), each of LLC and IgAL (Table 3).

In our study, 89% cases demonstrated monoclonal protein, while in Kyle study [16] serum protein electrophoresis study revealed M band in 82% of patients and Kaur et al [14] reported it in 92.8%. In our study the band migrated in gamma region in 83%, in other ranges such as beta (5.8%), alpha 2(1.06%) and between gamma and beta (9%), and case of biclonal gammopathy (1.06%). M band was not seen in 11% of patients and we feel that all clinicians must be aware of the fact that M band won’t be seen in all cases.

There was significant increase (p=0.001) in concentration of M-protein in 3 stages which were 1.83, 2.85 and 3.61gm/dl respectively.

The mechanism of anemia in most patients is inadequate production of red blood cells due to either erythropoietin deficiency or pronounced marrow replacement by myeloma cells or from accompanying renal failure [16]. Our study also supports this finding by showing the decrease in hemoglobin and increase in bone marrow plasma cells as the stage increases. In some patients anemia is disproportionate to renal failure or marrow involvement and is thought to be due to cytokine mediated marrow suppression. Biochemical data helps to assess tumor mass and renal involvement. In this study the serum creatinine level was increased as stage is increasing which was statistically significant. The major cause of renal failure is myeloma nephropathy (precipitation of monoclonal light chains in distal and collecting tubules). Other causes include dehydration and hyperuricemia [16].

Hyperuricemia was noted, uric acid increasing as the stage is progressing which was statistically significant. Serum Albumin has also been identified as a reliable prognostic factor in various studies. Elevated beta 2 microglobulin levels have been repeatedly shown to have independent prognostic value in myeloma [21][22].

Hypercalcemia, even though considered as one among the important diagnostic criteria (CRAB symptoms), in our study mean values were not high in different stages. Kyle et al [16], also reported hypercalcemia only among 13% of the 1027 patients. In their study diagnosis of MM was made in those with normal calcium 21 (66%) and below normal levels 5 (16%). Low calcium levels might be due to renal impairment. Hypocalcemia in MM secondary to Vitamin D deficiency was reported previously [23]. Factors including vitamin D deficiency may be contributing to hypocalcemia other than renal failure in myeloma patients.

Serum LDH is a simple, inexpensive and readily available blood test, which identifies a subset of patients with poor outcome. Our data suggests that as the stage is progressing LDH also is increasing. In a multivariate analysis, elevated serum LDH was found to be an independent factor and had a major prognostic impact associated with a 5.4-fold increased risk for death [24]. Further they suggested that the elevated baseline serum LDH should be included in the current criteria (i.e. poor risk cytogenetics, high plasma cell labeling index) which are being used to characterize high risk myeloma. The revised International Staging System(R-ISS) [25] has been developed that incorporates the original staging system with chromosomal abnormalities and serum lactate dehydrogenase.

In conclusion, having baseline data on the varied laboratory characteristics of a disease is of immense help to clinicians in the diagnosis and prognosis of that disease. It also helps laboratorians in their reporting work. MM is a disease affecting 2.1 per 100,000 of world population [26] and 1.2 to 1.8 per 100,000 of Indian population [27]. However there is paucity of data on laboratory parameters in various stages of MM, especially in India. Our study made a beginning to fill this gap by collating the data of age, sex, type of myeloma, biochemical parameters (urea, creatinine, uric acid, calcium, LDH, total proteins, albumin, globulins, immunoglobulins and M-protein) and FLC etc as well as the presenting data across different stages of MM. We have particularly shown that male preponderance with a male to female ratio of 1.47:1. The overall mean age was 55.5 years in the present study, with the mean age of presentation being 54.3, 53.9 and 57.7years respectively in ISS stages I, II & III. Most common clinical presentation (46%) was bone related such as low backache, bone pain, joint pains and pathological fractures and most of our patients presented in advanced clinical stage in stage III. The most commonly occurring paraprotein type is IgG, followed by IgA and light-chain myelomas. The presentation of MM is nonspecific and patient can come with varied presentations at onset. The quality of life and survival in MM patients can be improved significantly if detected early in stage I and II.

We hope that the information presented in this study will form a basis for clinicians and other laboratorians to plan further studies including large prospective cohorts on these lines and develop stage-based algorithms for early and better diagnosis and prognosis of MM.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare no conflict of interest