Clinicopathological profile of multiple myeloma at a tertiary care hospital in a resource-poor setting: A retrospective study

INTRODUCTION

Multiple myeloma (MM) is the second most common hematologic malignancy and is associated with significant morbidity due to its potential for end-organ destruction.^[1] Timely diagnosis of myeloma remains challenging due to non-specific symptomatology, consequently requiring a high index of suspicion.

In a suspect, blood and urine tests for antibodies and protein detection act as screening tools, followed by an examination of bone marrow, biochemical tests, and radiological parameters to assess for end-organ damage and classify, stage, and prognosticate the disease.^[2,3]

We present the clinical manifestations of myeloma and its correlation with hematologic and laboratory profiles to help document the disease in this part of the country.

MATERIAL AND METHODS

Records of MM patients who presented to the Jawaharlal Nehru Hospital and Research Center, Bhilai, C.G, over seven years (January 2013–December 2019) were reviewed after the Ethical Committee approval (AIIMSRPR/IEC/JLNH-5/2019/382). Demographic, clinical, laboratory, radiographic, treatment, and follow-up data were collected. Bone marrow aspirate smears, and biopsy slides were reviewed to study the histomorphological characteristics.

The following laboratory parameters were evaluated in all the patients: complete blood count with an erythrocyte sedimentation rate (ESR), renal and liver function tests, urinary Bence-Jones proteins, serum protein electrophoresis (SPEP) with immunofixation, a skeletal survey by X-ray, bone marrow aspiration and biopsy, immunohistochemistry with CD 138, anti-k, and anti-l light chains.

Patients were administered the VRD regimen (Bortezomib 1.3 mg/m2 s.c, Lenalidomide 10 mg oral, Dexamethasone 40 mg i.v) with injection Zoledronic Acid (4 mg i.v once every four weeks), tablet Acyclovir 400 mg BD, tablet Trimethoprim 160 mg + tablet Sulfamethoxazole 800 mg, as induction and tablet Lenalidomide 10 mg as maintenance monotherapy. Treatment response was assessed with clinical profile, SPEP, and immunofixation.

The data were analyzed using mean, median, and percentage with MS Excel.

RESULTS

Seventy-two patients of plasma cell neoplasm were registered, of which 65 (n) were diagnosed as MM and seven as other plasma cell neoplasms. Clinical and laboratory workup was recorded for the 65 patients. Response to treatment and outcomes were recorded for 36 of 65 patients, as 29 were excluded (1 death before initiating therapy, two deaths during ongoing therapy, four discontinued therapy <1 month, five after > one month, and 17 lost to follow-up).

Clinical staging

Durie salmon staging (DSS)

The DSS (hemoglobin, serum calcium, the extent of bone lesions, level of serum, and urine M-component, along with serum creatinine for sub-categorization into A and B) was used to classify the patients.

About 76.92% of the patients were classified as class III, 18.75% were classified as class II, and only 4.61% as class I.

International staging system (ISS)

The ISS utilizes only two parameters: serum beta-2 microglobulin levels and serum albumin levels.

A total of 34 patients were assessed using the ISS, of which the majority (58.82%) were classified as stage II. About 26.74% were assigned to stage III and 17.64% to stage I.

Treatment outcomes

Twenty-one of the 36 patients (58.82%) demonstrated complete response to therapy (i.e., negative immunofixation on the serum and urine and disappearance of any soft-tissue plasmacytomas and <5% plasma cells in bone marrow). In contrast, 9 (25%) showed very good partial response (serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h), 4 (11.11%) showed partial response (>50% reduction of serum M-protein and reduction in 24 h urinary M-protein by >90% or to <200 mg/24 h), and 2 (5.55%) were nonresponders (not meeting any of the above criteria) [Figure 1].

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Figure 1:

Response to therapy.

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A total of 13 of 36 patients (36.11%) patients relapsed in the course of the study, one during therapy, one within six months of completing therapy, and 11 patients after six months of therapy completion.

Significant adverse events noted in those who completed therapy were as follows: neuropathy in 9 (25%), anemias in 4 (4.23%), diarrhea in 1 (2.77%), and cytopenia in 1 (2.77%) patients [Figure 2].

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Figure 2:

Treatment adverse effects.

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DISCUSSION

In our study, patient ages ranged from 24 to 85 years with a mean age of 61 years, with maximum patients belonging to the 6^th decade and late 5^th decade, similar to data by Kaur et al., Kyle et al., Kaushik et al., and Marla.^[4-7] A high male-to-female ratio of 1.3:1 is similar to Indian studies by Fousad et al., Kaushik et al., and Stifter et al.^[6,8,9]

Bone pain and backache are the most common presenting symptoms in the Indian subcontinent, as corroborated by our study (91.93%, 57 of 65 patients) and reported by Fousad et al. (96.9%) and Subramanian et al.^[8,10]

Fifty patients (73.84%) had Anemia, in agreement with Subramanian et al. (71%) and Kaur et al. (75%) but considerably lower than those reported by Chowdhury.^[4,10,11] Anemia was mostly normochromic and normocytic. The probable causes could be renal impairment, bone marrow infiltration by plasma cells, or coexisting iron deficiency.

The mean ESR of 100.4 mm/1^st h reported in 58.46% of our patients is comparable to Kaushik et al. (51%) but considerably lower than Kaur et al. (85.7%) and Chowdhury (100%).^[4,6,11]

Prominent Rouleaux formation was seen in 66.1% of patients, as compared to 82.1% by Kaur et al. and 91% by Subramanian et al.^[4,10]

Hypercalcemia was recorded in only 36.92% (24) patients, although 70.76% (46) patients had evidence of osteolytic lesions. Comparable data were seen in studies by Sharma et al. (42%) and Kaur et al. (42.8%).^[4,12]

Renal failure (S. creatinine > two g/dL) was seen in 63.07% of patients (41), which was considerably higher than values reported by Jacob et al. (27%) and Sharma et al. (28%).^[12,13]

The high proportion of patients with renal failure can explain Anemia in a large number of our patients.

Osteolytic lesions were the most common skeletal manifestation (80.7%, 46 of the 57 patients) presenting either in isolation or with osteoporosis and pathologic fractures, comparable to Pegu et al. 80%) and Diwan et al. (85%).^[14,15] Most of the lesions were concentrated in the axial skeleton (60.87%), with the skull being the most common site (45.65%). Of the 39.13% appendicular skeletal involvement, the pelvis was the most common bone involved (21.73%).

Even though vertebral involvement was only 10.86%, vertebral fractures accounted for 87.5% (n = 14) of the total pathologic fractures noted (n = 16); thoracolumbar vertebrae fractures were the most common, in 62.5%. This discrepancy between the low incidence of vertebral osteolytic lesions and the high vertebral fracture rate could be explained due to the presence of osteoporosis in 51.38% of the study population.

Low serum albumin concentrations (<3 g/dL) were seen in 67.69% (n = 44) patients, similar to the studies by Pegu et al. (66%) and Hussain et al. (55%).^[15,16]

A: G ratio reversal appeared to be the most sensitive laboratory indicator of MM, seen in 92.30% of patients, and similar percentages have been recorded by Shukla et al. (91.2%) and Ramani et al. (80%).^[17,18]

Among the serum monoclonal proteins, IgG Kappa was the most common subtype in 55.88% of patients, similar to the study by Mohammed et al. (53.3%).^[19] Serum beta-2 microglobulin (which reflects tumor load and is the most important prognostic marker) was positive (>3.5 μg/mL) in 70.58% of patients. It should be noted that beta-2 microglobulin is a cause of renal dysfunction and serum levels of it are raised. High serum beta-2 levels were also seen in the studies by Pegu et al. (75%), Chowdhury (84.37%), Kaur et al. (71.4%), and Kyle et al. (75%).^[4,5,11,15]

In our study, bone marrow aspiration demonstrated >50% plasma cells in 49.23% of patients, while 60.71% of patients were detected on bone marrow biopsy. Aspiration may tend to underestimate the plasma cell burden because it is subject to various preanalytical variables (poorly representative bone marrow aspirate due to technical faults such as blood dilution and sample clotting, among others). Therefore, a biopsy should always be performed, preferably simultaneously with aspiration, to prevent diagnostic delay and patient inconvenience. Bone marrow aspiration studies demonstrated hypercellular marrow in 85.71% of patients and reduced hematopoiesis in 64.28%, in agreement with Subramanian et al. (93%) and Marla (67%).^[7,10] The biopsies also showed >50% plasma cells in 60.71% of patients, consistent with other studies, and 8.92% had high-grade bone marrow fibrosis.

ISS staging is the standard of practice in developed countries, while developing nations follow the DSS. The ISS staging is simpler, requiring only blood samples and consequently a faster turnaround time. Various international comparison studies have demonstrated equivalent outcomes and prognostication between both systems.

In our study, all the patients were classified under the DSS. About 76.92% of patients were classified as DSS stage III, similar to Subramanian et al. (76%) and Griepp et al. (66%).^[10,20] Only 34 out of the 65 participants were classified under the ISS system, with 58.82% designated as stage II, similar to the studies by Pegu et al. (45%) and Dimopoulous et al. (38%).^[15,21]

In our study, 83.82% of patients demonstrated satisfactory response to therapy (either complete response or VGPR) as compared to 70% by the ICMR consensus document 2017 and 80% by Jacob et al.^[13,22] [Table 3].

Peripheral neuropathy (tingling and numbness of the extremities) was the predominant adverse effect seen in 25% of patients. Supplementing methylcobalamin, folate and the addition of gabapentinoids helped increase therapy compliance by reducing peripheral neuropathy symptoms.

CONCLUSION

The present study concludes that MM is a disease of the middle-aged and elderly with male preponderance. A differential of myeloma should be borne in mind for such an age group, presenting with diffuse bone pain and normochromic normocytic Anemia. Monitoring for gamma gap and A: G reversal can hasten diagnosis as these are the most sensitive markers of the disease.

Bone marrow aspiration should always be coupled with biopsy, helping prevent false negatives, reduce diagnostic delay, and prevent patient discomfort if a biopsy is planned separately. Bone marrow examination continues to be the gold standard for diagnosis and is advantageous in resource-poor countries like India, where laboratory tests are not available uniformly. ISS staging should preferably be used for its simplicity and faster turnaround.

The Velcade (Bortezomib) - Revlimid (Lenalidomide) - d (Dexamethasone) regimen leads to disease remission in a substantial proportion of patients. This should encourage clinicians to keep a low threshold for diagnosis of myeloma, as treatment can significantly alter morbidity and increase survival.