Mrs. Mamulla Begum, 62-year-old female, a known case of hypertension, presented to ER with complaints of shortness of breath(grade III – IV), sudden onset for 2 days, cough with expectoration, mucoid in nature for 2 days, palpitation, on and off, for 2 days on 26/3/22. She also had lower back pain, and left shoulder pain since January 2022. On arrival @ ER, her temperature was 99.1 F, blood pressure- 160/90 mmHg, pulse – 146/min, respiratory rate-20/min, SpO2- 98% Room air, CBG- 132 mg/dl, GCS- 15/15. On examination, she was conscious, orientated and febrile. Pallor +, bilateral pitting pedal edema +

CVS- S1 S2 heard, no murmur, jvp- normal
PER ABDOMEN- soft, non-tender, no organomegaly
CNS- no focal neurological deficit
RS- bilateral air entry, left infraaxillary and inframamillary coarse crepitations.

Routine ECG done revealed irregular rhythm-atrial fibrillation. She was treated with appropriate antiarrhythmic drugs.

Basic blood workup revealed Haemoglobin – 7.2, WBC Count- 7900, ESR- 140, Serum total protein – 12.14 g/dl, Serum albumin- 2.66 g/dl, Serum globulin- 9.48g/dl, Serum albumin globulin- ratio – 0.3 Serum urea- 38.8 mg/dl, Serum Creatinine- 0.62 mg/dl. CT chest done showed left lower lobe consolidation, lytic lesions in left clavicle, left humerus, left scapula and pelvis, Right iliac fossa mass (3 cm * 2.1 cm). Sputum culture and sensitivity revealed Escherichia coli infection which was treated appropriate antibiotics. Blood culture and urine culture were negative. CTPA done ruled out pulmonary embolism. In view of lytic lesions and AG reversal, S. IgG, S.Ig A, S. IgM, S. LDH, S. Beta 2 microglobulin, Urine Bence Jones protein, Serum electrophoresis, Serum immune fixation electrophoresis, Serum free light chain assay, Serum CEA, Serum CA 19-9 were done. IgG – 5810 mg/dl, Serum protein electrophoresis- Hypoalbuminemia and hypogammaglobulinemia, strong monoclonal band seen beta 2 region, Serum immune fixation- IgG Kappa monoclonal antibodies, Serum LDH 603 U/L. Urine Bence Jones protein was negative, CEA and CA 19-9 was within normal range. Bone marrow aspiration done showed few myeloid precursors, marrow diluted with peripheral blood. CT guided biopsy of lytic bone lesions showed features suggesting round cell tumour- Plasmacytoma or lymphoma. PET CT done showed features of multiple myeloma with involvement of right pleura and myrelomatous pleural effusion. She was started on VRD regimen (Bortezomib, Lenalidomide, Dexamethasone) and was followed up on op basis.

CASE DISCUSSION

MULTIPLE MYELOMA is a malignant monoclonal plasma cell tumour. It causes bone pain, fracture, anaemia, renal failure, Hyper-viscosity syndrome, hypercalcaemia. ETIOLOGY Radiation exposure, exposure to petroleum products. Hyper-diploidy, 13q14 deletions, translocations t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16), 1q amplification or 1p deletion, and 17p13 deletions. Antibody heavy chain switch mechanism errors, N-ras, K-ras, and B-raf mutations, IL- 6 mutation also plays a role.

PATHOGENESIS

Ras/Raf/MAP kinase, Pi3k/AKT, Protein C signalling mutations cause multiple myeloma.

CLINICAL FEATURES

Bone pain due to pathological fracture. MM cells produce OAFs (osteoclast activating factor) which activates osteoclasts and suppresses osteoblast. The bone lesions are lytic and not osteoblastic. Hence, radioisotope scan is not useful. Bone lysis causes hypercalcaemia which has acute and chronic complications. Localized bone lesions may cause the collapse of vertebrae leading to spinal cord compression. Recurrent bacterial infections like pneumonia and pyelonephritis due Staphylococcu aureus, Streptococcus pneumoniae, Klebsiella pneumoniae and Escherichia coli can occur. Hypogammaglobulinemia causes recurrent infections. Poor antibody response to bacterial cell wall polysaccharides, abnormal t cell function, decreased th1, increased th17 response, low granulocyte lysozyme, complement abnormality contributes to infection. Renal failure can occur due to hypercalcaemia. However, tubular damage associated with the excretion of light chains is almost always present. Light chains filtered in nephron is tubulo toxic and results in adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine. Non selective proteinuria may be seen. Normocytic normochromic anaemia is due to inhibition of haematopoiesis by MM cells and decreased erythropoietin production by kidney. Patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency. Clotting abnormality can be caused due to defects in factors 2,5,7,8 and anti-platelet antibodies. Hyper-viscosity due to M component causes hyper-viscosity syndromes and Raynauds phenomenon due to cryoglobulins formation. Hyper-viscosity may lead to shortness of breath, exacerbation or precipitation of heart failure. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Myeloma neuropathy is sensory more than motor. Since proliferation not MM cells is within bone and bone marrow, splenomegaly and lymphadenopathy are rarely seen. MGUS: Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. Two variants of myeloma—solitary bone plasmacytoma and solitary extra-medullary plasmacytoma. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Both tumours are highly responsive to local radiation therapy. Serum protein electrophoresis, free light chain assay help in diagnosis. Quantification of serum β2-microglobulin and albumin is important. Patients with serum M components also have urinary light chains. Heavy chain isotype has impact on Hyperviscosity syndromes. Erythrocyte sedimentation rate is elevated. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. MRI is used to identify bone marrow infiltration and cord compression. PET/CT is used to distinguish between smouldering and active MM.

PROGNOSIS

Serum β2-microglobulin, Serum albumin, LDH, circulating plasma levels, kras, nras, tp53 mutation help in prognosis. Chromosome 17p deletion, and translocations t(4;14), (14;16), and t(14;20) and 1q34 amplification can also help in prognosis. The ISS system is used in prognosis.

TREATMENT

MGUS does not require intervention. MGUS with neuropathy requires intervention- plasmapharesis or rituximab. Early intervention of smoldering myeloma with Lenalidomide and Dexamethasone prevent s progression to MM. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas -local radiation therapy. Patients with symptomatic and/or progressive myeloma require therapeutic intervention. The purpose of therapy is to control systemic disease, treat symptoms and complications. The therapy of myeloma includes induction, consolidation and maintenance. Therapy depends on age. Lenalidomide, Dexamethasone and Bortezomib (protease inhibitor) combination is used. Bortezomib causes herpes zoster flare up and Lenalidomide causes DVT. Initial therapy is continued until maximal cytoreduction. Melphalan is avoided in transplant candidates. Lenalidomide added to MP followed by lenalidomide maintenance also prolonged progression-free survival compared with MP alone. High-dose therapy (HDT) and consolidation/maintenance produces more cytoreduction than standard dose therapy. Studies show that there is no difference between early and late transplantation and hence transplantation can be delayed. Maintenance therapy prolongs remissions following standard- dose regimens as well as HDT. Lenalidomide as maintenance therapy after HDT may cause secondary cancer. High risk patients can be treated with Bortezomib and Lenalidomide as maintenance therapy. The combination of bortezomib and liposomal doxorubicin is active in relapsed myeloma. Carfilzomib and pomalidomide are used in refractory MM. Ixazomib, Lenalidomide and Dexamethasone combination is used in relapsed MM. Daratumumab targeting CD38 can be used as a single drug to prevent progression. Elotuzumab, Lenalidomide and Dexamethasone can be used for relapsed refractory MM. Panobinostat, Bortezomib and Dexamethasone combination can also be used for relapsed refractory MM.

Dr Azharuddin M
DNB Resident (General Medicine)
Kauvery Hospital