Australian Doctor Australian Doctor 15th September 2017 | Page 22

How to Treat – Multiple myeloma Pathophysiology MULTIPLE myeloma involves the clonal proliferation of plasma cells within the bone marrow, most commonly secreting a monoclonal immunoglobulin (called a parapro- tein) which can be detected in the blood or urine (see figure 1). 2,6 A paraprotein is a clonal immu- noglobulin that reaches detectable levels in the bloodstream due to abnormal excessive production by the malignant clone. Immuno- globulin consists of two main com- ponents — heavy chains and light chains (see figure 2). Most multiple myeloma involves secretion of whole immunoglobu- lin in which the heavy chain is clonally IgG or IgA, is seen in around 80% of cases. 7 Secretion of only the light chain component of the immunoglobulin, referred to as light-chain myeloma, occurs in around 18% of cases. Excess light chains, known as Bence Jones pro- teins, are excreted in the urine (see figure 3). There are also rare cases (around 2%) of non-secretory myeloma where disease manifestations relate solely to plasma cell expansion within the bone marrow. Clonal expansion of plasma cells results from genetic mutations, most often involving gene translo- cations between chromosomes or alterations in the number of chro- mosomes (hyperdiploidy or hypo- diploidy). With time, myeloma cells accrue further genetic abnormalities lead- ing to increasing proliferation and/ or treatment resistance. Plasma cell development also relies on a con- ducive bone marrow environment, and thus treatments aimed at dis- rupting the bone marrow microen- vironment are under investigation. 2 Renal impairment While whole immunoglobulin is too large for glomerular filtra- tion, light chains are secreted in the glomeruli, then reabsorbed in the proximal tubule. Once this resorptive capacity is saturated, they precipitate as casts in the dis- tal tubules. This causes obstruction and local inflammation, resulting in acute kidney injury. Most renal impairment in myeloma is due to A IgG Heavy chain | Australian Doctor | 15 September 2017 Light chain Figure 2. Heavy and light chains. B Figure 1. Serum protein electrophoresis normal (A) and paraprotein (B). Figure 3. Bence Jones protein Source: Simon Caulton bit.ly/1SXJ0DE Source: National Institutes of Health, US http://bit.ly/2uxDrtG SEVERE HYPERCALCAEMIA, INFECTION, HYPERURICAEMIA AND MEDICATIONS ARE OTHER POTENTIAL CAUSE FOR RENAL IMPAIRMENT IN MULTIPLE MYELOMA. Figure 4. Skull x-ray with classic myeloma lytic lesions. 22 IgA dimer such cast nephropathy. 2,6 Less common causes of renal impairment in myeloma are light chain amyloidosis and monoclo- nal immunoglobulin deposition disease (MIDD). 8 Severe hypercal- caemia, infection, hyperuricaemia and medications are other potential cause for renal impairment in mul- tiple myeloma. Bone disease Dysregulation of the balance between osteoclast and osteoblast activity is responsible for the ostey- olytic bone lesions seen in multiple myeloma. This dysregulation is due to production of various stimula- tory/inhibitory factors by the mye- loma cells. This relatively increased osteoclast activity leads to a state of osteolysis, leading to the lytic lesions and hypercalcaemia com- monly seen in multiple myeloma. 2 Figures 4 and 5 depict the clas- sic appearance of ‘punched out’ lesions seen on X-ray in multiple myeloma. Lesions are most com- monly seen in the axial skeleton. The standard X-ray skeletal survey for the detection of lytic lesions has now largely been replaced by the low-dose CT skeletal survey, MRI or PET-CT. Anaemia Multiple myeloma causes anae- mia via two mechanisms — most significantly, expansion of plasma cells within the marrow occupies space needed for normal erythro- poiesis. Secondly, like all malig- Figure 5. Pelvis and femur X-rays with diffuse myeloma lytic lesions. www.australiandoctor.com.au nancies, multiple myeloma causes an inflammatory state, contribut- ing to anaemia of chronic disease. 9 Recurrent infection The cause of infection varies depending on disease stage. Defi- ciency of normal/functional immu- noglobulins is common in myeloma due to the clonal expansion of one plasma cell line. In bone marrow crowded with myeloma cells, nor- mal haematopoiesis is prevented, which may lead to neutropenia. 7 Immunosuppressive and immu- nomodulatory treatments in patients with known multiple myeloma can also contribute to recurrent infection in those on treatment. cont’d page 24