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Dealing with multiple myeloma


Multiple myeloma is a malignant disorder of plasma cells producing a monoclonal immunoglobulin; current diagnostic criteria are summarised in Table 1. Renal involvement is a common — and often serious — complication. Thus, general physicians, nephrologists and haematologists should have some knowledge of the renal complications of myeloma. Renal involvement can manifest clinically in several different ways — these are summarised in Table 2. Acute kidney injury (AKI) can actually be the presenting feature in some patients; other patients with known myeloma may develop AKI during the course of their disease.

Table 1: Current diagnosic criteria for multiple myeloma

Table 2: Clinical renal syndromes that can occur in multiple myeloma

In contrast to multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic plasma cell disorder — its definition is summarised in Table 3. Approximately 1 per cent of MGUS cases per year progress to multiple myeloma. By definition, there is no kidney injury in MGUS. However, there is increasing recognition that some patients may develop kidney injury due to abnormal production of a monoclonal immunoglobulin, even though the full criteria for diagnosis of multiple myeloma are not fulfilled. The term ‘monoclonal gammopathy of renal significance’ (MGRS) is increasingly being used to describe such cases. MGRS is an important distinction from MGUS because i) there is end-organ (renal) damage; and ii) some form of treatment to reduce the burden of the toxic monoclonal immunoglobulin may be indicated.

Table 3: Current diagnosis criteria for MGUS (all three must be present)

Cases discussion

The first case report makes several important teaching points: myeloma can cause severe acute and chronic kidney disease; myeloma kidney disease can mimic other conditions such as RPGN; and treatment for myeloma has improved significantly over the last 10 years (older literature generally described a very poor renal and overall prognosis for patients presenting with myeloma and severe renal failure).

Although acute cast nephropathy is the best known (and probably most serious) cause of AKI in the myeloma patient, there are many other causes — see Table 4. Myeloma should always be considered in the differential diagnosis of causes of AKI in patients over 50 years of age. Suspected cases require urgent investigation and treatment. Investigations include serum electrophoresis, urine electrophoresis, bone marrow biopsy and aspirate, and skeletal radiography or other skeletal imaging. Some centres now use the serum-free light chain (FLC) assay as an aid to diagnosis. Kidney biopsy is sometimes performed — as here — where the cause of kidney injury is not yet clear or where it is clinically useful to determine the cause of kidney injury in a known myeloma patient.

Table 4: Causes of acute kidney injury in multiple myeloma

Immediate treatment includes IV fluids, rapid control of any hypercalcaemia and cessation of nephrotoxic drugs such as NSAIDs. An important goal is rapid reduction of the light chain burden. High-dose dexamethasone works relatively quickly in this regard and should be started as soon as the diagnosis is confirmed, or even before confirmation where the pre-test probability of myeloma cast nephropathy is high.

Increasingly, bortezomib is also used in the setting of AKI because it tends to decrease light chain production relatively quickly. Plasmapheresis can remove the toxic light chain from the circulation and its use has been advocated by some. However, the most recent randomised, controlled trial of plasmapheresis in this setting showed little benefit. High cut-off dialysis is a modified form of dialysis, which allows much more removal of light chains than conventional dialysis. Randomised, controlled trials are currently assessing its benefits (and risks) in the setting of AKI and multiple myeloma.

The second case report illustrates the increasingly recognised phenomenon of MGRS. Here, the patient is presumed to have abnormal proliferation of a clone of plasma cells, leading to overproduction of a nephrotoxic monoclonal immunoglobulin. This immunoglobulin is then being deposited in the glomeruli, eliciting a severe inflammatory response. Although there is significant end-organ damage, he does not fulfil the diagnostic criteria for multiple myeloma (Table 1). There had been a tendency to label such patients as MGUS, which implies surveillance rather than treatment. It is now well described, however, that monoclonal immunoglobulins can cause significant kidney damage, even when myeloma per se is not present. Such cases are now aptly labelled MGRS.

The type of nephrotoxic monoclonal immunoglobulin and the type of renal damage/inflammation that may occur are quite variable. For example, one patient might present with nephritic syndrome and renal dysfunction with the renal biopsy showing glomerulonephritis (as here); another patient might present with nephrotic syndrome alone, with the renal biopsy showing AL amyloid. The important point of course is to recognise that the monoclonal immunoglobulin is nephrotoxic. Note that the simultaneous presence of a monoclonal immunoglobulin (in the serum or urine) and kidney injury do not imply MGRS. Both can occur independent of each other, especially in the elderly. It is important to exclude other causes of kidney injury and to establish that the monoclonal immunoglobulin is causing the injury. Typically, this will require a renal biopsy.

At the very least, patients diagnosed with MGRS require close renal and haematological follow-up. In some cases (as here) where the degree of kidney injury is severe and the link between the monoclonal immunoglobulin and kidney damage is strong, a course of chemotherapy to reduce production of the monoclonal immunoglobulin is reasonable. Of course, such chemotherapy can have significant adverse effects so the risks and benefits of chemotherapy should be carefully assessed for a given patient.


Despite major improvements in the treatment of multiple myeloma, it remains an important cause of severe acute and chronic kidney injury.

Suspected cases of myeloma-induced AKI require urgent investigation and treatment.

Some patients with a monoclonal immunoglobulin may not satisfy the criteria for the diagnosis of multiple myeloma but the immunoglobulin can be nephrotoxic; such cases are now termed MGRS.

Reference available on request

Case report 1

A 78-year-old male was referred urgently to the renal service because of plasma creatinine 750mmol/L. He had presented to the GP with a several-week history of malaise, fatigue and low-back pain. There was no history of renal disease and the patient had previously been very well and was not on medication. Examination showed pulse 90/minute, BP 144/88 and was otherwise unremarkable. The urine dipstick showed 2+ blood, 2+ protein and trace WBCs. Other tests included: K 5.4, calcium 2.51, albumin 41, LDH 484 (normal), Hb 7.3, WBC 2.7, platelets 112. Renal ultrasound showed echogenic, normal-sized kidneys. Because of concern about a rapidly-progressive glomerulonephritis (RPGN) syndrome or multiple myeloma, the following tests were requested: anti-neutrophil cytoplasm antibodies (ANCA), anti-GBM, C3, C4, anti-dsDNA, serum electrophoresis and urine electrophoresis. A kidney biopsy was urgently performed but pending the results of this, he was given IV fluids and high-dose steroids (the latter would treat both RPGN and ‘myeloma kidney’). The renal biopsy subsequently showed classic features of acute and chronic myeloma cast nephropathy (myeloma kidney) — Figure 1. Serum electrophoresis showed a monoclonal band: free kappa light chain. Urine electrophoresis showed a large monoclonal band; again, free kappa light chain. The bone marrow biopsy demonstrated a large number of plasma cells (approximately 80 per cent of nucleated cells based on special stains). The diagnosis was thus multiple myeloma (see Table 1). In this case, the malignant plasma cells were producing an excess kappa light chain immunoglobulin. The light chains were being filtered through the glomeruli into the lumina of the tubules, and there causing tubule obstruction and inflammation (Figure 1) and hence renal dysfunction.

The patient was treated initially with steroids (dexamethasone) and bortezomib and later with additional anti-plasma cell agents. Renal function improved quickly to a creatinine c. 350mmol/L and he did not require dialysis. Four years later, his renal function remains poor but very stable: creatinine c.386mmol/L and eGFR 12ml/min/1.73m2. He has no symptoms of uraemia and has never required dialysis. He is still undergoing intermittent treatment for a persistent monoclonal immunoglobulin in the serum.


Figure 1: Renal biopsy

Left panel (low power) shows large numbers of casts in the lumina of the tubules. There is also atrophy and inflammation of the tubules and interstitium (blue arrows). Right panel (higher power) shows that some of the casts are fractured (yellow arrow); many casts are also surrounded by inflammatory cells (green arrows). The casts are composed in part of monoclonal immunoglobulin light chains.

Case report 2

A 68-year-old male was referred in 2013 because of plasma creatinine 208mmol/L. A recent ultrasound had shown ‘normal-sized kidneys’. Other tests on referral were Hb 11.5, WBC 13.4, platelets 241, LDH 270, albumin 34, K 5.3 and CRP 0.5; plasma calcium and phosphate were normal. His medical history was significant for kidney stones and hypertension. Medications were rosuvastatin, aspirin, esomeprazole and amlodipine.

Examination showed pulse 100/minute, BP 159/89 and moderate leg oedema. The urine dipstick showed 3+ blood and 3+ protein; the spot urine protein/creatinine was 603mg/mmol. The clinical diagnosis was a nephritic syndrome. Tests for ANCA, C3, C4, anti-ds DNA and anti-glomerular basement membrane (GBM) were negative. The renal biopsy showed a membranoproliferative glomerulonephritis (MPGN) with immune complexes. The exact cause of the glomerulonephritis was not initially clear but he was noted to have a small monoclonal band on serum electrophoresis (IgG kappa). Further review of the electron microscopy slides from the kidney biopsy showed immune deposits, which could have been formed from a monoclonal immunoglobulin.

Because of the concern that the monoclonal immunoglobulin was depositing in the glomeruli and causing the inflammation/damage, he was referred to the haematology service. The bone marrow biopsy did not show an increase in plasma cells and the skeletal survey showed no lytic lesions. He was not hypercalcaemic and had mild anaemia only. Thus, a diagnosis of multiple myeloma was not appropriate — see Table 1. However, he was diagnosed with MGRS. Initial management was conservative: control of hypertension, ACE inhibition and diuretics. Twelve months later, his creatinine remained elevated at 280mmol/L and the proteinuria remained quite severe: spot urine protein/creatinine c. 400mg/mmol.

After discussion with the patient, the haematology and nephrology services decided to treat the MGRS with a course of dexamethasone and bortezomib. The patient tolerated this regimen quite well. As of May 2015, his creatinine had stabilised at 213mmol/L and the spot urine protein/creatinine had fallen to 28mg/mmol. Serum electrophoresis showed only trace IgG kappa paraprotein.

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