Multiple myeloma with kidney damage, how to solve the problem?

Introduction Multiple myeloma (MM) is a malignant disease characterized by abnormal proliferation of clonal plasma cells [1], often manifested as bone disease, anemia, renal insufficiency and/or abnormal metabolism, and patients have poor health-related quality of life [2] ]
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The prevention and treatment of MM complications is one of the cornerstones to improve the survival of MM patients [2]
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In recent years, with the approval of various drugs, such as the application of oral regimens such as ixazomib-lenalidomide-dexamethasone (IRd), the survival and compliance problems of MM have been greatly improved.
Diagnosis and treatment has gradually transformed into a chronic disease management model
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Therefore, in addition to mastering more flexible MM treatment strategies, clinicians need to deal with the complications of MM more than ever
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In the last issue of "Blood Chat Room", we sorted out the diagnosis and treatment of multiple myeloma bone disease
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In this issue, we focus on another common complication of MM, kidney injury, to help clinicians better manage the disease
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20% to 40% of MM patients have renal injury at the initial diagnosis or during the disease process, and 20%-50% of MM patients have renal injury at the initial diagnosis or at different stages of the disease [3,4]
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About half of the renal function can be completely reversed, while the rest may evolve into different degrees of renal insufficiency, and about 2%-12% of MM patients require renal replacement therapy [4]
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Kidney injury can be the first clinical manifestation in MM patients, manifested as chronic kidney disease (CKD) or acute kidney injury (AKI) [4]
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Patients present with symptoms such as edema of both lower extremities or face, increased foam in urine, increased nocturia, oliguria or proteinuria [5]
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How does MM-induced kidney damage occur? As described in the literature, the main reason is that the free light chains secreted by MM cells produce protein casts that block the distal renal tubules, leading to tubular renal insufficiency; it may also be the free light chains that lead to renal amyloidosis, which clinically manifests as white Proteinuria without hypertension; or renal light chain deposition disease caused by free light chains, manifested as microscopic hematuria, mixed proteinuria, and hypertension
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In addition, light chain can cause proximal renal tubular dysfunction, leading to renal tubular reabsorption dysfunction [5]
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How to do a good job in the diagnosis and differential diagnosis of kidney injury? 1.
In the consensus on how to diagnose the "Expert Consensus on the Diagnosis and Treatment of Multiple Myeloma Kidney Injury" led by Chinese experts, it is pointed out that MM kidney injury should be considered in the following clinical manifestations [4]: ​​age >40 years of age with unexplained renal insufficiency, anemia and renal function The degree of damage is not proportional to nephrotic syndrome without hematuria, hypertension, early anemia and renal failure with early renal insufficiency with high blood calcium erythrocyte sedimentation rate (ESR) significantly increased, hyperglobulinemia and susceptibility to infection (such as urinary tract, Respiratory tract, etc.
) 24h urine protein (more) and urine routine protein (less or negative) test inconsistent IMWG recommendation on the diagnosis and management of myeloma kidney injury, symptomatic MM kidney injury is defined as: serum creatinine (sCr) > 2.
0 mg/ dl or creatinine clearance (CrCl) <40mL/min[3]
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The International Myeloma Working Group (IMWG) also recommends that sCr, electrolyte testing, and electrophoresis of 24-hour urine collection samples should be performed in all MM patients when diagnosing and evaluating the disease (level A); Serum free light chain (sFLC) testing (level A); if nonselective proteinuria or macroalbuminuria is detected, renal biopsy should be performed to determine the cause of renal insufficiency (level B) [3]
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In the Canadian Myeloma Collaborative Group consensus on the management of complications in MM, it is recommended that at diagnosis, work-up should include 24-hour urine sample collection and urine electrophoresis, and renal biopsy when indicated
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Renal biopsy remains the gold standard for diagnosis; however, renal biopsy can be omitted when the likelihood of light chain cast nephropathy is high or the cause of renal injury is clearly reversible (eg, dehydration, hypercalcemia, or nephrotoxic drugs); Kidney biopsy can usually be postponed when the sFLC level is ≥1500 mg/L, the urine albumin concentration is low, and the proteinuria is mainly light chain; if the patient has non-selective proteinuria, macroalbuminuria, or sFLC<500 mg/L, Kidney biopsy is usually required to exclude light chain amyloidosis and light chain deposition disease [2]
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2.
Differential diagnosis should be made with primary renal disease.
The Canadian Myeloma Collaborative Group’s consensus on the management of MM complications mentioned that the most common cause of MM-related renal insufficiency is light chain cast nephropathy, but it may also be caused by a single Clonal immunoglobulin deposition disease, amyloidosis, cryoglobulinemia, associated with hypercalcemia or hyperuricemia, use of nephrotoxic drugs (eg, NSAIDs, aminoglycosides), use of contrast imaging Differential diagnosis should be done due to drug or (rare) plasma cell infiltration, etc.
[2]
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Professor Chen Mingming stated in his literature: "The renal insufficiency in MM patients first needs to determine whether it is caused by pre-renal, renal or post-renal factors
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In MM patients, due to factors such as hypercalcemia, the patient's nausea, Vomiting, anorexia, loss of appetite and other symptoms, patients with insufficient intake, secondary hypovolemia, and prerenal renal insufficiency, clinically through rehydration, diuresis, renal function will be corrected in time
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Very few patients due to urinary system Post-renal renal insufficiency is induced by factors such as stones, urinary tract malformations, and plasmacytoma compression.
If these factors are removed in time, renal function may also recover
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However, in patients with MM, renal factors (including renal tubules, renal interstitium and renal The most common renal insufficiency caused by glomeruli, etc.
The
most
common MM nephropathy is cast nephropathy, followed by amyloidosis and light chain deposition disease” [5]
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The article also pointed out that MM with renal insufficiency needs to be differentiated from hypertensive nephropathy and diabetic nephropathy because MM is mostly elderly patients, often with hypertension and/or diabetes
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Both hypertensive nephropathy and diabetic nephropathy patients showed hypertension, mixed proteinuria, kidney shrinkage, and cortical thinning; while MM with renal insufficiency showed elevated urinary light chain or albuminuria, without hypertension, The kidneys were normal or slightly larger in size and had normal cortical thickness [5]
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In the era of traditional chemotherapy, the median survival time of patients with MM with renal impairment was only about 2 years; in recent years, with the use of new anti-myeloma drugs, the survival of patients with MM with renal insufficiency has been significantly improved.
However, severe MM with renal impairment is associated with an increased risk of early mortality [3]
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The treatment strategies for patients with MM and renal impairment are mainly anti-myeloma therapy based on the cause combined with supportive therapy based on symptoms, and plasma exchange
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It is worth noting that for MM with AKI (which is an emergency), consultation with the nephrology department is required, and the diagnosis must be made as soon as possible, and anti-myeloma treatment should be started immediately after the diagnosis to quickly restore renal function; for patients requiring dialysis, treatment The goal should be to avoid dialysis [2,3]
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1.
Anti-myeloma treatment The current drugs for the treatment of MM include proteasome inhibitors (PIs), immunomodulators, monoclonal antibodies, cytotoxic drugs and glucocorticoids [5]
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Anti-MM therapy based on PIs and immunomodulators is the main treatment strategy for MM with renal injury.
Timely initiation of anti-MM therapy is crucial to reduce the toxic effects of high-load light chains on renal function and to restore renal function[6]
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No dose adjustment is required for bortezomib, thalidomide, daratumumab, doxorubicin, and dexamethasone in patients with renal insufficiency; ixazomib, lenalidomide, melphalan, benda The dosage of mustine and other drugs needs to be adjusted according to the degree of renal insufficiency; cyclophosphamide is safe to use in the case of normal urine output, but it is not safe to use in oliguria or anuria, and there is a risk of inducing hemorrhagic cystitis ; Anthracycline drugs such as doxorubicin have cardiotoxicity, and the use of these drugs should evaluate the cardiac function of patients, especially whether they are associated with myocardial amyloidosis [5]
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The IMWG believes that the bortezomib regimen is the cornerstone of the treatment of MM with renal impairment (level A); the all-oral regimen IRd can be safely used for relapsed and refractory MM patients with CrCl ≥ 30 mL/min (level A) [3]
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2.
Supportive care Adequate supportive care must be given to all patients with suspected renal insufficiency caused by MM
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Supportive care includes adequate hydration and fluid intake ≥3 L/d or approximately 2 L•m-1•d-2 while anti-MM therapy, which is especially important in patients with dehydration associated with hypercalcemia [3,4]; Urine alkalinization may be beneficial in cast nephropathy, but should be used with caution in patients with hypercalcemia and hypercalciuria [4]; Avoid nephrotoxic drugs such as aminoglycosides, furosemide, and contrast [3]; bisphosphonates are used to correct hypercalcemia, pamidronate sodium or zoledronic acid can be used, but it is contraindicated in patients with severe renal insufficiency (CrCl<30 mL/min) [3 ,4]
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3.
The IMWG recommendation for blood purification treatment mentions that high retention volume dialysis (HCO-HD) can be used in patients with AKI caused by MM with cast nephropathy (level B); when HCO-HD is ineffective, plasma exchange may be effective for AKI or strongly suspected Beneficial in patients with light chain cast nephropathy (Grade C) [3]
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Plasma exchange for the treatment of MM kidney injury helps to increase the proportion of patients who are out of dialysis [4]
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4.
Other things to pay attention to in the treatment process are: ① Hydration and diuresis, try to keep the daily urine output at about 2000 ml; if the urine output decreases or there is no urine, oral or continuous intravenous infusion of diuretic drugs should be used
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The appropriate amount of fluid replacement is appropriate for mild edema of the lower extremities or face
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② Dialysis patients should not limit their intake, and their body weight should be monitored daily.
It is safe to gain 2 to 3 kg of body weight between two dialysis sessions
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Patients who need hemodialysis should undergo dialysis as soon as possible to help restore renal function; high-flux dialysis is recommended for patients with high serum free light chains, which helps to remove free light chains and reduce further damage to the kidneys by light chains
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③ In terms of nutrition, do not limit protein intake excessively, and do not limit sodium intake (unless accompanied by hypertension) [5]
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Conclusion Renal insufficiency, as one of the most common complications of MM, brings a heavy clinical burden to patients
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Once MM with renal injury is diagnosed, reasonable anti-myeloma treatment and supportive treatment should be carried out as soon as possible to improve the prognosis and quality of life of the patients
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To be continued.
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The wonderful content about the management of adverse reactions of MM treatment will be released in "Blood Chat Room" one after another, so stay tuned! References: 1.
Chinese Medical Doctor Association Hematologist Branch, Chinese Medical Association Hematology Branch, Chinese Medical Doctor Association Multiple Myeloma Professional Committee.
Guidelines for the diagnosis and treatment of multiple myeloma in China (revised in 2020) [J].
Chinese Journal of Internal Medicine.
2020;59(5):341-346.
2.
LeBlanc R, Bergstrom DJ, Côté J, et al.
Management of Myeloma Manifestations and Complications: The Cornerstone of Supportive Care: Recommendation of the Canadian Myeloma Research Group (formerly Myeloma Canada Research Network) Consensus Guideline Consortium[J].
Clin Lymphoma Myeloma Leuk .
2022 Jan;22(1):e41-e56.
3.
Dimopoulos MA, Sonneveld P, Leung N, et al.
International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma -Related Renal Impairment[J].
J Clin Oncol.
2016 May 1;34(13):1544-57.
4.
Expert consensus on diagnosis and treatment of multiple myeloma kidney injury.
Expert consensus on diagnosis and treatment of multiple myeloma kidney injury[J].
Chinese Journal of Internal Medicine.
2017;56( 11 ):871-875.
5.
Chen WM.
How I treat multiple myeloma with renal impairment[J].
Chinese Journal of Hematology.
2021 Feb;
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Edit: Evelyn Typesetting: Wenting Execution: Youshi pokes "read the original text", we make progress together