IMWG Recommendations on Managing Multiple Myeloma-Related Renal Impairment

The following is a summary of the paper: 

Management of multiple myeloma-related renal impairment: recommendations from the International Myeloma Working Group. Dimopoulos, Meletios A et al. The Lancet Oncology, Volume 24, Issue 7, e293 - e311. Visit The Lancet Oncology for the abstract and to gain access to the actual publication.

The International Myeloma Working Group (IMWG) has updated its recommendations for managing kidney problems in multiple myeloma patients, using data available up to December 31, 2022. All patients should have tests for serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs), along with a 24-hour urine test for protein, electrophoresis, and immunofixation. If there's significant albumin in the urine or serum FLCs are under 500 mg/L, a kidney biopsy is recommended. 

The IMWG criteria should be used to define kidney response. Supportive care and high-dose dexamethasone are necessary for patients with myeloma-related kidney impairment. Mechanical treatments do not increase survival rates. Bortezomib-based treatments are key for managing kidney issues in newly diagnosed patients. New combinations of treatments, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, show improved kidney and survival outcomes for both new and relapsed patients. Advanced therapies like conjugated antibodies, CAR T-cells, and T-cell engagers are effective and safe for patients with moderate kidney impairment. 

Introduction

 

Renal impairment is a common issue in multiple myeloma, affecting up to 50% of patients at diagnosis, with 2–4% needing dialysis. Differences in reported rates of kidney issues may be due to varying definitions, such as serum creatinine levels or estimated glomerular filtration rate (eGFR) thresholds. Renal impairment in multiple myeloma is linked to lower survival rates and a higher risk of early death. A meta-analysis of 11 clinical trials showed that patients with kidney problems had a higher risk of disease progression or death than those without, both in newly diagnosed and relapsed cases. New treatments, like proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, have improved survival and kidney function, though patients with kidney impairment still have a shorter overall survival compared to those without. The International Myeloma Working Group (IMWG) reviewed current evidence to update guidelines for managing renal impairment in multiple myeloma. 

Methods

 

An interdisciplinary panel of experts in multiple myeloma and kidney impairment developed these updated recommendations for the IMWG. The panel reviewed evidence from randomized clinical trials, meta-analyses, systematic reviews, observational studies, and case reports. The experts, including myeloma specialists and nephrologists, assessed the levels of evidence and systematically graded the clinical data. The draft recommendations underwent several revisions until consensus was reached. The panel searched databases like MEDLINE, Embase, and Cochrane, along with abstracts from major hematology-oncology conferences, for studies up to December 31, 2022. Search terms included "multiple myeloma," "renal impairment," "acute kidney injury," and related terms. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used to assign levels of evidence and grades to the recommendations. When clinical data were insufficient, expert consensus guided the recommendations. The main updates in this version focus on the therapeutic approach to managing multiple myeloma-related kidney impairment. 

Pathophysiology of renal impairment in patients with multiple myeloma 

 

Renal impairment in multiple myeloma patients is mainly caused by the toxic effects of monoclonal free light chains (FLCs) on the kidneys. Normally, FLCs are filtered through the kidneys and broken down by the proximal tubule cells. However, in multiple myeloma, the excessive production of FLCs can overwhelm these cells' capacity to absorb and break them down. This leads to residual FLCs triggering inflammation and fibrosis in the kidneys. When FLCs reach the distal parts of the kidney, they can form aggregates with Tamm-Horsfall protein, leading to tubular obstruction and inflammation, resulting in a condition called light-chain cast nephropathy or myeloma cast nephropathy, a common cause of acute kidney injury in multiple myeloma. 

Other kidney diseases may also occur in multiple myeloma, involving the deposition of monoclonal immunoglobulins, such as amyloidosis, monoclonal immunoglobulin deposition disease, and cryoglobulinaemic glomerulonephritis. When these conditions are present without other symptoms of multiple myeloma, they fall under the category of monoclonal gammopathy of renal significance.  

Non-immunoglobulin factors like dehydration, high calcium levels, infections, tumor lysis syndrome, and certain medications can also lead to kidney impairment in multiple myeloma patients. Additionally, age-related decline in kidney function and comorbidities like diabetes and heart disease, especially since the median age of diagnosis is around 70, can increase the risk of kidney issues in these patients. 

Diagnosis and staging of renal impairment in patients with multiple myeloma 

 

Early detection and prompt treatment of kidney impairment in multiple myeloma are crucial for improving patient outcomes. The International Myeloma Working Group (IMWG) defines renal impairment in these patients as having a serum creatinine level above 2 mg/dL or a creatinine clearance rate below 40 mL/min. An algorithmic approach helps identify the cause of kidney impairment, which may involve multiple kidney diseases simultaneously. Tests like 24-hour urine protein electrophoresis and serum free light chain (FLC) measurements aid diagnosis, and a renal biopsy may be necessary if results are unclear. Early collaboration with a nephrologist is essential for evaluation and treatment. 

The estimated glomerular filtration rate (eGFR) can be calculated using the CKD-EPI equation to assess kidney function. Using cystatin C in this equation improves sensitivity for detecting kidney impairment and helps predict survival in newly diagnosed multiple myeloma patients. The National Kidney Foundation and the American Society of Nephrology recommend using cystatin C along with creatinine for more accurate eGFR measurement. Additionally, β2-microglobulin levels are elevated in patients with multiple myeloma and renal impairment and are part of the revised International Staging System for the disease, though its exact prognostic significance remains unclear. 

For acute kidney injury (AKI), criteria such as KDIGO, RIFLE, and AKIN can be used to assess severity. KDIGO and AKIN are more sensitive in critically ill patients, while RIFLE may identify more cases of AKI in patients with hematologic malignancies, including those after transplantation, and may predict long-term outcomes. More studies are needed to determine the best method for evaluating AKI in multiple myeloma patients. 

Recommendations: Assessment for Multiple Myeloma and Renal Impairment 

 

For patients with multiple myeloma and renal impairment, recommended assessments include serum creatinine, estimated glomerular filtration rate (eGFR), electrolytes, free light chains (FLCs), total protein, urine electrophoresis, and immunofixation of a 24-hour urine sample (Grade A). If non-selective proteinuria (mainly albuminuria) or serum FLCs below 500 mg/L are found, and other causes of kidney impairment are ruled out, a renal biopsy is recommended to identify the cause (Grade B). The CKD-EPI formula (excluding the race variable) should be used to evaluate kidney function and stage chronic kidney disease (CKD) in stabilized patients (Grade B). Adding cystatin C to this calculation, if available, can improve accuracy (Grade B). Baseline β2-microglobulin levels should also be measured in all patients (Grade A). For acute kidney injury, KDIGO, RIFLE, and AKIN criteria should be used (Grade C). 

The main goal of treatment is to reverse kidney impairment, which is linked to better outcomes. The IMWG criteria for renal response to treatment are well-established and widely used. Most studies emphasize the importance of an early and significant reduction in FLCs for kidney recovery. In dialysis patients, reducing serum FLCs to below 500 mg/L after the first chemotherapy cycle is associated with kidney response. In non-dialysis patients, FLC reduction within the first six months, AKIN stage 3, and pre-existing mild-to-moderate CKD are predictors of kidney outcomes. However, FLC response is not the only factor; pre-existing CKD and kidney biopsy findings also play roles. Rapidly reducing nephrotoxic FLCs is crucial, as interruptions in treatment or side effects can lead to permanent kidney damage. Patients with myeloma cast nephropathy are particularly frail, requiring careful assessment of treatment efficacy and toxicity. For patients on dialysis, gaining independence from dialysis is linked to improved survival. 

Recommendations for Supportive Care 

 

The IMWG recommends using its criteria for defining renal response in both clinical trials and routine practice (Grade B). Renal impairment caused by multiple myeloma is a medical emergency that requires immediate anti-myeloma treatment and supportive care. Supportive care includes proper hydration (at least 3 liters per day) and monitoring fluid balance, particularly in patients with congestive heart failure. If patients present with anuria, a fluid challenge is appropriate.  

Correcting calcium levels is also essential. While bisphosphonates and denosumab can treat myeloma-associated hypercalcemia, bisphosphonates are not recommended if creatinine clearance is below 30 mL/min. In cases where dialysis patients cannot restore their GFR above this threshold, bisphosphonates might still be used to manage bone disease. Denosumab is safe for patients with renal impairment but requires close monitoring for hypocalcemia and hypophosphatemia. High-dose steroids and calcitonin can be administered safely. Furosemide is not advised as it may promote cast formation in the renal tubules. 

Nephrotoxic agents, including contrast agents, renin-angiotensin-aldosterone system blockers, non-steroidal anti-inflammatory drugs, and certain antibiotics like aminoglycosides, should be avoided. Bacterial infections should be ruled out or treated with antibiotics if confirmed. 

For patients with multiple myeloma and renal impairment, high fluid intake (at least 3 L/day) should be initiated alongside anti-myeloma therapy (Grade B). Urine alkalization does not significantly help reverse renal impairment (Grade B). Bisphosphonates can reduce calcium in hypercalcemia but should be avoided in severe renal impairment (creatinine clearance <30 mL/min) unless the patient is on chronic dialysis without GFR recovery potential (Grade A). Denosumab can be used for hypercalcemia in renal impairment, but calcium and phosphate levels need close monitoring (Grade B). Nephrotoxic agents like aminoglycoside antibiotics, NSAIDs, and contrast agents should be avoided (Grade A). 

Recommendations: Anti-myeloma therapy 

 

Mechanical approaches, like high-cutoff hemodialysis, aim to rapidly reduce serum free light chain (FLC) levels. Though this approach, combined with anti-myeloma treatment, has shown some benefits in trials like MYRE and EuLITE, its overall effectiveness is uncertain. High-cutoff hemodialysis did not significantly improve dialysis independence at 3 months, though some benefits were seen at 6 and 12 months for anuric patients. However, it showed lower overall survival in some cases, primarily due to infections. Other mechanical methods include polymethyl-methacrylate dialyzers and continuous venovenous hemofiltration, but their efficacy requires further evaluation. 

The timing of mechanical interventions is debated. While some studies delayed treatment to correct factors like hydration, others initiated it immediately. Dialysis should start in patients with acute kidney injury due to severe volume overload or electrolyte imbalances. For those with monoclonal cast nephropathy, early intervention is crucial to prevent irreversible kidney damage. 

 

For managing renal impairment in multiple myeloma patients: 

 

1. High-Dose Dexamethasone: Administer 40 mg/day (or 20 mg for patients ≥75 years) for 4 days on and 4 days off for three pulses during the first cycle, then follow the treatment protocol (Grade B). 
2. Bortezomib-Based Regimens: Bortezomib remains the standard first-line treatment, showing rapid and significant responses, including potential renal improvement and dialysis independence. Both intravenous and subcutaneous bortezomib are effective, but intravenous may be preferable in severe kidney injury due to faster effects. Triplet regimens with bortezomib may enhance renal response compared to bortezomib–dexamethasone alone. Cyclophosphamide adds no benefit to this combination in acute kidney injury cases. Treatment should be tailored based on patient frailty (Grade B). 
3. Carfilzomib: Effective in relapsed or refractory cases, with similar efficacy and safety in patients with varying renal function. It shows improved survival and response rates compared to bortezomib in some studies. However, carfilzomib can cause renal complications, such as thrombotic microangiopathy and acute kidney injury, particularly in those with existing renal issues. Caution is advised for patients with impaired renal function, making bortezomib the preferred option unless resistance is present (Grade B). 
4. Ixazomib: This oral proteasome inhibitor is used in relapsed or refractory cases. It is safe for patients with mild-to-moderate renal impairment, though a lower starting dose (3 mg) is recommended for those with creatinine clearance <30 mL/min (Grade B). 
5. Bortezomib remains the first choice for renal impairment, with carfilzomib as a secondary option under careful monitoring. Ixazomib is also viable for specific cases with renal impairment. 

 

Recommendations for Immunomodulatory Drug Regimens in Multiple Myeloma with Renal Impairment: 

 

• Thalidomide: 
  • Effectiveness: Effective for treating multiple myeloma with renal impairment (Grade B). 
  • Dosage: No dose modifications required (Grade A). 
• Lenalidomide: 
  • Effectiveness: Safe and effective in combination with dexamethasone for multiple myeloma with renal impairment (Grade B). 
  • Dosage Adjustments: Required based on creatinine clearance. For patients with a clearance <30 mL/min, up to 15 mg daily is recommended (Grade B). 
• Pomalidomide: 
  • Effectiveness: Safe and effective for relapsed or refractory multiple myeloma with renal impairment, including those on dialysis (Grade A for creatinine clearance ≥45 mL/min; Grade B for <30 mL/min). 
• Iberdomide: 
  • Effectiveness: Similar efficacy and safety in patients with mild-to-moderate renal impairment, but its use in severe renal impairment or kidney failure requires further study. 
  • Current Status: Not yet approved for use in multiple myeloma. 

Thalidomide and pomalidomide are effective for myeloma-related renal impairment with specific dosage and safety considerations. Lenalidomide requires dose adjustments based on renal function, and iberdomide's use is still under evaluation. 

 

Recommendations: 

• Triplet Combinations: 
  • Use: In the upfront setting and at first relapse for patients with creatinine clearance <50 mL/min. 
  • Benefit: Improve complete renal response rates and survival outcomes (grade B recommendation). 
• Specific Triplet Combinations: 
  • Examples: Pomalidomide–bortezomib–dexamethasone and carfilzomib–lenalidomide–dexamethasone. 
  • Benefit: Enhance hematological and renal response rates, and improve survival outcomes compared to doublet combinations like bortezomib–dexamethasone and lenalidomide–dexamethasone, in patients with relapsed or refractory multiple myeloma and creatinine clearance of 30–59 mL/min (grade B recommendation). 

 

Recommendations for Monoclonal Antibody-Based Regimens: 

 

• Daratumumab with Dexamethasone: 
  • Safety and Efficacy: Effective for patients with multiple myeloma and renal impairment, including those on dialysis (grade B recommendation). 
• Daratumumab-Based Regimens: 
  • Newly Diagnosed: Safe and effective for patients with creatinine clearance of 40 mL/min or higher (e.g., daratumumab–bortezomib–melphalan–prednisone, daratumumab–bortezomib–thalidomide–dexamethasone) or 30 mL/min or higher (e.g., daratumumab–lenalidomide–dexamethasone) (grade B recommendation). 
• Anti-CD38-Based Triplet Combinations: 
  • Relapsed or Refractory Myeloma
  • Moderate-to-Severe Renal Impairment: Effective with proteasome inhibitors (e.g., daratumumab–bortezomib–dexamethasone, daratumumab–carfilzomib–dexamethasone) or with moderate renal impairment using immunomodulatory drugs (e.g., daratumumab–lenalidomide–dexamethasone, daratumumab–pomalidomide–dexamethasone, isatuximab–pomalidomide–dexamethasone) (grade B recommendation). 
• Elotuzumab-Based Regimens: 
  • Relapsed or Refractory Myeloma 
  • With Renal Impairment: Effective and well tolerated, particularly elotuzumab–lenalidomide–dexamethasone for creatinine clearance ≥30 mL/min and elotuzumab–pomalidomide–dexamethasone for ≥45 mL/min (grade C recommendation). 

 

Recommendations for Autologous HSCT in Multiple Myeloma:

 

• High-Dose Melphalan and Autologous HSCT: 
  • Standard Care: Remains a standard treatment for eligible, newly diagnosed multiple myeloma patients (grade B recommendation). 
• Feasibility with Renal Impairment: 
  • Stable Renal Impairment: Autologous HSCT is feasible and effective. 
  • Acute Kidney Injury: Generally not recommended, but if eGFR is less than 30 mL/min per 1.73 m², consider reducing melphalan dose to 140 mg/m², though 200 mg/m² is also shown to be safe (grade C recommendation). 
• Outcomes: 
  • Improvement: Autologous HSCT may improve renal function in up to one-third of patients and achieve dialysis independence in over one-quarter. 
  • Mortality: Mortality related to transplantation is similar to patients without renal impairment when using bortezomib-based and daratumumab-based induction regimens. 
  • Dose Adjustment: 
    • Melphalan Dose: 100 mg/m² or 140 mg/m² can be used based on renal impairment severity, but full dose (200 mg/m²) is also an option (grade C recommendation). 

 

Belantamab Mafodotin and Renal Impairment: 

 

• Drug Overview: Belantamab mafodotin is an antibody-drug conjugate targeting B-cell maturation antigen (BCMA) used for treating triple-class refractory multiple myeloma patients who have already been treated with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. 
• Efficacy and Safety: A post-hoc analysis of the DREAMM-2 study showed that belantamab mafodotin's effectiveness (overall response rate and progression-free survival) and safety profile were consistent across different levels of renal function (eGFR levels: 90, 60–89, and 30–59 mL/min per 1.73 m²). 
• Ongoing Research: The DREAMM-12 study is currently investigating the drug's pharmacokinetics and safety in patients with severe and end-stage renal impairment. 

 

CAR T-cell Therapy in Multiple Myeloma 

• Overview: CAR T-cell therapies targeting BCMA are approved for relapsed or refractory multiple myeloma, showing significant benefits in triple-class refractory patients after multiple lines of prior therapy. 
• Clinical Findings: 
  • Registrational Studies: Idecabtagene vicleucel (KarMMA) and ciltacabtagene autoleucel (CARTITUDE-1) trials included patients with adequate renal function (creatinine clearance ≥45 mL/min for idecabtagene vicleucel and ≥40 mL/min for ciltacabtagene autoleucel), due to the use of fludarabine, which impacts renal function. 
  • Post-hoc Analysis: Data from two phase 1 studies showed that while patients with renal dysfunction (eGFR 30–89 mL/min) had an improvement in eGFR, their prognosis was worse compared to those with normal renal function. 
  • Specific Case Report: A small study of seven patients with severe renal impairment (eGFR 15–29 mL/min) showed 100% overall and renal response rates. 
  • Fludarabine Dosing: For patients with an eGFR of 30–70 mL/min, fludarabine should be reduced to 24 mg/m² due to nephrotoxicity risk. No dosing recommendations are provided for those with eGFR <30 mL/min. 

 

Bispecific T-cell Engagers in Multiple Myeloma 

 

• Overview: Bispecific T-cell engagers, such as teclistamab, are emerging immunotherapy options for relapsed or refractory multiple myeloma. They have shown potential for deep and lasting responses. 
• Current Status: 
  • Approved: Teclistamab has been approved for treating relapsed or refractory multiple myeloma. 
  • Near Approval: Other bispecific T-cell engagers like talquetamab and elranatamab are expected to gain approval soon. 
• Clinical Findings: 
  • Current Studies: Existing studies involve patients with a creatinine clearance higher than 40 mL/min, showing no significant renal toxicity. 
  • Future Research: Studies are needed to assess the efficacy and safety in patients with moderate-to-severe renal impairment. 

 

RECOMMENDATIONS 

 

• Belantamab mafodotin: Effective and well tolerated in patients with relapsed or refractory multiple myeloma and moderate renal impairment (grade C recommendation). 
• Selinexor-based regimens: Effective and well tolerated in patients with relapsed or refractory multiple myeloma and moderate-to-severe renal impairment (grade C recommendation). 
• CAR T-cell Therapy and Bispecific T-cell Engagers: More research is needed to confirm safety in patients with moderate-to-severe renal impairment.  
• Ciltacabtagene autoleucel and idecabtagene vicleucel appear safe for patients with creatinine clearance of ≥40 mL/min and ≥45 mL/min, respectively. 
• Teclistamab is well tolerated in patients with creatinine clearance >40 mL/min (grade C recommendation). 

 

Kidney Transplantation and Multiple Myeloma Patients:  

 

• Kidney Transplantation: Considered for eligible patients with end-stage renal impairment who have achieved long-term myeloma control (e.g., MRD negativity for 2 years) and have previously undergone autologous HSCT.  
  • A multidisciplinary approach is crucial to manage the risks associated with combined immunosuppressive and anti-myeloma therapies. 
  • The best timing for transplantation and the potential impact of post-transplant immunosuppression on myeloma relapse remains uncertain. 
  • MRD negativity at 2 years after autologous HSCT might indicate a suitable time for kidney transplantation, although this is based on expert opinion rather than data specific to end-stage renal impairment. 
  • Routine MRD testing is encouraged to guide treatment and transplantation decisions, as it predicts prolonged progression-free survival and overall survival (grade D recommendation). 

 

Conclusions

 

Diagnosing and managing renal impairment in multiple myeloma patients is complex and requires a multidisciplinary approach. Updated clinical guidelines highlight advancements in treatment and the integration of new therapies for these patients. Key challenges include defining and evaluating renal impairment, excluding patients with severe renal issues from trials, and using inappropriate methods for assessing kidney function in different conditions. 

There is a need for more prospective studies focusing on renal outcomes to develop robust treatment recommendations, especially for those with severe renal impairment. Despite progress with various regimens showing both myeloma and renal responses, the optimal therapy for relapsed or refractory cases remains uncertain. Effective treatment initiation is critical, and new therapies, including advanced immunotherapies, can be used in patients with renal impairment. Future research is strongly encouraged to address these gaps.