Recommendations for the management of multiple myeloma-related renal impairment: International Myeloma Working Group

Renal impairment is a common complication of multiple myeloma (MM), affecting up to 50% of patients. Renal impairment is defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min per 1.73 m². Poor overall survival (OS) and increased risk of early death are associated with renal impairment in patients with MM.

The International Myeloma Working Group (IMWG) recently updated their previous recommendations for the diagnosis and management of renal impairment in patients with MM.¹ The recommendations were published by Dimopoulos et al.¹ in The Lancet. An interdisciplinary panel comprising clinical experts on MM and renal impairment reviewed and graded the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation system.¹ We are pleased to summarize the IMWG recommendations particularly those relating to therapeutic approaches.

IMWG Recommendations

Pathophysiology, diagnosis, and staging recommendations

In patients with MM, residual free light chains (FLCs) in the proximal tubules, other co-existing renal diseases, and non-immunoglobulin-related factors have been found to be associated with renal impairment. Early identification and prompt management of renal impairment at diagnosis and relapse is crucial to improve patient outcomes. Figure 1 shows the algorithm for the differential diagnosis of renal impairment in patients with MM.

AL, amyloid light-chain; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; FLC, free light chain; MM, multiple myeloma.
*Adapted from Dimopoulos et al.¹

• The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula without race variable should be used to calculate eGFR.
• CKD classification should be used for the staging of stable renal impairment (Table 1).
  • Patients with acute kidney injury should be staged using the Kidney Disease Improving Global Outcomes (KDIGO), Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE), and Acute Kidney Injury Network (AKIN) criteria can also be used. 
• β-microglobulin at baseline should be measured in all patients with MM.

Table 1. Staging of chronic kidney disease*

eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy. *Adapted from Dimopoulos et al.1
	Description	eGFR (mL/min per 1.73 m2)
1	Normal or elevated eGFR	≥90
2	Mild reduction in eGFR	60–89
3	Moderate reduction in eGFR	30–59
4	Severe reduction in eGFR	15–29
5	Renal failure or end-stage renal disease	<15 or RRT

Criteria for renal response

Reversal of renal impairment should be the main aim of treatment in patients with MM-related renal impairment. Table 2 shows the IMWG criteria for renal response to anti-myeloma treatment and should be used in both clinical trials and practice.

• Specific renal response criteria should be used in the presence of biopsy-confirmed amyloid light-chain amyloidosis.
• Careful evaluation of efficacy and toxicity of chemotherapy should be considered in patients with myeloma cast nephropathy.

Table 2. Criteria for renal response*

eGFR, estimated glomerular filtration rate. *Adapted from Dimopoulos et al.1 †eGFR calculated with the Chronic Kidney Disease Epidemiology Collaboration equation.
Responses	Baseline eGFR (mL/min per 1.73 m2)†	Best creatinine clearance response (mL/min)
Complete response	<50	≥60
Partial response	<15	30–59
Minor response	<15	15–29
15–29	30–59

Supportive care

Adequate and immediate supportive care is important for all patients with MM-related renal impairment. Figure 2 shows the supportive care recommendations.

MM, multiple myeloma.
*Adapted from Dimopoulos et al.¹

Mechanical approaches

In patients with MM and renal impairment, mechanical approaches have been employed to rapidly decrease the serum FLCs concentrations. In addition, administration of anti-myeloma treatment is also important to reduce the production of monoclonal FLC (Figure 3).   

MM, multiple myeloma.
*Adapted from Dimopoulos et al.¹

Anti-myeloma therapy

• Patients with MM should receive immediate treatment for renal impairment, as it may be reversible.
  • Patients with newly diagnosed MM and renal impairment have a high chance of improvement.
  • Patients with relapsed or refractory (R/R) MM and renal impairment tend to be more challenging to manage.
• Bortezomib regimens remain the mainstay of first-line therapy in the management of MM and is also seen as the gold-standard therapy for the treatment of patients with MM and renal impairment.
• Recommendations for high-dose steroids, protease inhibitors, and immunomodulatory drugs are shown in Figure 4

IV, intravenous; MM, multiple myeloma, R/R, relapsed/refractory.
*Adapted from Dimopoulos et al.¹

• Monoclonal antibodies, when used in combinations as triplet or quadruplet have enhanced outcomes in patients with relapsed or newly diagnosed MM, respectively (Figure 5).
  • Anti-CD38-based triplet combinations in patients with R/R MM and moderate-to-severe renal impairment include:
    • Daratumumab–bortezomib– dexamethasone
    • Daratumumab–carfilzomib–dexamethasone
    • Isatuximab–carfilzomib–dexamethasone
  • Anti-CD38-based triplet combinations in patients with R/R MM and moderate renal impairment include:
    • Daratumumab–lenalidomide–dexamethasone
    • Daratumumab–pomalidomide–dexamethasone
    • Isatuximab–pomalidomide–dexamethasone
• In patients with newly diagnosed MM, autologous hematopoietic stem cell transplantation (auto-HSCT) remains a standard of care and may be feasible in patients with stable renal impairment with a potential dose adjustment (Figure 5).
  • However, in patients with acute kidney injury, auto-HSCT is not an option.
• Bispecific T-cell engagers offer deep and durable responses in patients with R/R MM.
• Chimeric antigen receptor T-cell targeting B-cell maturation antigen is safe and effective in patients with R/R MM.
  • However, there is no dosing recommendation in patients with an eGFR of <30 mL/min per 1.73 m².

HSCT, hematopoietic stem cell transplantation; MM, multiple myeloma, R/R, relapsed/refractory.
*Adapted from Dimopoulos et al.¹

Kidney transplantation

Although kidney transplantation in some patients with MM and end-stage renal impairment who have previously undergone auto-HSCT have shown encouraging results, the best time for transplantation is unknown.

• The recommendation by IMWG is to consider kidney transplantation in referral centers only for patients with end-stage renal impairment who are fit and have sustained MM disease control (minimal residual disease negative status for 2 years).
  • A multidisciplinary approach is recommended to manage the adverse events from combined immunosuppressive treatment and anti-myeloma therapy.

Conclusion

These updated recommendations by IMWG address the therapeutic innovations in MM and the introduction of new options for the management of patients with MM and renal impairment. It also reiterates that diagnosis and management of renal impairment in patients with MM is often challenging and requires a multidisciplinary approach. However, the recommendations are limited by variation in renal impairment definition and exclusion criteria in available studies, inappropriate use of formulae for the estimation of renal function in chronic kidney disease in patients with acute kidney injury, potential differential diagnosis of renal impairment in patients with MM, and the lack of prospective data. Future studies should address these limitations to optimize clinical practice and patient outcomes.