Multiple myeloma and renal failure

Hartmut Goldschmidt1, Heinrich Lannert1, Jürgen Bommer2 and Anthony D. Ho1

1 Medizinische Klinik und Poliklinik V and 2 Sektion Nephrologie, Medizinische Klinik und Poliklinik I, Universtität Heidelberg, Heidelberg, Germany

Correspondence and offprint requests to: Anthony D. Ho, Medizinische Klinik und Poliklinik V, Universität Heidelberg, Hospitalstr. 3, 69115 Heidelberg, Germany.

Introduction

Multiple myeloma (MM) is a clonal B-cell disease of slowly proliferating plasma cells, accompanied by monoclonal protein production and lytic bone lesions. Up to 50% of newly diagnosed patients have a decrease in creatine clearance and ~9% require dialysis because of severe renal impairment [1]. Despite progress in polychemotherapy regimens with improvements in response rates, the median survival time with conventional chemotherapy remains no more than 2–3 years [2]. High-dose chemotherapy (HDT) supported by autologous bone marrow or peripheral blood stem-cell transplantation has achieved higher complete remission (CR) rates and prolonged event-free and overall survival [3]. However, patients with renal failure are often excluded from aggressive or high-dose chemotherapy protocols because of an expected higher toxicity rate.

Renal involvement in multiple myeloma

Approximately 20% of the patients with MM will develop progressive renal failure during the course of myeloma disease. Cast nephropathy is a typical renal complication found in myeloma patients. It is well known that free light chains play a crucial role in causing such renal damage. Experimental studies in rats and mice have shown that infusion of light chains purified from patients with renal failure may induce tubular cast nephropathy. The incidence of renal damage was much lower in animals treated with light chains from patients with no evidence of renal disease [4,5]. This indicates that the physicochemical properties of light chains differ markedly. In this respect, some light chains, causing Franconi syndrome, may be digested by cathepsin B. In contrast, other forms of light chains forming obstructing casts in the distal tubules are resistant to proteolysis by trypsin and pepsin [6]. Some nephrotoxic light chains appear to be able to self-aggregate into large polymers under physiological conditions found in the distal tubuli [7].

Also, in healthy controls, B cells synthesize heavy and light chains and there is normally a slight excess of light compared with heavy chains. Consequently, small amounts of light chains are regularly filtered at the glomerulus and reabsorbed in the proximal tubuli where they can be catabolized. In myeloma, the capacity of the proximal tubular cells to reabsorb and catabolize light chains is exceeded. In consequence, light chains not reabsorbed in the proximal tubuli reach the distal segment of the nephron where they can combine with the Tamm–Horsfall mucoprotein (THP) and precipitate forming obstructing casts. Such obstruction of distal tubuli results in the leakage of tubular content into the interstitium and leads to the classic appearance of tubular cast and myeloma kidney.

Quite often renal failure develops rapidly even at an unchanged ratio of production and serum concentration of light chains. Various factors can favour renal cast formation in myeloma patients. Dehydration, sometimes due to diuretics, reduces the glomerular filtaration rate (GFR) and causes an increase in the plasma concentration of light chains which then exceeds the capacity for reabsorption and catabolism of light chains in the proximal tubuli. Hypercalcaemia may induce vasoconstriction followed by a decrease in GFR (Figure 1Go). Several drugs, in particular non-steroidal anti-inflammatory agents (NSAIDs), reduce renal blood flow. Radiographic contrast agents may induce acute renal failure in myeloma patients, particularly if patients are dehydrated and ionic contrast media are used.



View larger version (18K):
[in this window]
[in a new window]
 
Fig. 1. Pathogenesis of myeloma cast nephropathy. Reproducedwith permission from Winearls [8].

 
Management of renal failure in multiple myeloma

Although as many as 50% of patients with MM may experience some degree of renal insufficiency, in the majority renal function will improve in response to simple measures such as rehydration, correction of hypercalcaemia with bisphosphonates, fluid rehydration and administration of glucocorticoids, or discontinuation of nephrotoxic drugs such as NSAIDs.

Half of those who recover will improve within the first 6 weeks. Late recovery is still possible and in one series myeloma was the most common diagnosis in patients who were able to discontinue long-term dialysis. Most of the patients who do not regain normal renal function will be left with only mild to moderate renal impairment and <1% will require long-term renal replacement therapy [9].

Plasma exchange or plasmapheresis has been proposed as a method of preventing light-chain-associated renal failure by removing the light chains from the plasma. A retrospective case study suggests that plasma exchange may offer some benefit in preventing initiation of dialysis, as well as preventing acute renal failure progressing to CRF [10]. Its efficacy has been established only in patients with hyperviscosity syndrome, however. A randomized, controlled, prospective study is needed to determine whether plasma exchange should be recommended as a standard treatment for patients with progressive renal failure due to Bence-Jones MM.

The risk of renal failure certainly rises as the tumour load increases, but it is also the underlying tumour burden that ultimately determines survival. Therefore, treatment of myeloma to achieve remission might also reduce the incidence of renal insufficiency.

Current treatment for multiple myeloma

For decades, the standard treatment for overt symptomatic disease has been chemotherapy with melphalan and prednisone (MP), which induced an objective response in up to 60% of patients. In an attempt to improve efficacy, various combination regimens, including vinca alkaloids, nitrousureas and anthracyclines, have been tested. However a meta-analysis of studies on 6633 patients found no difference between MP and various multiple chemotherapy regimens [11]. Therefore, patients older than 70 years should be treated using MP-regimen with known low toxicity. Younger patients should not be treated with melphalan and nitrousureas before haematopoietic stem cells have been harvested for autotransplantation, because these substances have a very intense stem-cell toxicity. High-dose chemotherapy can induce five times the level of complete remission compared with conventional chemotherapy. The transplantation of autologous haematopoietic stem cells (HSC, bone marrow or peripheral blood cells) reduced the rate of treatment-related death from ~15% to <5%. A randomized study has shown significantly higher remission rates and better survival after high-dose treatment with HSC transplantation compared with conventional therapy. The most effective substance for high-dose therapy in MM is melphalan. The addition of total body irradiation to melphalan enhances the toxicity of HDT and does not increase the CR rates [12]. Patients up to the age of 65–70 years should be offered a treatment with melphalan 200 mg/m2 followed by HSC transplantation. In order to further improve the outcome after transplantation immunotherapeutic approaches, repeated HDT and antiangionetic treatments are currently being examined. Allogenic HSC transplantation may also reduce drastically tumour mass. However, even when human leucocyte antigen-identical siblings are used for HSC transplantation, the risk of death is at least 20%. Reduced conditioning regimens and manipulation of allografts (e.g. T-cell depletion) can reduce transplantation-related mortality. The graft vs. myeloma effect is a well-known phenomenon which, in some patients, may be responsible for a stable CR.

Therapy of multiple myeloma patients with renal impairment

Conventional chemotherapy
In three studies, the response rate to chemotherapy in patients with MM and renal failure ranged from 43 to 50%. For newly diagnosed patients without renal failure remission rates of up to 70% were reported. In a recently published study the 39% response rate of patients with renal failure was significantly lower than the 56.4% reponse rate observed in patients with normal renal function [13]. If patients who died during the first 2 months (early mortality) after starting treatment were excluded, the response to therapy was similar irrespective of whether they had impaired renal function. The response rate of patients with renal failure treated with single alkylating agents plus prednisone (melphalan and prednisone or cyclophosphamide and prednisone) was 24%, whereas the response rate in patients who received combination chemotherapy (e.g. VAD: vincristine, adriamycin and dexamethasone) was 50%. However, Bladé and collaborators [13] found that the survival of patients treated with single alkylating agents plus prednisone (12.9 months) was similar to that for patients treated with combination chemotherapy (14.2 months), instead of 34.5 months for patients with normal renal function. Unfortunately, the early mortality rate of ~30% within 2 months of diagnosis was still a constant finding in patients with MM and renal failure. It has been stressed that in patients with renal failure, cycles of melphalan and prednisone are not the most appropriate treatment because of the need for dose adjustment of melphalan to avoid severe myelosuppression, which might imply the risk of suboptimal treatment. Combination chemotherapy produced a more rapid response with a faster reduction in monoclonal protein production, thereby avoiding further renal damage. The VAD regimen is very effective and can be given in patients with renal failure without dose reduction. The exclusive pulsed dexamethasone treatment reduces the risk of side effects and can decrease the rate of infection.

To achieve fast reduction in the myeloma protein load we recommend VAD chemotherapy for patients up to the age of 65 years. Patients with renal failure should be treated in hospital to detect infections early to enable early start antibiotic therapy. Patients older than 65 years should be treated with cyclophosphamide plus prednisone or melphalan plus prednisone, because the incidence of complications caused by high-dose pulsed immunosuppressive glucocorticoid therapy is high in this age bracket. In addition, chemotherapy with alkylating agents could induce leucocytopenia in MM patients. Antibiotic prophylaxis is recommended for patients with MM at the time of chemotherapy. If the level of polyvalent IgG is <6 g/l during chemotherapy we substitute immunoglobulins to prevent infections.

Factors that affect renal recovery included severity of renal failure, presence of hypercalcaemia and amount of proteinuria. These factors seemed to be inversely correlated to the long-term outcome of patients with renal failure in MM. The most important prognostic factor associated with significantly longer survival is response to chemotherapy.

As septicaemia is the major cause of early mortality, prevention, early diagnosis of infection and therapy is recommended.

High-dose therapy
More than 100 patients with creatinine >= 2 mg/dl were treated with melphalan-based high-dosis therapy (melphalan >=140 mg/m2). The prognosis of patients treated with HDT in stage B is not different from patients without renal involvement [14]. In a single-centre study at the University of Arkansas patients up to the age of 80 years are treated with HDT. Corresponding results of studies provided evidence of improved outcome for MM patients only up to 60–70 years of age when high-dose treatment was administered. In the literature there is no consensus concerning the dosage of melphalan in patients with impaired renal function. Some case reports suggest that the dose of melphalan should be reduced to prevent severe mucositis. In contrast Barlogie and collaborators [14,15] found no change in the pharmacokinetics of high-dose melphalan in patients with renal failure. Such patients received standard melphalan at a dose of 200 mg/m2, even when they were on haemodialysis and early mortality remained below 5%. In our clinic the dose of melphalan is adjusted to the creatinine clearance in patients with impaired renal function [16]. Haematological and non-hematological toxicity, as well tumour reduction, after five courses of HDT are not different in patients undergoing dialysis compared with normal patients.

Supportive therapies
Bisphosphonates are potent inhibitors of bone resorption. In MM bisphosphonates are used primarily for the treatment of hypercalcaemia. They also contribute to the long-term control of bone disease. The multicentre placebo-controlled study of Berenson and colleagues [17] investigated this possibility. In this study a reduction in pathological fractures, bone pain, hypercalcaemia and also an improved qualitiy of life were described for patients receiving intravenous bisphosphonates. The recent availability of more potent bisphosphonates will open new avenues for the treatment of bone diseases in MM.

Erythropoetin is effective in anaemia due to renal failure. Phase 1–2 clinical trials have yielded encouraging results with recombinant human erythropoetin for the treatment of the anaemia in MM. Two recent randomized studies confirmed that recombinant erythropoetin therapy is safe in MM and can decrease the need for transfusion [18,19]. In patients with MM and renal failure we used blood transfusions during the first 3 months of chemotherapy.

Conclusion

In MM patients it is necessary to look for potential renal impairment. In MM cast nephropathy with renal failure can be aggravated by: volume depletion, hypercalcaemia, infection, administration of nephrotoxic drugs or contrast agents and by proteinuria. In elderly patients with MM, it is essential to identify unrelated causes of renal impairment such as renovascular disease and prostatic obstruction.

The early mortality of MM patients with renal failure is up to 30%. This high early mortality rate is due mainly to infection and septicaemia. The incidence of infections is favoured by the immunosuppressive effects of myeloma per se, of renal failure, and of the administration of corticosteroids and cytostatic drugs. Prevention, early diagnosis and optimal therapy for infections are recommended.

Rapid reduction or removal of light chains by aggressive chemotherapy/HDT and/or plasmapheresis may prevent irreversible renal failure or reduce the risk of renal damage. In cases where renal failure proves irreversible, maintenance dialysis should be considered in virtually all patients in whom treatment of myeloma is warranted.

Factors affecting the recovery of renal function are the degree of renal failure, the presence of hypercalcaemia and the amount of protein excreted. Effective treatment of renal failure in combination with myeloma therapy will reduce adverse events and prolong survival in patients with MM.

References

  1. Knudsen L, Hippe E, Hjorth M, Holmberg E, Westin J. Renal function in newly diagnosed multiple myeloma—a demographic study of 1353 patients. Eur J Haematol 1994; 53: 207–212[ISI][Medline]
  2. Boccadero M, Palumbo A, Argentino C et al. Conventional induction treatments do not influence overall survival in multiple myeloma. Br J Haematol 1997; 96: 333–337[ISI][Medline]
  3. Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma and renal insufficiency. Bone Marrow Transplant 1996; 335: 91–97
  4. Sanders PW, Herrera GA, Galla JH. Human Bence-Jones protein toxicity in rat proximal tubule epithelium in vivo. Kidney Int 1998; 32:851–861
  5. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of Bence Jones proteins. N Engl J Med 1991; 324:1845–1851[Abstract]
  6. Leboulleus M, Lelongt B, Mougenot B et al. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 1995; 48: 72–79[ISI][Medline]
  7. Myatt EA, Westholm FA, Weiss DT, Solomon A, Schiffer M, Stevens FJ. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci USA 1994; 91:3034–3038[Abstract]
  8. Winearls CG. Nephrology forum: acute myeloma kidney. Kidney Int 1995; 48:1347–1361[ISI][Medline]
  9. Magee C, Vella JP, Tormey WP, Walshe JJ. Multiple myeloma and renal failure: one center's experience. Renal Fail 1998; 20: 597–606[ISI][Medline]
  10. Moist L, Nesrallah G, Kortas C, Espirtu E, Ostbye T, Clark WF. Plasma exchange in rapidly progressive renal failure due to multiple myeloma. Nephrology 1999; 19: 45–50
  11. Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol 1998; 16: 3832–3842[Abstract]
  12. Goldschmidt H, Hegenbart U, Wallmeier M, Engenhart R, Wannenmacher M, Haas R. High-dose therapy with peripheral blood progenitor cell transplantation in multiple myeloma. Ann Oncol 1997; 8: 1–4[Medline]
  13. Blade J, Fernándes-Llamá P, Bosch F et al. Renal failure in multiple myeloma. Arch Intern Med 1998; 158: 1889–1893[Abstract/Free Full Text]
  14. Tricot G, Alberts DS, Johnson C et al. Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study. Clin Cancer Res 1996; 2: 947–952[Abstract]
  15. Barlogie B. Advances in therapy of multiple myeloma: lessons from acute leukemia. Clin Cancer Res 1997; 3: 2605–2613[Abstract]
  16. Schmoll HJ, Höffken K, Possinger K. Kompendium internistische Onkologie. Springer-Verlag, Berlin, 1996
  17. Berenson JR, Lichtenstein A, Porter L et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 1996; 334: 488–493[Abstract/Free Full Text]
  18. Cazzola M, Messinger D, Battistel V. Recombinant human erythropoetin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response. Blood 1995; 87: 2675–2682[Abstract/Free Full Text]
  19. Osterborg A, Boogaerts MA, Cimino R. Recombinant human erythropoetin in transfusion-dependent anemia patients with multiple myleloma and non-Hodgkin's lymphoma—a randomized multicenter study. Blood 1996; 87: 2673–2682




This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (8)
Disclaimer
Request Permissions
Google Scholar
Articles by Goldschmidt, H.
Articles by Ho, A. D.
PubMed
PubMed Citation
Articles by Goldschmidt, H.
Articles by Ho, A. D.