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Plasma Exchange When Myeloma Presents as Acute Renal Failure: A Randomized, Controlled Trial

William F. Clark, MD; A. Keith Stewart, MD; Gail A. Rock, MD; Marion Sternbach, MD; David M. Sutton, MD; Brendan J. Barrett, MD; A. Paul Heidenheim, MA; Amit X. Garg, MD; David N. Churchill, MD, the Canadian Apheresis Group
[+] Article and Author Information

From University of Western Ontario, London, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada; University of Ottawa, Ottawa, Ontario, Canada; McMaster University, Hamilton, Ontario, Canada; and Memorial University of Newfoundland, St. John's, Newfoundland, Canada.


ClinicalTrials.gov identifier: NCT00120263.

Grant Support: By the Canadian Institute of Health Research, Gambro BCT, and The Kidney Foundation of Canada.

Potential Financial Conflicts of Interest: Grants received: W.F. Clark (Kidney Foundation of Canada, Canadian Institute of Health Research, Gambro BCT).

Requests for Single Reprints: William F. Clark, MD, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.

Current Author Addresses: Drs. Clark and Garg and Mr. Heidenheim: London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada.

Dr. Stewart: Princess Margaret Hospital, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada.

Dr. Rock: The Ottawa Hospital, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.

Drs. Sternbach and Churchill: McMaster University, St. Joseph's Hospital, 50 Charlton East, Hamilton, Ontario L8N 1A6, Canada.

Dr. Sutton: Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5C 2G4, Canada.

Dr. Barrett: Memorial University of Newfoundland, 300 Prince Philip Drive, St. Johns, Newfoundland A1B 3V6, Canada.

Author Contributions: Conception and design: W.F. Clark, A.K. Stewart, G.A. Rock, M. Sternbach, B.J. Barrett, A.P. Heidenheim, D.N. Churchill.

Analysis and interpretation of the data: W.F. Clark, A.K. Stewart, B.J. Barrett, A.P. Heidenheim, A.X. Garg, D.N. Churchill.

Drafting of the article: W.F. Clark, A.K. Stewart, A.P. Heidenheim, D.N. Churchill.

Critical revision of the article for important intellectual content: W.F. Clark, A.K. Stewart, M. Sternbach, D.M. Sutton, B.J. Barrett, A.P. Heidenheim, A.X. Garg, D.N. Churchill.

Final approval of the article: W.F. Clark, A.K. Stewart, A.X. Garg, D.N. Churchill.

Provision of study materials or patients: W.F. Clark, G.A. Rock, M. Sternbach, D.M. Sutton, D.N. Churchill.

Statistical expertise: W.F. Clark, A.P. Heidenheim, A.X. Garg, D.N. Churchill.

Obtaining of funding: W.F. Clark, A.K. Stewart, D.N. Churchill.

Administrative, technical, or logistic support: W.F. Clark, G.A. Rock.

Collection and assembly of data: W.F. Clark, A.P. Heidenheim, D.N. Churchill.


Ann Intern Med. 2005;143(11):777-784. doi:10.7326/0003-4819-143-11-200512060-00005
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Of 104 patients who were initially enrolled in the study, 7 were withdrawn. Of these 7 patients, 3 were ineligible and 4 were lost to follow-up (Figure 1). Among the 4 patients lost to follow-up, 1 was a homeless person and the other 3 withdrew from all medical care and follow-up after diagnosis. Thus, intention-to-treat analyses included 58 patients in the plasma exchange group and 39 patients in the conventional therapy control group. No patient crossed over from his or her treatment assignment group during the trial, and all 58 patients randomly assigned to receive plasma exchange received 5 to 7 treatments.

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Figures

Grahic Jump Location
Figure 1.
Flow of patients through the study to death or dialysis dependence.

No cases crossed over from plasma exchange to control or vice versa. VAD = vincristine–adriamycin–dexamethasone.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Kaplan–Meier analysis of time to death.

Treatment groups did not statistically significantly differ.

Grahic Jump Location

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Plasma Exchange in Multiple Myeloma
Posted on December 20, 2005
Nelson Leung
Mayo Clinic Rochester
Conflict of Interest: None Declared

The long awaited randomized controlled plasma exchange trial by Clark et al. (1) is finally here. As the largest trial on the subject, it was supposed to help define the role of plasma exchange in this disease. However, on closer evaluation of the data more questions were found than answers.

First, what disease was actually treated with plasma exchange in this study? Autopsy data by Ivanyi found light chain deposition disease, amyloidosis and cast nephropathy in 5%, 11% and 32% of the patients who died with myeloma respectively (2). Others have shown acute tubular necrosis, tubulointerstitial nephritis and plasma cell infiltration as additional causes of acute renal failure in this population (3). With majority of the patients with no renal biopsy, how did the authors insure only cast nephropathy was being studied? It is equivalent to treating patients with monoclonal gammopathy without a bone marrow biopsy? Since plasma exchange is only intended to treat cast nephropathy, it is therefore not unexpected that this study found no benefit.

Next, why was death at 6 months included in the primary outcome? Since plasma exchange lacks the ability to decrease the tumor burden, increase the CD4 cell count or improve the cytogenetics, factors that are prognostic in this population (4), it would seem unfair to expect it to improve the short term survival. This was reinforced by the fact that dialysis did not appear to influence the short term survival in this study (1). Unfortunately, with death making up one-third of the events in both groups, this weakened an already underpowered study to a point where no difference could be demonstrated.

Despite the randomized controlled design of this study, it led us no closer to the role of plasma exchange in cast nephropathy. It is important for nephrologists to understand the limitations of the study because our role in this disease is not to provide anti-myeloma therapy but to reverse the renal failure and preserve renal function. The main concern should not be limited to prolongation of life but should include improving the quality of life by getting patients off dialysis. Preservation of renal function also keeps therapeutic options open as many clinical trials exclude patients who are dialysis dependent. As Nephrologists, our role in this disease is clear even though the results of this study are not.

1. Clark WF, Stewart AK, Rock GA, et al. Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med. 2005;143(11):777-84. 2. Ivanyi B. Frequency of light chain deposition nephropathy relative to renal amyloidosis and Bence Jones cast nephropathy in a necropsy study of patients with myeloma. Archives of Pathology & Laboratory Medicine. 1990;114(9):986-7. 3. Sakhuja V, Jha V, Varma S, et al. Renal involvement in multiple myeloma: a 10-year study. Renal Failure. 2000;22(4):465-77. 4. San Miguel JF, Garcia-Sanz R. Prognostic features of multiple myeloma. Bailliere's Best Practice in Clinical Haematology. 2005;18(4):569-83.

First, Treat the Cancer
Posted on January 13, 2006
Burton J. Lee
No Affiliation
Conflict of Interest: None Declared

Dr. William Clark et al, with the Canadian Apheresis Group have reasonably and accurately presented data in the Dec. 6th issue of the AIM (Annals of Internal Medicine) that show that plasma exchange does not improve treatment results in myeloma patients presenting with renal failure.

In 1971, and again in 1974, we presented our results with the M2 protocol (melphalan, cytoxan, vincristine, BCNU, prednisone) at the Memorial Sloan Kettering Cancer Center. Responses were rapid and occurred at the 85% level in patients with generalized, symptomatic, progressing, prior untreated disease and 50% in patients who had failed prior therapy. Partial responses were usually seen in the remaining 15%. Renal failure did not preclude response. Exceptions were the problematic cases with plasma cell leukemia, profound pancytopenias, and significant amyloid.

We made the point with our house staff and Fellows, as forcefully as we could, that very sick patients with cancer, and certainly with myeloma, require instant and maximally effective therapy for their malignancy, and that all the other forms of supportive care are vital but they are secondary. Critically ill patients are lost while Doctors focus exclusively on the secondary manifestations of their tumors.

The M2 is a far better treatment than melphalan/prednisone. The M2 brings down serum protein levels within days sometimes even within hours. Tumor cell kills are far higher and more rapid with the M2 and were documented by ourselves and Dr. Syd Salmon at the University of Arizona. Today, there are newer more highly effective treatments for myeloma. Cell kill by newer systemic therapies such as Thalidomide, Bortezemide, and Lenolidomide, along with high dose Dexamethasone is even more rapid and more substantial.

Dr. Clark and his group deserve credit for refocusing our efforts on immediate and aggressive systemic treatment of the underlying cancer and away from important, but less vital intensive support.

Sincerely,

Burton J. Lee, MD

Acknowledgement: The author thanks Dr. Paul Hetzel of Springfield Medical Associates for his assistance in preparing this letter.

Plasma Exchange in Multiple Myeloma
Posted on January 20, 2006
Murat O. Arcasoy
Duke University Medical Center, Hematology-Medical Oncology, Durham, North Carolina
Conflict of Interest: None Declared

The study by Clark and colleagues concludes that plasma exchange for patients with acute renal failure at the onset of multiple myeloma does not improve renal function, reduce dialysis dependence or death(1). This conclusion should be interpreted with caution by practicing physicians who take care of such patients. The authors thoughtfully listed some of the limitations of the study. However, other significant limitations preclude the interpretation of the results in a meaningful manner.

The study recruited 97 patients, 20 of whom had monoclonal protein detectable only in the urine and not in plasma. Although not specified by the authors, immunofixation electrophoresis (IFE) was presumably used to detect monoclonal proteins in plasma and urine samples. It is likely that patients with no detectable plasma monoclonal protein by IFE constitute a subgroup that is not expected to benefit from plasma exchange which is performed to physically remove the pathogenic monoclonal protein to potentially improve renal function while awaiting chemotherapy to take effect. The authors raise the issue of whether patients with high serum immunoglobulin-free light chain levels might represent a subgroup that is likely to benefit from plasma exchange and yet, no subgroup analysis results are presented for the 20 patients who had no detectable monoclonal protein in their plasma. The justification for performing plasma exchange on patients with no detectable plasma monoclonal protein is unclear.

It is difficult to understand the rationale for not reporting the reduction in light chain proteinuria. This omission is justified by citing the results of two smaller randomized studies, as clearly demonstrating reduction in light chain proteinuria using plasma exchange in association with cytotoxic therapy(2,3). If the presence or absence of response to chemotherapy (±plasma exchange) was not assessed in this cohort of patients, then it is not possible to determine the effect of plasma exchange. The study should have been designed to assess both the presence and the rapidity of response to chemotherapy (±plasma exchange) and how these factors relate to the evolution of renal function. Many patients with myeloma do not exhibit an adequate response to initial chemotherapy and this subgroup of patients would likely exhibit persistent or progressive renal dysfunction regardless of whether 5 to 7 plasma exchanges had been performed at the time of diagnosis. Furthermore, the designation by the authors of melphalan and prednisone as "standard chemotherapy" for newly diagnosed multiple myeloma is questionable(4).

REFERENCES 1. Clark WF, Stewart AK, Rock GA, et al. Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med. 2005;143(11):777-84. 2. Zucchelli P, Pasquali S, Cagnoli L, Ferrari G. Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int. 1988;33(6):1175-80. 3. Johnson WJ, Kyle RA, Pineda AA, O'Brien PC, Holley KE. Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy. Arch Intern Med. 1990;150(4):863-9. 4. Boccadoro M, Pileri A. Diagnosis, prognosis, and standard treatment of multiple myeloma. Hematol Oncol Clin North Am. 1997;11(1):111-31.

Conflict of Interest:

None declared

Plasma Exchange when Myeloma Presents as Acute Renal Failure.
Posted on January 24, 2006
William F. Clark
London Health Sciences Centre
Conflict of Interest: None Declared

We concur with Dr. Leung's comment that, on closer observation of the data more questions are found than answers. We would hope that most careful readers would experience this same phenomenon when looking closely at data from other randomized control trials. He then raises the issue of an absence of renal biopsies and refers to a study published by Ivanyi in 1990, which indicated that a necropsy study of patient's with myleoma revealed 37% had light chain or cast nephropathy and 11% amyloidosis. Less than 20% of myeloma patients at the time of their diagnosis have a clinical picture of acute renal failure and heavy proteinuria. As indicated in our methods and discussion section these are the entry criteria for patients who were enrolled in our study. This clinical picture of progressive, or acute renal failure has been shown on two (2) pathological studies (referenced in our previous discussion) to have a 77 to 97% incidence of light chain or myeloma cast nephropathy (Ref. 2 & 3). Dr Leung asks why death was included in the primary outcome measure in our study (initiated in 1998). The decision to include death was based on the prior published findings of the randomized control study by Zucchelli et al. Their small (n =29) randomized control study indicated that the plasma exchange arm had a significant reduction in mortality that was attributed to the plasma exchange procedure (4). We would agree at this time with Dr. Leung that plasma exchange lacks the ability to decrease the tumor burden and increase the CD4 cell count or improve the cytogenetics factors that have been shown in a publication in 2005 to be prognostic in this population.

I as a nephrologist and as a physician would concur that it is important for nephrologists and other physicians to not limit our concerns to prolongation of life but rather to include improving the quality of life for patients with acute renal failure at the onset of myleoma. We also believe our role in this disease is clear and that is to carry out, where ever possible, interventions which are more likely to benefit and less likely to harm our patients based on the best available evidence to date. We would strongly encourage all our colleagues to actively participate in randomized control trials to provide clearer treatment options for our patients.

References: 1. Ivanyi B, Frequency of Light chain deposition nephropathy relative to renal amylodosis and Bence Jones cast nephropathy in a necropsy study of patients with myeloma. Arch Pathol Lab Med. 1990 Sep;114(9):986-7

2. Montseny JJ, Kleinknecht D, Meyrier A, Vanhille P, Simon P, Pruna A, et al. Long-term outcome accordingt o renal histological lesions in 118 patients with monoclonal gammopathies. Nephrol Dial Transplant. 1998:13:1438-45

3. Pasquali S, Zucchelli P, Casanova S, Cagnoli L, Confalonieri R, Pozzi C, et al. Renal histological lesions and clinical syndromes in multiple myeloma. Renal Immunopathology Group. Clin Nephrol. 1987;27:222-8

4. Zucchelli P, Pasquali S, Cagnoli L, Ferrari G. Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int. 1988;33:1175-80

Conflict of Interest:

None declared

Free Light Chain removal in Multiple Myeloma
Posted on March 22, 2006
Colin A Hutchison
University Hospitals Birmingham, UK
Conflict of Interest: None Declared

Dear Editor

We read with interest the study by Clark et al and the conclusion that there was no significant benefit of plasma exchange in multiple myeloma patients with acute renal failure (1). Quite rightly, this raises the question of the appropriateness of including plasma exchange on international guidelines for this indication (2). However, the study did not address the efficacy of plasma exchange to reduce serum free light chain (sFLC) concentrations in the blood. Only when it has been demonstrated that sFLC levels have been significantly reduced can we comment on whether a particular method of direct removal is of clinical benefit. The standard course of 7 plasma exchange treatments and chemotherapy may be ineffective at rapidly reducing FLC levels (3): our mathematical modelling indicates that prolonged haemodialysis is a far better treatment. Hence the Clark et al study must only be viewed as evidence that this regime of plasma exchange does not improve outcomes, not that reduction in sFLC concentrations is not of clinical benefit. Further work is needed to determine the best haemodialysis schedule to rapidly reduce sFLC levels, followed by an RCT of renal and patient outcomes with a protocol that includes this approach.

1. Clark WF et al. Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med. 2005 Dec 6;143(11):777-84.

2. Williams R. Plasma exchange does not ameliorate myeloma-induced acute renal failure. Nat Clin Pract Oncol. 2006 Mar;3(3):119-20.

3. Bradwell AR et al. Rapid removal of FLC from the serum by haemodialysis for patients with myeloma kidney. Presented at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005

Conflict of Interest:

None declared

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Summary for Patients

Plasma Exchange Treatment Is Not Effective in Treating Acute Kidney Failure Caused by Multiple Myeloma

The summary below is from the full report titled “Plasma Exchange When Myeloma Presents as Acute Renal Failure. A Randomized, Controlled Trial.” It is in the 6 December 2005 issue of Annals of Internal Medicine (volume 143, pages 777-784). The authors are W.F. Clark, A.K. Stewart, G.A. Rock, M. Sternbach, D.M. Sutton, B.J. Barrett, A.P. Heidenheim, A.X. Garg, D.N. Churchill, and the Canadian Apheresis Group.

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