Clin. lab. Haemat. 1994, 16, 149-156 Intensive treatment of renal failure in patients with myeloma ANDREW INNES, ROBERT J.G. CUTHBERT*, NIGEL H. RUSSELL*, ANTHONY G. MORGAN & RICHARD P. BURDEN Departments of Renal Medicine and * Haematology, City Hospital, Nottingham NG5 IPB, UK Accepted 13 January 1994 Summary We have reviewed our experience in the management of myeloma patients who present with features of severe renal impairment, to examine the role of intensive treatment of the renal failure, and to assess the role of renal biopsy. Between March 1983 and August 1991, 16 patients, who were subsequently diagnosed as having myeloma, presented to the Department of Renal Medicine for investigation of renal failure; nine with symptoms of uraemia and seven with pneumonia, bone pain, emphysema, or ischaemic heart disease. Renal biopsy was performed on 14 patients. Eleven patients had myeloma cast nephropathy, two of whom had concurrent hypertensive nephropathy, two patients had light chain deposition disease, and one patient had interstitial nephritis. Renal function improved in six patients with aggressive rehydration, but three of them subsequently required dialysis. In all 11 patients required dialysis, two short-term and nine long-term. Seven patients were given conventional melphalan and prednisolone and nine patients received VAMP as induction cytotoxic chemotherapy. Five of the VAMP sub-group received interferon cr2b as maintenance therapy. The median renal survival was five months (range 0-36 months) and median overall survival was 20 months (rangc 1-54 months). We conclude that intensive treatment, including dialysis, in myeloma patients with renal failure may result in survival durations approaching those of unselected myeloma patients, and a significant proportion will enjoy a reasonable quality of life. Keywords: myeloma, renal failure Renal failure is often present at the diagnosis of myeloma, and it may be the presenting feature (Editorial 1988; Iggo & Parsons 1990). Numerous factors including hypercalcaemia, infection, dehydration, nephrotoxic drug therapy, and light chain deposition, may be implicated in the aetiology (Iggo & Parson 1990). Aggressive rehydration will improve the survival of a significant proportion of those who present with renal failure (MRC Working Party 1984). However, patients who continue to demonstrate significant renal impairment following such an approach have been considered to have a poor prognosis (Iggo et al. 1988). Correspondence: Dr Robert Cuthbert, Altangelvin Hospital, Londonderry, N. Ireland BT47 ISB, UK. 149
Transcript
Clin. lab. Haemat. 1994, 16, 149-156
Intensive treatment of renal failure in patients with myeloma
A N D R E W I N N E S , R O B E R T J . G . C U T H B E R T * , N I G E L H . RUSSELL*, A N T H O N Y G. M O R G A N & R I C H A R D P . B U R D E N Departments of Renal Medicine and * Haematology, City Hospital, Nottingham NG5 IPB, UK
Accepted 13 January 1994
Summary We have reviewed our experience in the management of myeloma patients who present with features of severe renal impairment, to examine the role of intensive treatment of the renal failure, and to assess the role of renal biopsy. Between March 1983 and August 1991, 16 patients, who were subsequently diagnosed as having myeloma, presented to the Department of Renal Medicine for investigation of renal failure; nine with symptoms of uraemia and seven with pneumonia, bone pain, emphysema, or ischaemic heart disease. Renal biopsy was performed on 14 patients. Eleven patients had myeloma cast nephropathy, two of whom had concurrent hypertensive nephropathy, two patients had light chain deposition disease, and one patient had interstitial nephritis. Renal function improved in six patients with aggressive rehydration, but three of them subsequently required dialysis. In all 11 patients required dialysis, two short-term and nine long-term. Seven patients were given conventional melphalan and prednisolone and nine patients received VAMP as induction cytotoxic chemotherapy. Five of the VAMP sub-group received interferon cr2b as maintenance therapy. The median renal survival was five months (range 0-36 months) and median overall survival was 20 months (rangc 1-54 months). We conclude that intensive treatment, including dialysis, in myeloma patients with renal failure may result in survival durations approaching those of unselected myeloma patients, and a significant proportion will enjoy a reasonable quality of life.
Keywords: myeloma, renal failure
Renal failure is often present at the diagnosis of myeloma, and it may be the presenting feature (Editorial 1988; Iggo & Parsons 1990). Numerous factors including hypercalcaemia, infection, dehydration, nephrotoxic drug therapy, and light chain deposition, may be implicated in the aetiology (Iggo & Parson 1990). Aggressive rehydration will improve the survival of a significant proportion of those who present with renal failure (MRC Working Party 1984). However, patients who continue to demonstrate significant renal impairment following such an approach have been considered to have a poor prognosis (Iggo et al. 1988).
Correspondence: Dr Robert Cuthbert, Altangelvin Hospital, Londonderry, N. Ireland BT47 ISB, UK.
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150 A . Znnes et al.
Although renal replacement therapy has been reported in a small series, its role in the overall management of patients with myeloma remains controversial (Iggo et al. 1988; Pasquali et al. 1990; Tapson et al. 1988). Furthermore, renal biopsies are infrequently performed in patients with myeloma who have renal failure at presentation (Pasquali et al. 1987).
This study was conducted to assess the clinical features of patients with myeloma with renal impairment at presentation. It also examined the intensive treatment of renal failure and its effects on quality of life, patient survival and problems associated with chemotherapy.
Methods
The study consisted of all individuals who presented between March 1983 and August 1991 to the Department of Renal Medicine with renal failure who were found subsequently to have myeloma. The study design was a retrospective analysis based on examination of the clinical records. The management of renal failure in our department consists of standard assessment and investigations for reversible factors, and haemodialysis-if required urgently-via a subclavian venous catheter. An ‘immunological screen’ which includes examination of serum and urine for paraprotein is always requested. Serum calcium is measured in all patients. Percutaneous needle biopsy of the kidney is always performed, unless contraindicated, according to conventional criteria.
The diagnosis of myeloma was made on the presence of at least two of the following: bone marrow aspirate or biopsy sections containing > 20% plasma cells or < 20% plasma cells with evidence of monoclonality on immunocyto- chemistry; a paraprotein in the blood and/or urine; lytic bone lesions on X-ray (Durie 1988).
The initial cytotoxic chemotherapy regimens used were standard dose melphalan modified for renal failure (MacLennan et al. 1988) in seven patients, and vincristine, adriamycin, and methyl prednisolone (VAMP) (Forgeson et al. 1988) in nine patients. Mitoxantrone was substituted for adriamycin in patients who developed cardiac arrhythmias associated with VAMP (two patients). Response to treatment was defined as achievement of plateau: > 50% reduction of paraprotein and/or 24 h urinary light chain excretion, and resolution of all symptoms related to active myeloma. Five patients who achieved plateau (partial or complete response) after VAMP received recombinant interferon ct2b as maintenance therapy (Mandelli et al. 1990).
Results
The clinical features, histology, initial renal replacement therapy, induction cytotoxic chemotherapy and outcome of the study group is outlined in Table 1. The median age was 54 years (range 43-77 years) and 12 of the 16 patients were
MCN = Myeloma cast nephropathy; IN = Interstitial nephritis; LCDD = Light chain deposition disease; BHN = Benign hypertensive nephrosclerosis; HD = Haemodialysis; CAPD = Continuous ambulatory peritoneal dialysis; RRT = Renal replacement therapy. * = No renal biopsy but amyloid on joint biopsy.
male. Nine patients presented due to the symptoms of uraemia (lethargy, anorexia, nausea and vomiting). Seven patients were found to have renal impair- ment during the investigation of the following symptoms: pneumonia (two patients), bone pain (two patients), emphysema (one patient) or ischaemic heart disease (two patients). Evidence of bony involvement was present on X-ray in two patients presenting with concomitant bone pain. None of the patients had hypercalcaemia. The diagnosis of myeloma was suggested by the presence of paraprotein in blood or urine. The investigation protocol was, therefore, instru- mental in prompting further investigations which established the diagnosis.
Three patients showed sustained improvement in renal function following rehydration; three others showed initial improvement but required subsequent dialysis. Two patients initially treated with haemodialysis were subsequently changed to CAPD because of haemodynamic instability on haemodialysis; indeed five of the nine patients receiving long term dialysis (by either technique) tolerated it poorly. The problems were mainly CAPD peritonitis, anorexia, vomiting, cardiac arrhythmias and recurrent fluid overload in conjunction with hypo tension.
Median renal survival (time from diagnosis of myeloma to time of requiring dialysis, or patient death with functioning kidneys at that time) was five months (range 0-36 months) and median overall survival (time from diagnosis to patient death) was 20 months (range 1-54 months (Figure 1). Table 2 outlines the
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Table 2. Cytotoxic chemotherapy regimes, response to treatment and patient survival
while still in plateau No plateau Lost to FU Death notified Died: ARF, IHD,
myeloma
5
I 18
(Censored death) 28
1
cytotoxic chemotherapy regimes employed, response to treatment and outcome in the 16 study patients. Eight patients (50%) achieved plateau. The median duration of response was 11 months (range 7-40 months) and the median overall survival was 32 months (range 18-54 months) in responding patients. The median survival in the non-responding subgroup was 5 months (range 1-12 months). Survival duration was determined by the response to chemotherapy.
The use of melphalan was limited by neutropenia in three patients. Neutropenia was also noted to a lesser degree in two of the patients receiving VAMP. In these cases no significant delay in chemotherapy cycles occurred. VAMP therapy was associated with cardiac arrhythmias in two individuals. Itch and febrile reactions were observed on treatment with interferon in three patients. One patient developed significant hepatotoxicity due to interferon therapy, requiring discon- tinuatian after seven months of treatment.
t ‘L 0.2 -
0.0 -1 I I I I I
0 12 24 36 48 60 I
I I I
0 12 24 36 48 60
Months
Figure 1. Kaplan-Meier plot of probability of survival from diagnosis of myeloma.
154 A . Innes et al.
Discussion
This study addresses the problems of patients with myeloma presenting to nephrologists for investigation and management of renal impairment. The selec- tive nature of the group may explain why few patients responded to fluid challenge and why no patient had hypercalcaemia. Patients presenting in this manner may have a renal lesion that is not amenable to conservative therapy. Also, such patients may already have had failed attempts at rehydration before coming to the attention of our department. The study indicates the need to check blood and urinary paraproteins in patients with unexplained acute and chronic renal failure, even in those below 50 years of age (6/16 patients in our study). Such screening suggested the diagnosis which was subsequently confirmed by further investigations.
Renal biopsy showed ‘myeloma kidney’ in 11 cases adding further diagnostic evidence of the disease. Biopsy is useful prognostically (though the number in our study is too small) as other studies have shown that the degree of tubulointerstitial damage correlates with renal survival (Pasquali et al. 1987; Durie 1988; MacLennan et al. 1988; Forgeson et al. 1988; Mandelli et al. 1990; Rota et al. 1987). Biopsy can exclude amyloidosis and demonstrate other co-existing renal pathology. This has been useful in our study and also stresses the diverse pathology found in patients with renal manifestations of myeloma. Two patients also had severe hypertensive renal disease, one had interstitial nephritis and two had light chain deposition disease (Confalonieri et al. 1988).
CAPD and haemodialysis appear equally effective in terms of patient outcome and choice should probably be decided as for non-myeloma patients (Iggo & Parsons 1990). This is despite, on the one hand, the theoretical advantages of CAPD in removing immunoglobulins (Iggo et a!. 1988) and, on the other, an increased incidence of infective complications on CAPD (Tapson et al. 1988). In our study, as many patients required urgent dialysis, they received haemodialysis initially using temporary subclavian vascular access. The patients changed to CAPD because cardiovascular instability remained intolerant of dialysis. For over half the patients receiving dialysis, however, the course of their illness was dominated by unpleasant problems associated with dialysis.
The optimal cytotoxic chemotherapeutic regimen for myeloma patients with renal failure is not known. Although conventional melphalan and prednisolone are relatively non-toxic, melphalan clearance depends on adequate renal function, and excessive haematological toxicity (real or anticipated) tends to preclude satisfactory therapy. It is clear, however, that patient survival depends on an adequate response to chemotherapy (Iggo et al. 1988; Rayner et al. 1991). Whether more aggressive regimens can improve the overall survival in patients with renal failure remains to be established. The survival of our patients treated with conventional melphalan is relatively encouraging (median survival 20 months, range 0-54 months), and compares favourably with the VAMP sub- group (median survival 18 months, range 1-41 months). It is not possible, however, to draw any conclusion on which approach might be more efficacious
Myeloma and renal failure 155
since the study is too small to establish a meaningful statistical comparison. The advantages of the VAMP regimen are that the drugs’ clearance is independent of renal function, and overall toxicity is acceptable, as shown in the present study and in a previous study, which included some of the patients reported here (Aitchison et al. 1990). VAMP was thought, however, to be a contributing factor to cardiac arrhythmias in two patients with severe cardiac disease. Interferon a2b was generally well tolerated with only mild self limiting side effects, although one pa tien t developed hepa to toxici ty .
A recent local study in unselected patients with myeloma found a median survival of 25 months (Rayner et al. 1991) similar to the MRC trial (MacLennan et al. 1988). Rayner et al. (1991) reviewing all patients in Nottingham between 1976 and 1986 pointed out that, in general, over the study period survival had not improved. An increase in infective complications due to increased immuno- suppression may have offset any benefits of chemotherapy. Median patient survival of 20 months in our study is encouraging, comparing favourably with patients with renal failure in other studies (Iggo et al. 1988; Pasquali et al. 1990), and suggests that, although renal failure at presentation is said to be indicative of poor prognosis (Rota et al. 1987; Rayner et al. 1991) the outlook is not uniformly grim.
Intensive treatment of patients with myeloma presenting with renal failure using newer chemotherapeutic regimens, and short and long-term dialysis, when necessary, yields median patient survival rates that are approaching those of unselected myeloma patients. This suggests that treating such patients is worth- while and emphasises the usefulness of screening patients with undiagnosed renal failure for myeloma. A substantial proportion of patients have major problems on long term dialysis, but for some the quality of life is good and prolonged survival is possible.
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