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1 (2005) 35, & 2005 Nature Publishing Group All rights reserved /05 $ Melphalan 200 mg/m 2 with blood stem cell support as first-line myeloma therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and survival Department of Haematology, Uppsala University Hospital, Sweden Summary: In this retrospective single-centre study, 96 consecutive myeloma patients were treated with melphalan 200 mg/m 2 with blood stem cell support as first-line therapy. Their mean age was 55 (38 65) years. The impact of renal function on stem cell collection yield, engraftment, transplantation-related toxicity and overall survival was studied. Glomerular filtration rate (GFR) was evaluated by iohexol clearance, a median 32 days before high-dose administration. Chronic renal failure (GFR o60 ml/min) was present in 19 patients, with severe failure (GFR o30 ml/min) in five patients, including one patient on haemodialysis. No relationship between GFR and stem cell collection yield or engraftment was observed, nor was the incidence of neutropenic fever or infectious complications related to GFR. Patients with subnormal renal function, however, were more often affected by severe mucositis. In addition, the two patients with severe GI bleeding, the two pneumonia patients who needed ventilator support and the only therapy-related death were noted in the five patients with severe renal failure. Lower iohexol clearance at the time of high-dose administration was found to have a poor impact on survival. A reduction of melphalan dose in patients with severe renal failure, here defined as iohexol clerarance o30 ml/min, is suggested. (2005) 35, doi: /sj.bmt Published online 4 April 2005 Keywords: multiple myeloma; high-dose melphalan iohexol clearance; toxicity; OAS High-dose chemotherapy with blood stem cell rescue has been shown to significantly prolong survival in patients withmultiple myeloma. 1 3 At diagnosis, renal insufficiency Correspondence: Dr, Department of Haematology, Division of Internal Medicine, Uppsala University Hospital, Uppsala S , Sweden; kristina.carlson@akademiska.se Received 16 April 2004; accepted 26 January 2005 Published online 4 April 2005 is present in about 20% of myeloma patients, 4,5 of which 2 10% require dialysis In many high-dose protocols, renal impairment has been an exclusion criterion for participation, but several reports have shown that highdose therapy is feasible in renal failure, even in patients withterminal renal insufficiency In this single-centre study, the influence of renal function on stem cell harvest yield, engraftment, transplantation-related toxicity and overall survival (OAS) is evaluated in consecutive myeloma patients treated with high-dose melphalan as part of initial treatment. Renal function was evaluated by iohexol clearance measured before the start of high-dose therapy. Patients and methods Patients From April 1993 until April 2003, autologous transplantation withperipheral blood stem cells was performed in 101 myeloma patients as part of first-line therapy at the University Hospital, Uppsala, Sweden. Before high-dose treatment, renal function was evaluated by iohexol clearance in 96 of them. These 96 patients were included in the study. Treatment Induction chemotherapy. The majority of patients, 89, received induction therapy with three courses of VAD according to the Nordic Myeloma Study Group (NMSG) protocol 5/94, 3 NMSG protocol 7/98 19 or NMSG protocol 11/01. Regarding the latter protocol, patients were randomized to receive either three cycles of VAD (course interval of 4 weeks) or two cycles of cyclophosphamide 1 g/m 2 intravenously (i.v.) day 1 and dexamethasone 40 mg orally (p.o.) or i.v. on days 1 4 and 9 12 (course interval of 3 weeks) before stem cell mobilization. Seven patients were randomized to treatment with cyclophosphamide and dexamethasone (manuscript in preparation). Owing to clinical (pulmonary embolism, perforated diverticulitis, etc) or logistical reasons, the high-dose therapy had to be postponed in 16 patients. Accordingly, for these 16 patients additional chemotherapy before stem cell transplantation (SCT) was administered. Three of these 16 were administered additional VAD, one VMCP and 12 MP.

2 986 Stem cell mobilization. Stem cells were mobilized by cyclophosphamide 2 4 g/m 2 i.v. on day 1 and G-CSF (filgrastim) 5 mg/kg/day subcutaneously (s.c.) from day 4 until the last day of stem cell collection. The minimum stem cell yield accepted for SCT was CD34 þ cells /kg. Evaluation before high-dose therapy. Renal function was evaluated by iohexol clearance before the administration of high-dose therapy. Other tests performed were blood cell count, quantification of plasma paraprotein, plasma immunoglobulins, Bence Jones proteinuria, bone marrow aspirate, chest X-ray, electrocardiogram and isotope angiography for evaluation of left cardiac ventricular function. High-dose therapy. Conditioning treatment withmelphalan (200 mg/m 2 ) i.v. infusion for 1 hfollowed by hydration with2.5 l/m 2 for 24 h was given. The melphalan dose was not reduced in patients withrenal impairment. The peripheral stem cells were infused 48 h after melphalan administration. The fourth day after stem cell reinfusion, G-CSF 5 mg/kg/day s.c. was started and maintained until absolute neutrophil count (ANC) /l for 3 consecutive days or ANC /l on one occasion. Packed red cells and platelets were transfused to keep Hb 490 g/l and platelets /l. Prophylaxis with ciprofloxacin p.o., acyclovir p.o. and nystatin p.o. was initiated on the day of SCT and continued until ANC /l. Empirical antibiotic therapy i.v. was commenced if pyrexia was Severe mucositis was treated withcontinuous morphine i.v. infusion. When neutropenia resolved, sulphamethoxazol p.o. was given as pneumocystis prophylaxis 2 days/week until 3 months after high-dose therapy. Maintenance treatment with interferon. Treatment with interferon alpha-2b was started 2 3 months after high-dose therapy, with dose escalation, if possible, until a dose of U/m 2 s.c. three times weekly was maintained. Interferon was continued until myeloma progress occurred or until intolerable adverse event appeared. Evaluation of renal function Plasma creatinine was measured and glomerular filtration rate (GFR) was calculated at diagnosis. 20 GFR was determined using iohexol clearance before high-dose therapy. In accordance with K/DOQI (National Kidney Foundation s Dialysis Outcomes Quality Initiative) guidelines, 21 chronic kidney disease was defined as GFR o60 ml/ min for X3 months. Thus, patients were divided into the following groups according to iohexol clearance before high-dose treatment: normal renal function (X60 ml/ min 1.73 m 2 ), moderate renal impairment (30 59 ml/ min 1.73 m 2 ), severe renal impairment (15 29 ml/min m 2 ) and terminal renal insufficiency (o15 ml/min m 2 or dialysis). Evaluation of toxicity Haematological recovery. Haematological recovery was defined as the number of days from SCT until white cell count /l, ANC /l, ANC /l, platelets 420, 50 and /l and by counting the number of platelet and erythrocyte transfusions administered. Transplantation-related toxicity. The number of days patients had a temperature C were counted and infectious complications (eg positive blood cultures and radiologically verified pneumonia) were registered. The number of days on i.v. antibiotics was counted. As continuous i.v. morphine infusion has been standard treatment in severe mucositis at our centre, the number of patients treated withcontinuous i.v. morphine infusions and number of days on i.v. morphine infusion were used as surrogate markers for severe mucositis. Evaluation of therapy response Complete response (CR) was defined by the disappearance of M-protein in serum and urine (analysed by agarose gel electrophoresis) and o5% plasma cells in bone marrow aspirate. Partial response (PR) was defined by 450% reduction of the initial serum M-protein concentration and a reduction of Bence Jones proteinuria to o0.2 g/24 h. Minor response (MR) was defined by a 25 50% reduction of the initial serum M-protein concentration and a reduction in Bence Jones proteinuria by less than 50% but exceeding 0.2 g/24 h. To fulfil the criteria for CR, PR or MR, the patients were not allowed to have any other signs of myeloma progression suchas persisting hypercalcaemia or progressive renal insufficiency, skeletal disease or bone marrow insufficiency because of plasma cell infiltration. Progression was defined by a confirmed increase of the serum M-protein concentration 425% from the level at the time of best response, or an increase of Bence Jones proteinuria to 41.0 g/24 h, or by other unequivocal signs of disease progression (eg hypercalcaemia, progressive skeletal disease or soft-tissue plasmacytomas). Nonresponse (NR) was defined by an increase or decrease in the initial serum M-protein concentration of o25% concomitant withno criterion for progression. Statistics Categorical data were compared by w 2 analysis and continuous numerical data were analysed using the Mann Whitney test for nonparametric data. All probabilities were two-tailed. OAS was determined using the Kaplan Meier method and the log-rank test was used for survival comparisons. The Cox proportional-hazard regression model was employed to estimate the prognostic importance of different variables. Serum b 2 -microglobulin at diagnosis, number of CD34 þ cells infused, age and number of plasma cells in bone marrow aspirate at highdose therapy start and iohexol clearance before high-dose therapy were included as continuous variables. The variables gender (male vs female), stage according to Durie and Salmon (I and II vs III) and therapy response at the time of SCT (NR and MR vs PR and CR) were dichotomized.

3 Results GFR and patient characteristics The assessment of GFR with iohexol clearance was performed at the time of stem cell collection, median 32 (3 274) days before high-dose therapy. The median time from the start of induction therapy until high-dose therapy was 144 (82 473) days. The mean GFR was 92 (range ) ml/min 1.73 m 2. Chronic renal impairment with GFR o60 ml/min was diagnosed in 19 patients, of whom five had severe renal failure (one patient was on haemodialysis). Patient characteristics are summarized in Table 1. Stem cell mobilization No correlation was found between stem cell yield and renal function at the time of mobilization. However, a significantly lower yield was noted in the 15 patients with poor therapy response (MR or NR) at the time of collection as compared withthe 81 patients withgood response (PR or CR), witha mean yield of 5.8 ( ) and 9.9 (1.5 35) CD34 þ cells 10 6 /kg, respectively. Transplantation-related toxicity Haematological toxicity and recovery. The haemoglobin level fell below 90 g/l and the platelet count o /l Table 1 Patient characteristics correlated with GFR before highdose therapy Iohexol clearance before high-dose therapy X60 ml/min ml/min o30 ml/min (n ¼ 77) (n ¼ 14) (n ¼ 5) P-value* Age (years), median 55 (38 65) 57 (49 63) 58 (48 65) NS (range) Males/females 50/27 4/10 2/3 o0.01 M-component o0.05 G A BJ Nonsecretory Stage I/II/III 7/18/52 0/5/9 0/1/4 NS S-b2-microglobulin Mean (range) 3.8 (1 9) 4.9 (2 23) 11.4 (4 22) o0.001 (n ¼ 41) (n ¼ 9) (n ¼ 4) CD /kg collected Mean (range) 9.3 (1.5 35) 9.8 (2.3 22) 6.6 (2.0 11) Therapy response at start of high-dose treatment CR PR MR NR NS ¼ not significant. *P-values relate to comparison between patients witha GFR X60 ml/min or o60 ml/min. NS NS in all five patients withsevere renal failures, whereas in patients without chronic renal failure, a haemoglobin level below 90 g/l and a platelet count o /l was never reached in 33 (43%) and 10 (13%) of patients, respectively. Renal impairment had no negative influence on haematological recovery (Table 2). The median number of days to engraftment withplatelet count /l and ANC X /l was 10 and 11 days, respectively. Treatment-related morbidity (TRM). Severe mucositis was observed more frequently in patients withchronic renal failure. Whereas all five patients with severe renal failure received continuous i.v. morphine infusion for their mucositis, only 34% of the patients with a GFR X60 ml/ min received suchtreatment. However, renal impairment had no impact on the duration of treatment in patients requiring i.v. morphine infusion (Table 2). The administration of i.v. antibiotics was also more common in patients withchronic renal failure. All patients withsevere renal dysfunction and 63% of patients withgfr X60 ml/min were administered i.v. antibiotics. For patients given i.v. antibiotics, the median treatment time was 7 days. No correlation withrenal function was recorded (Table 2). Fever was recorded for a median of 2 days in 53% of patients: an infectious cause of fever was found in 21 patients (11 withpneumonia, eight withsepticaemia and two withsoft-tissue infection). No statistical relationship was noted between infectious complications and renal function, but three of five patients (or 60%) with severe renal failure had a documented infection as compared to 22% for the entire patient population (Table 2). Life-threatening gastrointestinal bleeding with haematemesis and melena occurred in two patients, a woman aged 47 years who was on chronic haemodialysis and a man aged 60 years (GFR 13 ml/min), who later succumbed because of multi-organ failure. No other severe bleeding was reported. Two patients, a 57-year-old woman and a 60-year-old man, bothwithsevere renal failure (GFR 29 and 13 ml/ min, respectively), needed ventilator support and continuous veno-venous haemodialysis (CVVH), which was due to the combination of pneumonia and severe mucositis. In the 57-year-old woman, the ventilator treatment could be withdrawn after 4 days and the CVVH after 14 days. Transplantation-related mortality. One transplantationrelated death, which was due to multiorgan failure, occurred 1.9 months after high-dose therapy in a 60-yearold man witha GFR of 13 ml/min. He never recovered from pneumonia, withonset during the neutropenic post transplantation phase. GFR o30 ml/min compared with a GFR X60 ml/min. Data for the five patients with severe renal failure at the time of high-dose therapy are shown in Table 3. All these patients received blood and platelet transfusion, an i.v. morphine infusion and i.v. antibiotics. The only therapy-related death as well as the two life-threatening bleeding episodes occurred among these patients. The majority of patients who never needed an i.v. morphine infusion, i.v. antibiotics, blood and platelet transfusion were found in the group with GFR X60 ml/ 987

4 988 Table 2 myeloma Haematological recovery and TRM following melphalan (200 mg/m 2 ) withstem cell support given as initial therapy for multiple Iohexol clearance before high-dose therapy X60 ml/min ml/min o30 ml/min P-value* (n ¼ 77) (n ¼ 14) (n ¼ 5) ANC X /l, days after stem cell infusion Median (range) 11 (9 20) 11 (9 16) 11 (10 13) NS Platelets /l, days after stem cell infusion Median (range) 10 (0 19) 12 (0 18) 14 (12 22) NS Never platelets o /l Number of patients (%) 10 (13) 1 (7) 0 (0) NS Number of platelet transfusions Median (range) 1 (0 6) 1 (0 8) 6 (1 20) NS Never Hb o90 g/l Number of patients (%) 33 (43) 3 (21) 0 (0) o0.05 Number of packed erythrocytes transfused Median (range) 2 (0 6) 2 (0 4) 6 (2 40) NS Treatment with i.v. morphine infusion for mucositis Number of patients treated (%) 26 (34) 9 (65) 5 (100) o0.01 Days with i.v. morphine infusion for treated patients Median (range) 5 (3 11) 5 (4 15) 6 (3 9) NS Treatment with i.v. antibiotics Number of patients (%) 48 (63) 13 (93) 5 (100) o0.01 Days on i.v. antibiotics for treated patients Median (range) 7 (2 25) 7 (2 15) 10 (7 52) NS Patients with neutropenic fever Number of patients (%) 39 (51) 7 (50) 5 (100) NS Number of days with fever (in patients with fever) Median (range) 2 (1 11) 3 (1 12) 1.5 (1 6) NS Proven infection Number of patients (%) 16 (21) 2 (14) 3 (60) NS NS ¼ not significant. Data for groups of patients withno chronic renal failure (GFR X60 ml/min), moderate renal impairment (GFR ml/min) and severe chronic renal impairment (GFR o30 ml/min) are shown. *P-values relate to comparison between patients witha GFR X60 ml/min or o60 ml/min. min. In all, 56 patients never developed severe mucositis, thus i.v. morphine was not given. Of these, 50 (90%) had GFR X60 ml/min. Corresponding data for patients not requiring i.v. antibiotics, blood transfusions and platelet transfusions were 29/30 (97%), 33/36 (92%) and 10/11 (91%), respectively. Survival Stage (according to Durie and Salmon) and GFR as a continuous variable correlated independently and significantly withsurvival withshorter OAS in patients witha more advanced stage or lower GFR. However, when patients were divided into three renal function groups (normal function, moderate failure and severe failure), OAS did not differ between the groups (Figure 1). No significant impact on OAS was noted regarding age, gender, serum b 2 -microglobulin, percentage of plasma cells in bone marrow aspirate at transplantation, therapy response at transplantation or amount of CD34 þ cells infused. Discussion In many high-dose treatment protocols for myeloma patients, renal failure has been a common exclusion criterion. However, several reports have demonstrated that high-dose treatment is feasible even in myeloma patients withterminal renal disease Data on the influence of renal function on stem cell mobilization, engraftment, transplantation-related toxicity, TRM and survival after high-dose therapy have also been published. In a Spanish register study, 13 no correlations were noted between renal

5 Table 3 Data on the five myeloma patients with severe or terminal renal failure at the time of high-dose treatment 989 Patient gender and age Myeloma type Iohexol clearance (ml/ min 1.73 m 2 ) Response at SCT Adverse event associated with high-dose melphalan therapy Outcome Female, 57 years BJ 29 NR Pneumonia, alpha-streptococcus septicaemia, mucositis Intensive care unit from day +10 until day +24 for assisted ventilation (4 days) and CVVH (14 days) Female, 47 years BJ Haemodialysis PR Pneumonia, mucositis, haematemesis and melena Male, 60 years BJ 13 PR Pneumonia, mucositis, melena, critical care illness polyneuropathy Intensive care unit from day +10 for assisted ventilation and CVVH, which continued until death Female, 63 years IgA 27 haemodialysis at diagnosis, previous nephrectomy Alive 23 months Dead 6 months, myeloma Dead 54 days, multiorgan failure PR Mucositis Dead 32 months, myeloma Male, 57 years BJ 22 PR Mucositis Alive 82 months Survival GFR 60 ml/min (n = 77) GFR ml/min (n = 14) GFR < 30 ml/min (n = 5) Months Figure 1 OAS for high-dose-treated myeloma patients according to renal function measured before the start of high-dose melphalan therapy. No significant correlations were observed. Normal function (GFR X60 ml/ min 1.73 m 2 ), moderate chronic renal failure (GFR ml/min m 2 ) and severe or terminal chronic renal failure (GFR o30 ml/ min 1.73 m 2 ). function, stem cell yield at harvest or engraftment. OAS, on the other hand, was significantly prolonged in patients withnormal renal function. In this Spanishstudy, renal dysfunction was defined as S-creatinine 42 mg/dl. Using a similar design, 22, a Danishsingle-centre study found that the need for erythrocyte transfusions, transplantationrelated toxicity (fever and proven infections) and mortality were increased in patients withimpaired renal function. However, S-creatinine can only give a roughidea of renal function and hence measurement of GFR is a more reliable option in evaluating renal function. In a report from Royal Marsden, UK 14 GFR was determined using CrEDTA clearance. The patients in this study were divided into normal or subnormal renal function groups. Although no correlation was found between renal function and engraftment, mucositis, diarrhoea and infection occurred more frequently after high-dose therapy and OAS was significantly shortened in patients with subnormal renal function. The present study differs from earlier reports in that it is a single-centre study of myeloma patients given high-dose therapy with stem cell support as first-line therapy. All patients received the same conditioning treatment with melphalan (200 mg/m 2 ), no dose reduction was performed and peripheral stem cells were used as the only stem cell source in all cases. In other reports, various conditioning regimes have been used and stem cell sources have been bothmarrow and peripheral stem cells. 13,14 Furthermore, in our study, renal function was evaluated in all patients by iohexol clearance at the time of pre-transplantation check-up. Our study is consistent withother reports 11,13,14 in that no relationship was observed between renal function and stem cell yield at harvest and engraftment was not affected by renal function. The present data are also consistent with those previously reported on therapy-related toxicity. An increased incidence of severe mucositis was seen in patients withimpaired renal function and the two cases withsevere GI bleedings, which is associated with mucositis, occurred only in patients withsevere renal impairment. In contrast withother studies, 14,22 we did not observe an increased incidence of proven infections or days withneutropenic fever in renal failure patients. However, among the 11 patients with pneumonia, the two who needed ventilator support bothhad severe renal failure and bothhad to start dialysis in association with the pneumonia, indicating that if complications occur post transplantation, the consequences are more serious in renal impaired patients. In our study, the TRM was low (one in 96 patients) and the correlation between TRM and renal impairment described by others 13,22 could not be confirmed. One plausible explanation for the near absence of TRM may be that only patients treated with high-dose therapy as part of first-line treatment were included and that patients with progressive disease after induction therapy were not eligible for high-dose therapy. If TRM is expected to be related to renal failure, another explanation might be that only five

6 990 patients witha GFR o30 ml/min were included in the study. In this subgroup, TRM was 1/5 (20%). For myeloma patients treated withmelphalan and prednisone p.o. as first-line therapy, it is known that renal failure at diagnosis is an independent risk factor for survival. 9 Sirohi et al 14 have shown that renal function, evaluated by CrEDTA at the time of high-dose therapy and used as a dichotomized variable (normal vs subnormal), was associated withpoor OAS. In our study, iohexol clearance at the time of high-dose melphalan administration correlates withoas as a continuous variable, which confirms that renal dysfunction has a poor prognostic impact at the time of high-dose therapy. Whether the melphalan dose should be reduced in highdose-treated myeloma patients withrenal failure remains controversial. This lack of consensus may partly be due to various definitions of renal failure coupled withwidely varying study populations. Badros et al 11 have shown an increase in transplant-related toxicity in patients with creatinine mmol/l and suggest a reduction in melphalan dose (from 200 mg/m 2 to 140 mg/m 2 ) for these patients. The authors found that this dose reduction was able to decrease toxicity without having a negative impact on OAS for this patient group. Sirohi et al, 14 on the other hand, suggest that the melphalan dose should not be modified in patients with low GFR, which has been defined in their study as age-related subnormal GFR. As only three patients had GFR o40 ml/min in their study, this factor may have underestimated the toxicity problems normally associated withsevere renal failure. Althoughfrom our results no firm conclusions can be drawn, data nevertheless suggest that in patients with severe renal failure (defined here as iohexol clearance o30 ml/min) the melphalan dose should be reduced in order to reduce toxicity, especially in that increased toxicity does not seem to translate into better survival. In conclusion, this report shows that transplantationrelated toxicity and OAS are related to iohexol clearance at the time of high-dose melphalan administration. High-dose therapy is feasible in renal insufficient patients, and renal function alone should not be an exclusion criterion for treatment. A reduction of the melphalan dose in patients withsevere renal failure is suggested. References 1 Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: Fermand JP, Ravaud P, Chevret S et al. 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Are myeloma patients withrenal failure candidates for autologous stem cell transplantation? Hematol J 2000; 1: Sirohi B, Powles R, Kulkarni S et al. Glomerular filtration rate prior to high-dose melphalan 200 mg/m 2 as a surrogate marker of outcome in patients withmyeloma. Br J Cancer 2001; 85: Tosi P, Zamagni E, Ronconi S et al. Safety of autologous hematopoietic stem cell transplantation in patients with multiple myeloma and chronic renal failure. Leukemia 2000; 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: Lee C-K, Zangari M, Barlogie B et al. Myeloma. Dialysisdependent renal failure in patients withmyeloma can be reversed by high-dose myeloablative therapy and autotransplant. Bone Marrow Transplant 2004; 33: Child A, Morgan G, Davies F et al. High-dose chemotherapy withhematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: Lenhoff S, Hjorth M, Westin J et al. Impact of age on survival after high-dose therapy with autologous stem cell support in newly diagnosed multiple myeloma: a population-based study. (submitted for publication). 20 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39 (Suppl. 1): S1 S Knudsen LM, Nielsen B, Gimsing P, Geisler C. Autolgous stem cell transplantation in multiple myeloma withrenal failure. Blood 2003; 102: 985a (abstract 3667).