VOLUME 28
NUMBER 33
NOVEMBER 20 2010
JOURNAL OF CLINICAL ONCOLOGY
REVIEW
ARTICLE
Renal Impairment in Patients With Multiple Myeloma: A
Consensus Statement on Behalf of the International
Myeloma Working Group
Meletios A. Dimopoulos, Evangelos Terpos, Asher Chanan-Khan, Nelson Leung, Heinz Ludwig,
Sundar Jagannath, Ruben Niesvizky, Sergio Giralt, Jean-Paul Fermand, Joan Blade´, Raymond L. Comenzo,
Orhan Sezer, Antonio Palumbo, Jean-Luc Harousseau, Paul G. Richardson, Bart Barlogie,
Kenneth C. Anderson, Pieter Sonneveld, Patrizia Tosi, Michele Cavo, S. Vincent Rajkumar,
Brian G.M. Durie, and Je´sus San Miguel
From the University of Athens School
ABSTRACT
of Medicine, Athens, Greece; Roswell
Park Cancer Institute, Buffalo; St
Renal impairment is a common complication of multiple myeloma (MM). The estimated
Vincents Catholic Medical Center; Weill
Medical College of Cornell University;
glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the
Adult Bone Marrow Transplantation
recommended method for the assessment of renal function in patients with MM with
Service, Memorial Sloan-Kettering
stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and
Cancer Center, New York, NY; Mayo
end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to
Clinic, Rochester, MN; Wilhelminenspi-
define the severity of renal impairment. Novel criteria based on eGFR measurements are
tal, Vienna, Austria; Service d'Immuno-
recommended for the definition of the reversibility of renal impairment. Rapid intervention to
He´matologie, Hopital Saint-Louis, Paris,
France; Hospital Clinic, Barcelona; the
reverse renal dysfunction is critical for the management of these patients, especially for those
University Hospital of Salamanca,
with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as
Salamanca, Spain; Tufts Medical
the treatment of choice for such patients. There is limited experience with thalidomide in
School, Boston, MA; Oncology and
patients with myeloma with renal impairment. Thus, thalidomide can be carefully adminis-
Stem Cell Transplantation, University
tered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the
Medical Center Hamburg, Hamburg,
rapidity and probability of response that is produced by the combination with bortezomib and
Germany; University of Torino, Torino;
Italian Cooperative Group; Seràgnoli
high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency
Institute of Hematology, Bologna
in a significant subset of patients, when it is given at reduced doses, according to renal function. The
University School of Medicine, Bologna,
role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment
Italy; Institute de Biology, Laboratoire
is controversial. High-dose melphalan (140 mg/m2) and autologous stem-cell transplantation should be
d'Hematologie, Nantes, France; Dana-
limited to younger patients with chemosensitive disease.
Farber Cancer Institute, Boston, MA;
Myeloma Institute for Research Ther-
apy, University of Arkansas Medical
J Clin Oncol 28:4976-4984. © 2010 by American Society of Clinical Oncology
Sciences, Little Rock, AR; Erasmus
MC, Rotterdam, the Netherlands; and
the Cedars-Sinai Samuel Oschin Cancer
on renal replacement therapy was 0.91 years in pa-
INTRODUCTION
Center, Los Angeles, CA.
tients with MM and 4.46 years in non-MM pa-
Submitted June 17, 2010; accepted
Renal impairment (RI) is a common feature of mul-
tients.4 Several studies in the era of conventional
August 23, 2010; published online
tiple myeloma (MM).1,2 A review of the United
chemotherapy have confirmed that RI was associ-
ahead of print at www.jco.org on
States Renal Data System showed that renal morbid-
ated with poor prognosis in MM, with a median
October 18, 2010.
ity from MM is a considerable burden.3 Of the
survival of shorter than 2 years.5-7 The introduction
Written on behalf of the International
of novel agents has led to an improved survival of
Myeloma Working Group.
375,152 patients in the registry who initiated therapy
for end-stage renal disease (ESRD) between January
patients with MM,8,9 even in those with RI. Some
Authors' disclosures of potential con-
flicts of interest and author contribu-
1992 and June 1997, 3,298 (0.88%) had MM. The
studies have also indicated that reversibility of RI is
tions are found at the end of this
2-year all-cause mortality of patients with ESRD due
associated with improved survival.10-12 In this con-
article.
to MM was 58% versus 31% in all other patients
sensus statement, we focus on the clinical implica-
Corresponding author: Meletios A.
(P
.01).3 Similarly, a recent update of the Euro-
tions and management of RI in patients with MM.
Dimopoulos, MD, University of Athens
pean Renal Association-European Dialysis and
School of Medicine, 80 Vas Sofias Ave,
Athens, 11528, Greece; e-mail:
Transplant Association registry showed that from
mdimop@med.uoa.gr.
1985 to 2005 1.5% (2,453) of the 159,637 patients
INCIDENCE AND DEFINITION OF RI
IN MYELOMA
© 2010 by American Society of Clinical
placed on renal replacement therapy had MM. The
Oncology
incidence of renal replacement therapy for ESRD
0732-183X/10/2833-4976/$20.00
due to MM increased from 0.70 per million people
Depending on the definition of RI, this complica-
DOI: 10.1200/JCO.2010.30.8791
(1986 to 1990) to 2.52 per million people (2001 to
tion is reported in 15% to 40% of patients with MM.
2005). The unadjusted median overall survival (OS)
At diagnosis, 30% to 40% of patients with MM have
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Renal Impairment in Multiple Myeloma
a serum creatinine above the upper limit of normal and the majority
have a serum creatinine lower than 4 mg/dL.11,13,14 In several series
Table 1. Prediction Equations for GFR Currently Used or Proposed For Use
in Clinical Practice
from tertiary hospitals, up to 10% of patients present with RI severe
Name
Equation
enough to require dialysis.10,15 RI can also evolve over time and an
estimated 25% to 50% of patients are affected during the course of
Cockcroft-Gault
CrCl (ml/min)
{ 140 age (years)
body
weight (kg)
constant}/Scr (micromol/L)
their disease.16
constant
1.23 if male or 1.04 if female
Serum creatinine is easily assessed and in several trials it is used to
or CrCl (ml/min)
{ 140 age (years)
body weight (kg)
0.85 (if female)}/ Scr
define RI in MM. A serum creatinine higher than 2.0 mg/dL represents
(mg/dL)
72
one of the Hypercalcemia, Renal Impairment, Anemia, and Bone
MDRD
Disease (CRAB) diagnostic criteria for symptomatic MM requiring
Original equation
GFR (ml/min/1.73 m2)
186
(Scr/88.4) 1.154
age 0.203
(0.742 if female)
1.212
therapy.17 However, serum creatinine may depend on factors such as
(if African-American)
age, sex, and muscle mass.12 Glomerular filtration rate (GFR) is a more
IDMS traceable
GFR (ml/min/1.73 m2)
175
(Scr) 1.154
accurate parameter, providing a true reflection of renal function. GFR
age 0.203
(0.742 if female)
1.212 (if
African-American)
in healthy subjects is considered to be in the range of 90 to 130
Equation based on both
GFR (ml/min/1.73 m2)
177.6
Scr 0.65
mL/min/1.73 m2. The inulin infusion method with concomitant urine
serum creatinine and
CysC 0.57
age 0.20
(0.82 if female)
collection is considered the gold standard method to measure GFR.
CysC21
(1.11 if black)
However, this method is unsuitable for clinical practice due to the
CKD-EPI by race, sex, and
serum creatinine
need for continuous infusion, multiple blood samples, and expense.18
mol/L (mg/dL)22
Radiolabeled and nonradioactive tracers, such as technetium-99 ­
Black
labeled diethylene-triamine-pentacetic acid, chromium-51­labeled
Female
ethylenediamine tetraacetic acid, and 125I-iothalamate require only a
62 (
0.7)
GFR
166
(Scr/0.7) 0.329
(0.993)Age
62 (
0.7)
GFR
166
(Scr/0.7) 1.209
(0.993)Age
single injection and blood sample, and their use would appear to be
Male
more practical than the inulin infusion method. However, due to
80 (
0.9)
GFR
163
(Scr/0.9) 0.411
(0.993)Age
expense and practical limitations, neither inulin nor radiotracers are
80 (
0.9)
GFR
163
(Scr/0.9) 1.209
(0.993)Age
widely used in clinical practice and mainly serve as reference standards
White or other
to validate other methods.18-20 The relation between GFR and serum
Female
creatinine levels is curvilinear, which compromises its sensitivity in
62 (
0.7)
GFR
144
(Scr/0.7) 0.329
(0.993)Age
62 (
0.7)
GFR
144
(Scr/0.7) 1.209
(0.993)Age
early detection of chronic kidney disease (CKD). In patients with
Male
reduced muscle mass, GFR may be significantly reduced despite near
80 (
0.9)
GFR
141
(Scr/0.9) 0.411
(0.993)Age
normal serum creatinine. As an example, a serum creatinine of 1.49
80 (
0.9)
GFR
141
(Scr/0.9) 1.209
(0.993)Age
mg/dL may correspond to a GFR of anywhere from 20 to 90 mL/min/
Abbreviations: GFR, glomerular filtration rate; CrCl, clearance of creatinine;
1.73 m2.21 Therefore, serum creatinine alone cannot be used to esti-
Scr, serum creatinine; MDRD, Modification of Diet in Renal Disease; IDMS,
mate renal function.
isotope dilution mass spectrometry; CysC, cystatin-C; CKD-EPI, Chronic
Kidney Disease Epidemiology Collaboration formula.
Clearance of creatinine (CrCl) is defined as the volume of plasma
The Cockcroft formula can also be expressed per 1.73 m2 body
which is completely cleared of creatinine per time unit (usually mL/
surface area.
min). This volume of plasma is not an actual but a virtual volume. In
The original MDRD equations were validated with the modified kinetic Jaffe
method used to assess creatinine. Because this commonly used assay overes-
contrast to mass removal, which is largely dependent on the concen-
timates creatinine, a different prediction equation has to be used when the (more
tration of the solute, the clearance is, under given circumstances,
expensive) enzymatic assay traceable to the reference method GC-IDMS is used
to assess creatinine. Estimation of GFR by MDRD equations can easily be
concentration independent.21 In the assessment of renal function, the
performed by the use of specific websites (http://www.mdrd.com).
CrCl by timed (24-hour) urine collections has long been a mainstay in
diagnostics. However, CrCl may overestimate GFR due to the addi-
tional tubular secretion of creatinine, a mechanism which becomes
relatively more important when renal function declines. Timed urine
near-normal GFR range and in kidney transplant recipients, other
collections to assess CrCl may also have a role in the estimation of GFR
prediction equations based on serum cystatin-C values were also con-
in less advanced renal failure. However, a potential drawback is that
sidered as possibly more sensitive GFR surrogate markers.23 Estimat-
timed collections are often incomplete and the collection process may
ing GFR based on both serum cystatin-C and serum creatinine seems
be cumbersome for the patient.18,21 Therefore, CrCl has been largely
to be more accurate than estimations based only on serum creati-
replaced by the prediction formulas of GFR.
nine.23,24 A novel classification of CKD, based on CrCl, has been
Prediction equations of GFR based on serum creatinine values
recently produced (Table 2).22 MDRD formula is the current recom-
are often used for the definition of renal impairment: the Cockcroft-
mendation for the evaluation of CrCl. However, the Chronic Kidney
Gault and Modification of Diet in Renal Disease (MDRD) study
Disease Epidemiology Collaboration has recently proposed a new
equations are the most commonly used (Table 1).21,22 The MDRD
formula for the estimation of GFR,25 which seems to be more accurate
equation generally outperforms the Cockcroft-Gault equation, but
than the MDRD equation in CKD and in kidney transplant pa-
may still have a high level of bias, depending on creatinine assay
tients.25,26 This equation has not been categorically evaluated in pa-
calibration, and low precision with at best approximately 80% of
tients with MM.
estimated GFR in the accuracy range of 70% to 130% of measured
However, we have to distinguish between acute and chronic RI in
GFR even in patients with known CKD.18 Because Cockcroft-Gault
MM. Both the MDRD equation and the five stages of the CKD classi-
and MDRD equations have limitations, especially in the normal or
fication have been validated only in patients with CKD, and not in
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2011
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Dimopoulos et al
Table 2. Classification of Chronic Renal Disorders
PATHOPHYSIOLOGY OF RI IN MYELOMA
Stage of Renal
GFR
RI in MM results primarily from the toxic effects of monoclonal light
Impairment
Description
(ml/min/1.73 m2)
chains on the kidney, as well as other contributing factors, such as dehy-
1
Kidney damage with normal
90
or elevated GFR
dration, hypercalcemia, hyperuricemia, the use of nephrotoxic drugs (eg,
2
Kidney damage with mild
60-89
nonsteroid anti-inflammatory drugs, antibiotics, and contrast media),
reduction of GFR
and rarely myeloma cell infiltration or hyperviscosity.1,2 Cast nephropa-
3
Moderate reduction of GFR
30-59
thy is the main cause of RI in MM (approximately 90% of cases) and is
4
Severe reduction of GFR
15-29
characterized by tubular atrophy and tubular-interstitial fibrosis.30-34
5
Renal failure
15 or on dialysis
Proximal tubule cells may be also affected.35-38 Some patients with my-
NOTE. Stage 5 is also defined as ESRD, while stage 4 is defined as
eloma present with acute oliguric renal failure, which is often associated
pre-ESRD.
Abbreviations: GFR, glomerular filtration rate; ESRD, end-stage renal
with significant dehydration, with massive cast deposition in distal and
disease.
mainly in proximal tubules and with poor outcome.34
Amyloid deposit is another cause of RI in MM; the deposits are
fibrillar and consequently show positive Congo red staining.39 In
monoclonal immunoglobulin deposition disease (MIDD), the glo-
those with acute renal injury. Several patients with myeloma cast
merular deposits of immunoglobulin light or heavy chains are nonfi-
brillar and Congo red negative.40,41 Diagnosis requires renal biopsy with
nephropathy present with acute renal injury and rapid deterioration
ultrastructural studies. In amyloid light chain (AL) amyloidosis and
of GFR within a few days. In 2004, the Acute Dialysis Quality Initiative
MIDD, proteinuria is usually nonselective and albuminuria is usu-
group developed the RIFLE (risk, injury, failure, loss and end-stage
ally predominant.
kidney disease) system for the definition and staging of acute renal
We recommend careful assessment of a sample from a 24-hour
injury,27 while in 2007, some minor modifications to the RIFLE crite-
urine collection with urine protein electrophoresis and immunofix-
ria were proposed (Table 3).28 The RIFLE criteria have been exten-
ation. If significant albuminuria is detected, then AL amyloidosis or
sively validated in more than 550,000 patients worldwide29 but not in
MIDD should be considered and further evaluation is needed.
patients with myeloma.
We recommend that the MDRD formula be used for the evalu-
ation of RI in MM with stabilized serum creatinine level and these
PROGNOSIS AND REVERSIBILITY OF RENAL FAILURE
patients be classified in the five stages of RI according to the Kidney
Disease Improving Global Outcomes classification (Table 2). Novel
RI reflects advanced disease and high tumor burden in patients with
formulas, such as the Chronic Kidney Disease Epidemiology Collabo-
myeloma cast nephropathy, but not in those with light chain deposi-
ration equation or others based on both serum cystatin-C and serum
tion disease or AL amyloidosis, who usually show mild or moderate
creatinine, can be used in clinical trials to examine their utility in
marrow infiltration by plasma cells.11,42,43 In the recent years, progno-
the MM setting. In patients with acute kidney injury, the RIFLE
sis of patients with MM with RI has improved due to the availability of
and Acute Renal Injury Network criteria are likely to be more
more effective treatments for MM and improvements in supportive
appropriate to define the severity of RI but have to be validated in
care. Prognosis, however, remains tied to the reversibility of RI, al-
MM (Table 3).
though this has not been confirmed in all series.10-12 When the reversal
Table 3. RIFLE and AKIN Definitions
RIFLE
AKIN
RIFLE and AKIN Urine Output
Stage
Creatinine/GFR Criteria
Stage
Creatinine/GFR Criteria
Criteria
R
Scr increase
50% or GFR decrease
25%
I
Scr increase
50% or
0.3 mg/dL
0.5 mg/kg/h for 6 hours
I
Scr increase
100% or GFR decrease
50%
II
Scr increase
100%
0.5 mg/kg/h for 12 hours
F
Scr increase
200% or GFR decrease
75% or pCr
4.0
III
Scr increase
200% or pCr
4.0 mg/dL
0.3 mg/kg/hours for 24 hours
mg/dL with an increase
0.5 mg/dL
with an increase
0.5 mg/dL or RRT
or anuria for 12 hours
III
L
Complete loss of kidney function (need for RRT)
4
weeks
E
End stage kidney disease (need for RRT)
3 months
AKI
Abrupt (1-7 days) and sustained (
24 hours) reduction in
Abrupt (within 48 hours) reduction in
kidney function
kidney function defined by stage Ib
NOTE. The AKIN modifications of RIFLE criteria can be summarized as follows: broadening of the risk category of RIFLE to include increase in Scr of at least 0.3
mg/dL even if this does not reach the 50% threshold; setting a 48-hour window on the first documentation of any criteria; categorizing patients as failure if they are
treated with RRT regardless of what their Scr or urine output is at the point of initiation; AKIN also proposed that stages 1, 2 and 3 be used instead of R, I, and F.
Abbreviations: RIFLE, risk, injury, failure, loss and end-stage kidney disease; AKIN, Acute Renal Injury Network; GFR, glomerular filtration rate; Scr, serum
creatinine; pCr, plasma creatine; RRT, renal replacement therapy.
A baseline Scr is required. If a measured Scr is unavailable, the Acute Dialysis Quality Initiative recommend back-calculating the Scr using the Modification of Diet
in Renal Disease equation with an estimated GFR of 75 to 100 mL/min.
4978
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Renal Impairment in Multiple Myeloma
of RI is defined as a decrease in the serum creatinine level to lower than
effective for control of malignancy-related hypercalcemia, they can
1.5 mg/dL, the frequency of reversal of RI ranges from 20% in the past
further impair renal function and cause symptomatic hypocalcemia in
to 73% in most recent series.10,12 Blade et al reported three parameters
patients with acute renal failure and their use is discouraged in such
associated with recovery of renal function: serum creatinine lower
patients.48 The use of loop diuretics for the management of hypercal-
than 4 mg/dL, 24-hour urine protein excretion lower than 1g, and
cemia is also discouraged due to the enhancement of the cast forma-
serum calcium higher than 11.5 mg/dL.10 With the CKD classification,
tion in the renal tubules. Drugs that may contribute to renal damage,
new criteria for the improvement of renal function in MM have been
such as nonsteroid anti-inflammatory drugs, intravenous contrast
recently proposed.44,45 Renal complete response (CRrenal) was de-
dyes, aminoglycosides or other antibiotics that cause renal adverse
fined as sustained (ie, lasting at least 2 months) improvement of CrCl
events, should be avoided.2,47 Contrast media can be efficiently re-
from lower than 50 mL/min at baseline to
60 mL/min. Renal partial
moved from blood by hemodialysis. In general, dialysis immediately
response (PRrenal) was defined as sustained improvement of CrCl
after radiographic contrast studies has been suggested for two groups
from lower than 15 at baseline to 30 to 59 mL/min. Renal minor
of patients--those on chronic hemodialysis and those at very high risk
response (MRrenal) was defined as sustained improvement of baseline
for contrast nephropathy, such as patients with MM and RI.49
CrCl of lower than 15 mL/min to 15 to 29 mL/min or if baseline CrCl was
15 to 29 mL/min improvement to 30 to 59 mL/min. Based on these
Mechanical Approaches
criteria, Dimopoulos et al44 recently described a series in which 30% of 46
Mechanical means include long-term dialysis, plasmapheresis,
patients had CRrenal after treatment with bortezomib-based regimens.
and novel dialysis filters for the removal of free light chains. Long-term
The same group also reported that in 96 patients with MM who presented
dialysis is a worthwhile procedure for patients with MM and ESRD. If
with RI, CRrenal was achieved in 41% treated with conventional chemo-
we exclude patients with dialysis-dependent RI who die within the first
therapy plus dexamethasone, in 45% treated with immunomodulatory
2 months of therapy (approximately 30% of the total), then long-term
drugs­based regimens and in 71% treated with bortezomib-based regi-
dialysis in combination with conventional antimyeloma therapy can
mens. CRrenal plus PRrenal was observed in 47%, 51% and 82% of
lead to a median survival of approximately 2 years.2,47
patients treated with these therapies, respectively.46 In that series,
Plasma exchange has been used as a temporary method of reduc-
bortezomib-based regimens and CrCl higher than 30 mL/min were
ing serum free light chain levels in the first 1 or 2 weeks after diagnosis
the only factors independently associated with a higher probability
until a response to chemotherapy can occur. So far, two small prospec-
of achieving renal response (PR CRrenal).
tive studies have shown no clear benefit of plasma exchange.50,51 In the
We recommend the use of the novel proposed criteria for the
largest study to date, 97 patients with acute renal failure at the onset of
definition of renal reversibility in both clinical trials and every day
myeloma were randomly assigned to conventional chemotherapy
clinical practice as they better reflect the depth of renal response to
(melphalan and prednisone [MP] or vincristine, adriamycin, and
therapy than criteria based on serum creatinine measurements only.
dexamethasone [VAD]) plus 5 to 7 plasmaphereses with albumin
The MDRD equation is recommended for the estimation of GFR as
replacement or to conventional chemotherapy alone. The authors
presented in Table 4.
found no significant differences in the probability of death, dialysis
dependence, or GFR lower than 30 mL/min/1.73 m2 at 6 months.51
This result is in accordance with smaller studies in the field.52 How-
MANAGEMENT OF PATIENTS WITH MYELOMA WITH RI
ever, due to the small sample size and the wide 95% CI ( 8.3% to
29.1%), one cannot rule out the possibility of benefit in subsets of
Supportive Care
patients.51 There were also other limitations of these studies including the
Adequate hydration, urine alkalinization, and management of
fact that renal pathology was confirmed in only a small percentage of
hypercalcemia are important measures for the management of pa-
patients and MRrenal was not included as a response. This may explain
tients with myeloma with acute renal failure and can improve renal
other reports suggesting that myeloma patients who were treated with
function in a subset of patients.2,47 Although bisphosphonates are
chemotherapy and plasma exchange recovered renal function more fre-
quently than those treated only with chemotherapy.53
Based on the available data we do not recommend plasma ex-
change as a standard procedure for the management of renal failure in
Table 4. Criteria for the Definition of Renal Response to
patients with myeloma. However, in selected patients with acute renal
Antimyeloma Therapy
failure that is proven or strongly suspected to be related to light chain
Baseline eGFR
Best CrCl
Response
(ml/min/1.73 m2)
Response (mL/min)
cast nephropathy, some of the physicians perform plasma exchange
daily for the first few days. Further studies are needed to reveal possible
CRrenal
50
60
PRrenal
15
30-59
subsets of patients who may be benefited from this procedure.
MRrenal
15
15-29
The removal of free light chains with dialysis is another alterna-
15-29
30-59
tive approach and a new hemodialysis membrane that removes effi-
Abbreviations: eGFR, estimated glomerular filtration rate; CrCl, clearance of
ciently the circulating light chains has been recently developed. In a
creatinine; CRrenal, sustained (ie, lasting at least 2 months) improvement of
small study of 19 patients with cast nephropathy and dialysis-
CrCl from lower than 50 mL/min at baseline to
60 mL/min; PRrenal,
dependent acute renal failure, Hutchison et al54 evaluated the role of
sustained improvement of CrCl from lower than 15 at baseline to 30 to 59
mL/min; MRrenal, sustained improvement of baseline CrCl of lower than 15
extended hemodialysis using a high-cutoff dialyzer that removes large
mL/min to 15 to 29 mL/min or if baseline CrCl was 15 to 29 mL/min
quantities of free light chains in combination with antimyeloma ther-
improvement to 30 to 59 mL/min.
eGFR based on Modification of Diet in Renal Disease equation.
apy. The authors found sustained early reductions in serum free light
chain concentrations in 13 patients (median 85% reduction) half of
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Dimopoulos et al
whom became dialysis independent by 27 days. These patients had
on the basis of decreased baseline renal function. Similarly, VAD can
better survival than the six patients who did not achieve dialysis inde-
be used without dose adjustments, as vincristine and doxorubicin
pendence. Standard dialysis membrane does not achieve this effect.
dosage does not need reduction in renal impairment.60
However, although promising, these results need further evaluation in
well-designed clinical trials.
Systemic Therapy With Bortezomib-Based Regimens
Bortezomib is the first-in-class proteasome inhibitor with proven
Systemic Treatment With Conventional and
efficacy in both newly diagnosed and relapsed/refractory MM. Bort-
High-Dose Therapy
ezomib can be administered at the full approved dose and schedule in
The response rate to alkylator-based conventional chemotherapy
patients with impaired renal function. The pharmacokinetics of bort-
is lower in patients with MM with RI than in those with normal renal
ezomib are not affected by the degree of renal impairment, as the
function (40% v 60%).2,10 In the study by Alexanian et al, the admin-
istration of chemotherapy with alkylating agents, doxorubicin and
primary metabolic pathway of bortezomib is the oxidative deborona-
steroids produced recovery of renal function (defined as a sustained
tion by hepatic cytochrome P450 enzymes.63,64
decrease of creatinine to
1.4 mg/dL) in 51% of patients within a
Studies indicate that bortezomib is effective and safe in patients
median of 1.2 months. Light-chain myeloma and creatinine higher
with RI,65,66 and additionally, that it can produce improvements in
than 3.1 mg/dL were associated with a lower probability of recovery.1
renal function.67 In a subanalysis of the Study of Uncontrolled
The combinations of VAD, or cyclophosphamide and dexametha-
Multiple Myeloma Managed with Proteasome Inhibition Therapy
sone, or even dexamethasone alone are superior to melphalan-
(SUMMIT) and Clinical Response and Efficacy Study of Bort-
containing regimens because of their lower dependency on renal
ezomib in the Treatment of Relapsing Multiple Myeloma (CREST)
clearance and more rapid antimyeloma effect.2 In a series of 41 pa-
phase II studies, three (30%) of 10 patients with CrCl
30 mL/min
tients with MM with RI treated with high-dose dexamethasone-
demonstrated responses to treatment, compared with a 45% overall
containing regimens, renal failure reversed in 73%.12
response rate in patients with baseline CrCl higher than 80 mL/min.
High-dose chemotherapy (HCT) with autologous stem-cell
Discontinuation rates and adverse-event profiles were similar between
transplantation (ASCT) may be another option. In a series of 81
patients with CrCl higher than 80 mL/min or
50 mL/min (Table
patients with MM with renal failure from Arkansas group, including
5).65-69 In a report of the phase III Assessment of Proteasome Inhibi-
38 patients on dialysis, the transplant-related mortality (TRM) was
tion for Extending Remissions (APEX) study of bortezomib versus
reported to be 6% and 13% after a single or tandem ASCT, respec-
high-dose dexamethasone, the efficacy and safety was assessed in pa-
tively. Renal failure did not affect the quality of stem cell collections or
tients with relapsed MM with varying degrees of renal impairment.
engraftment, while melphalan 140 mg/m2 appeared as effective as
Time to progression (TTP), OS, and safety were comparable between
melphalan 200 mg/m2 as a preparative regimen with less toxicity.55 In
subgroups with CrCl
50 mL/min and CrCl higher than 50 mL/min,
an update of this series, the 5-year event-free survival and OS of 59
although there was a trend toward shorter TTP and OS in patients
patients on dialysis at the time of ASCT were 24% and 36%. Moreover,
with CrCl
50 mL/min. Response rates with bortezomib were similar
13 (24%) of 54 patients evaluable for renal function improvement
and time to response was very rapid (0.7 to 1.6 months) across the
became dialysis independent at a median of 4 months after ASCT.56In
different subgroups. Toxicity after bortezomib treatment was similar
a series from the Spanish Programa para el Estudio de la Terape´utica
in all subgroups but the incidence of adverse events and discontinua-
en Hemopatía Maligna (PETHEMA) group that included 14 patients
tions was higher in patients with moderate-to-severe versus mild/no
with RI at diagnosis and at transplant, the TRM was 29% and the
renal impairment.66 Concerning patients with ESRD, Chanan-Kahn
3-year OS was 49%.57 In a report from M. D. Anderson Cancer
et al, in a retrospective series of 24 patients with relapsed/refractory
Center, 15 (32%) of 46 patients with myeloma with RI (21% were
MM and dialysis-dependent renal failure, reported an overall re-
dialysis dependent) showed improvement of CrCl of at least 25%
sponse rate of 75% with 30% CR/nearCR. Three patients became
above baseline post-ASCT. TRM was 4% and 3-year PFS and OS were
dialysis independent after bortezomib therapy. Importantly, the tox-
36% and 64%.58
icity profile was similar to that reported in patients with normal renal
Melphalan clearance is renal function dependent as it is both
function treated with bortezomib.70 Ludwig et al71 reported the rever-
secreted and reabsorbed by the renal tubules. Previous pharmacoki-
sal of light chain-induced acute renal failure (LC-ARF) with
netic studies have demonstrated large interindividual variations in the
pharmacokinetic parameters.59-61 The administration of standard-
bortezomib-based therapy in five of eight patients with MM. The same
dosage melphalan in patients with RI is accompanied by higher hema-
group reported the effect of bortezomib, doxorubicin, and dexameth-
tologic toxicity.56,62 Based on available data, we recommend a
asone regimen on the reversal of LC-ARF. They found that 42 (72%)
reduction of oral melphalan standard dosage (0.15 to 0.25 mg/kg/d for
of 58 patients achieved a renal response (36% CRrenal, 9% PRrenal,
4 to 7 days) by 25% when the CrCl is between 15 and 60 mL/min (0.11
and 27% MRrenal), and three of nine dialysis-dependent patients
to 0.19 mg/kg/d for 4 to 7 days) and by 50% when the CrCl is lower
became dialysis independent. Renal response was observed at a me-
than 15 mL/min or the patient is on hemodialysis (0.0175 to 0.125
dian time of 38 days, while the median time to CRrenal was 111 days.72
mg/kg/d for 4 to 7 days). For high-dose melphalan, 140 mg/m2 should
Blade et al reported that the response rate and median TTP were
be used when CrCl is lower than 60 mL/min or the patient is on
comparable in patients with RI (n
193) treated with bortezomib
hemodialysis. Regarding cyclophosphamide and its metabolites, their
plus pegylated liposomal doxorubicin compared with patients treated
excretion in the urine is similar in patients with and without renal
with bortezomib alone. There was an improvement of renal function
failure.59 Therefore, the amount of cyclophosphamide and metabolite
for patients with RI in both treatment arms; however, patients with RI
that are measured in the urine do not warrant dose adjustment solely
were at an increased risk of a drug-related serious adverse event.67
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Renal Impairment in Multiple Myeloma
Table 5. Effect of Bortezomib-Based Regimens on Patients With Multiple Myeloma and RI
No. of
Study
Patients
Study Drug Dosage
Efficacy Data
Discontinuation Rate
SAE Rate
Renal Response
Jagannath et al65 SUMMIT and
256
B: 1.0 or 1.3 mg/m2 on days
Percentage of Patients With CrCl; (No. of evaluable
Percentage of CrCl
Percentage of CrCl
CREST (phase II studies
1,4,8,11 of a 21-d cycles for
patients)
(ml/min)
(ml/min)
in relapsed/refractory
at least 6 cycles
myeloma)
dexamethasone: 20 mg on
30
30-50
51-80
80
50
51-80
80
50
51-80
80
the day of and the day after
30 (n
10) 23 (n
42) 33 (n
99) 45 (n
105)
38
22
28
60
51
41
In 10 patients with CrCl
30 mL/min,
B administration
a reduction in serum creatinine
was observed: from 3.1 to 2.1
mg/dL within the 3 first cycles of
therapy
San Miguel et al66 APEX
669
B: 1.3 mg/m2 on days 1, 4, 8, 11
Overall Response Rate
NE
(phase III study in
for eight 3-week cycles and
relapsed/refractory
then on days 1, 8, 15, 22 for
B Arm (%)
B Arm (%)
myeloma)
three 5-week cycles
(n
333) or dexamethasone: 47 (n
15) 37 (n
43) 40 (n
137) 36 (n
118)
38
35
37
49
39
46
40 mg on days 1-4, 9-12 and
Dexamethasone Arm
17-20 for four 5-week cycles
and then on days 1-4 for five
10 (n
10) 17 (n
52) 25 (n
118) 11 (n
123)
4-week cycles (n
336)
TTP (months)
BArm
4.2
5.6
6.2
6.3
Dexamethasone Arm
2.1
2.9
4.9
2.8
OS (months)
BArm
22.0
22.8
30.0
NE
Dexamethasone Arm
17.4
12.6
24.3
29.1
Blade et al67
646
B 1.3 mg/m2 on days 1, 4, 8, 11
CrCl ml/min (No. of evaluable patients)
NE
CrCl (ml/min)
NE
(retrospective
of each 3-week cycle
analysis of
(n
322) or the same B
60 (n
193)
60 (n
453)
60 (n
60 (n
a phase III
regimen plus IV PLD 30
188)
448)
trial in
mg/m2 on day 4 (n
324) of
Overall Response Rate
relapsed/refractory
each cycle.
patients
B PLD: 49% (n
88)
47% (n
215)
with renal
B only: 42% (n
94)
44% (n
216)
impairment,
TTP (months)
CrCl
60
mL/min)
B PLD: 11.0
9.0
B only: 6.6
6.3
Morabito et al68 (retrospective
117
BD standard dosage (n
54) or
CrCl (ml/min; No. of evaluable
Percentage of
Percentage of CrCl
Renal response (defined as
analysis including both
BD in combination with other
patients)
Patients With CrCl
(ml/min)
normalization of GFR) was
newly diagnosed and
agents (n
63)
documented in 41% of patients
relapsed/refractory MM)
30
30-50
51-80 (n
12)
30
30-50 51-80
30
30-50
51-80
after a median of 2.3 months;
(n
82)
(n
23)
11
5
0
65
52
50
more frequently in those with mild
to moderate RI (67% and 78%,
Overall Response Rate (%)
respectively, v 27% for patients
69.5
74
75
with severe RI; P
.001); in three
of 14 patients on dialysis, renal
BD v BD
other drug: 68.5% v 80% (P
NS)
replacement therapy was
discontinued after 1, 1 and 4
months of therapy including B
Dimopoulos et al69, VISTA trial
682
VMP: B 1.3 mg/m2, days
Percentage of Patients With CrCl (No. of evaluable
CrCl
CrCl
CRrenal PRrenal
(phase III study in newly
1,4,8,11,22,25,29,32, cycles
patients)
(ml/min)
(ml/min)
VMP: 44% (49/111)
diagnosed patients)
1-4 & days 1,8,22,29, cycles
MP: 35% (41/116)
5-9, plus melphalan 9 mg/m2
30
31-50
50
30
31-50
50
30
31-50
50
Median Time to Renal Reversal
and prednisone 60 mg/m2,
Overall Response Rate (%)
VMP: 11
17
14
VMP: 63
50
42
(months)
days 1-4, cycles 1-9
MP: 27
17
12
MP: 40
41
43
VMP: 2.1
(n
344) or MP (n
338)
MP: 2.4
VMP:
74 (n
19) 67 (n
92) 72 (n
229)
MP:
47 (n
15) 45 (n
101) 29 (n
221)
Median Time to First Response (months)
VMP
1.0
1.1
1.4
MP
3.5
3.3
4.9
Median TTP (%)
VMP
19.8
24.0
NE
MP
14.5
16.1
18.0
2-Year OS (%)
VMP
65.5%
70.9%
81.4%
MP
64.6%
59.8%
72.4%
Abbreviations: RI, renal impairment; SAE, serious adverse event; SUMMIT, Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy; CREST, Clinical
Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma; B, bortezomib; CrCl, creatinine clearance; PLD, pegylated liposomal doxorubicin; GFR,
glomerular filtration rate; APEX, Assessment of Proteasome Inhibition for Extending Remissions; NE, not evaluated; TTP, time to progression; OS, overall survival; CR, complete
response; PR, partial response; MR, minimal response; VMP, bortezomib, melphalan, prednisone; MP, melphalan and prednisone.
Patients who received at least six cycles were allowed to switch to less intensive schedules of bortezomib-- either twice weekly for 2 weeks with a 17-day rest
period or once weekly for 4 weeks with a 13 to 20-day rest period.
Includes CR PR MR.
Includes CR PR.
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Dimopoulos et al
Other retrospective studies confirmed the beneficial effect of bort-
methasone alone in patients with relapsed MM, efficacy and safety
ezomib on RI in the relapsed/refractory setting.44,68 In newly diag-
were assessed in patients with normal renal function and with mild,
nosed patients who are not eligible for an autologous transplantation,
moderate, and severe RI (assessed as CrCl
80, 50 to 79, 30 to 49,
Dimopoulos et al has recently reported the results of the subgroup
and
30 mL/min, respectively). The renal subgroups did not signif-
analysis of the Velcade as Initial Standard Therapy in Multiple My-
icantly differ regarding overall response rate (50% to 63%) or response
eloma: Assessment With Melphalan and Prednisone (VISTA) phase
quality (
very good PR: 30% to 38%). In all renal subgroups, except
III trial, regarding the effect of the VMP (bortezomib, melphalan,
for patients with severe RI, TTP, PFS, and OS did not differ signifi-
prednisone) combination on RI. Response rates were higher and TTP
cantly compared to patients with normal renal function. Patients with
and OS were longer with VMP versus MP across renal cohorts. RI
severe RI experienced an increased incidence of thrombocytopenia,
reversal, defined as a baseline eGFR lower than 50 improving to higher
required more frequent lenalidomide dose reductions or interrup-
than 60 mL/min, was seen in 49 (44%) of 111 patients receiving VMP
tions, and had shorter OS than those without RI. Improvement in
versus 40 (34%) of 116 of those receiving MP. Younger age (
75
CrCl by at least one level was documented in 68% of patients.79
years) and eGFR
30 mL/min were independently associated with
Similarly, in a series of patients with relapsed/refractory MM who
higher reversal rates. In both arms, rates of grade 4 and 5 adverse
received RD, three (25%) of 12 patients with RI (CrCl
50 mL/min)
events appeared higher in patients with RI; with VMP, rates of discon-
achieved a CRrenal and two (16%) achieved a MRrenal,80 while in a
tinuation or bortezomib dose reduction due to AEs did not appear to
Spanish retrospective analysis of 15 dialysis-dependent MM patients
be affected (Table 5).69 Bortezomib was also shown to reduce
who received RD, 57% achieved a response and one patient became
cystatin-C levels, a marker of GFR and thereby an early marker for RI,
independent of dialysis.81 RD was shown to be an active rescue treat-
in patients with relapsed MM.14
ment in a patient with renal failure due to cast nephropathy failing to
bortezomib-based induction treatment.82 In a phase II study of newly
Systemic Therapy With Immunomodulatory
diagnosed patients with MM treated with RD, baseline CrCl
40
Drugs­Based Regimens
mL/min was associated with grade
3 myelosuppression and an
Thalidomide is the first immunomodulatory drug with proven
8.4-fold increased likelihood of lenalidomide dose reduction com-
activity in MM. Thalidomide pharmacokinetics are not affected by RI,
pared with patients with CrCl higher than 40 mL/min.83
and thus, no dose reduction is required in patients with MM with RI.73
There are limited data for the efficacy of thalidomide-based regimens
in such patients with MM. In 20 patients with relapsed/refractory MM
RECOMMENDATIONS FOR THERAPY
and RI (defined as serum creatinine
2 mg/dL), treatment with
thalidomide alone (n
8) or thalidomide plus dexamethasone
High-dose dexamethasone-based therapies are highly active in pa-
(n
12) resulted in 45% PR and 30% MR. The median duration of
tients with myeloma with renal impairment. Available data support
response was 7 months, while 12 of 15 responding patients had im-
the safety and efficacy of bortezomib-based therapies in this setting
proved renal function defined as serum creatinine lower than 2 mg/
and thus bortezomib plus dexamethasone is the recommended treat-
dL, while two additional patients on chronic hemodialysis showed a
ment for patients with myeloma with RI of any grade. Bortezomib
reduction of serum creatinine. Toxicities were similar to those re-
should be started at the standard dose of 1.3 mg/m2 on days 1, 4, 8, and
ported with thalidomide in patients with normal renal function.74
11 of a 3-week cycle and dexamethasone at a dose of 20 mg on the day
Kastritis et al also observed reversal of renal failure with thalidomide,
of and the day after bortezomib administration. In elderly patients
in combination with high-dose dexamethasone, with or without bort-
who receive first-line therapy and have renal impairment, VMP is
ezomib, in 80% of previously untreated patients.12 Treatment with
another option at the reported dosage (Table 5). Thalidomide maybe
thalidomide has been associated with severe hyperkalemia in occa-
used with caution in the absence of results from randomized trials in
sional patients with RI, particularly those undergoing dialysis.75,76
this setting. A triple combination of bortezomib, thalidomide, and
Based on this data and in the absence of randomized results showing
dexamethasone may be considered in the context of a clinical trial.
that thalidomide adds a benefit in patients with myeloma with renal
Lenalidomide is a feasible and effective treatment option for patients
impairment, its use should be discouraged outside of the context of a
with mild-to-moderate renal impairment, if it is used at the recom-
carefully designed clinical trial with intensive electrolyte monitoring to
mended reduced dose based on renal function. However, we have to
maximize patient safety.
mention that these reduced dosages of lenalidomide have been re-
Lenalidomide is another effective agent for the management of
sulted by pharmacokinetic studies and modeling and not from studies
MM. It is mainly excreted by the kidneys, through both glomerular
of patients with myeloma with renal impairment. Such studies are
filtration and active tubular secretion.77 Based on pharmacokinetic
now underway and their results are highly anticipated. HDT/ASCT
studies, the following dose-adjustments have been recommended:
can be an option for such patients; high-dose regimen should consist
reduce the dose to 10 mg/d in patients with CrCl between 30 and 50
of melphalan 140 mg/m2 and the procedure should be restricted to
mL/min, to 15 mg every other day in patients with CrCl lower than 30
patients younger than 60 years of age with chemotherapy-sensitive
mL/min not on dialysis, and to 5 mg once daily, with postdialysis
disease and good performance status.
dosing on days of dialysis, in patients requiring renal replacement.78
The information for the effect of lenalidomide-based regimens on
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS
myeloma patients with RI is limited because in the majority of phase II
OF INTEREST
to III studies serum creatinine of higher than 2 mg/dL was an exclusion
criterion. In a combined analysis of the MM-009 and MM-010 phase
Although all authors completed the disclosure declaration, the following
III studies of lenalidomide and dexamethasone (RD) versus dexa-
author(s) indicated a financial or other interest that is relevant to the subject
4982
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---

Renal Impairment in Multiple Myeloma
matter under consideration in this article. Certain relationships marked
Orthobiotec, Canada; Joan Blade´, Janssen Cilag, Celgene; Orhan Sezer,
with a "U" are those for which no compensation was received; those
Celgene, Ortho-Biotech; Antonio Palumbo, Celgene, Janssen Cilag;
relationships marked with a "C" were compensated. For a detailed
Jean-Luc Harousseau, Celgene, Janssen Cilag; Michele Cavo, Celgene,
description of the disclosure categories, or for more information about
Janssen, Millennium Pharmaceuticals, Novartis; Je´sus San Miguel, Janse
ASCO's conflict of interest policy, please refer to the Author Disclosure
Cilag, Celgene, Milleniun Research Funding: Ruben Niesvizky, Celgene,
Declaration and the Disclosures of Potential Conflicts of Interest section in
Millennium, Onyx; Joan Blade´, Janssen Cilag, Celgene; Raymond L.
Information for Contributors.
Comenzo, Celgene, Genzyme; Orhan Sezer, Ortho-Biotech; Pieter
Employment or Leadership Position: None Consultant or Advisory
Sonneveld, Celgene, Ortho-Biotech Expert Testimony: Je´sus San Miguel,
Role: Meletios A. Dimopoulos, Celgene (C), Ortho-Biotech (C),
Jansen Cilag (U), Celgene (U) Other Remuneration: Ruben Niesvizky,
Millenium (C); Ruben Niesvizky, Celgene (U), Millennium (U), Onyx
Speaker for Millennium, Speaker for Celgene
(U); Raymond L. Comenzo, Millennium (C), Elan (C); Orhan Sezer,
Celgene (C), Ortho-Biotech (C); Antonio Palumbo, Celgene (C), Janssen
Cilag (C); Paul G. Richardson, Millennium (C), Celgene (C), Johnson
AUTHOR CONTRIBUTIONS
and Johnson (C), Novartis (C); Pieter Sonneveld, Celgene (C),
Ortho-Biotech (C), Millenium (C); Michele Cavo, Celgene (C), Janssen
Conception and design: Meletios A. Dimopoulos
(C), Millennium Pharmaceuticals (C), Novartis (C); Brian G.M. Durie,
Collection and assembly of data: Meletios A. Dimopoulos,
Celgene (C), Millennium Pharmaceuticals (C); Je´sus San Miguel, Jansen
Evangelos Terpos
Cilag (C), Celgene (C), Milenium (C) Stock Ownership: None
Data analysis and interpretation: Meletios A. Dimopoulos,
Honoraria: Meletios A. Dimopoulos, Celgene, Ortho-Biotech,
Evangelos Terpos
Millenium; Evangelos Terpos, Janssen-Cilag; Sundar Jagannath,
Manuscript writing: All authors
Millennium Pharmaceuticals, Celgene, Merck, Onyx Pharma, Proteolix,
Final approval of manuscript: All authors
12. Kastritis E, Anagnostopoulos A, Roussou M,
sis of 3,418 individuals with CKD. Am J Kidney Dis
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2011
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Clinical Oncology. All rights reserved.

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