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August 2011, Supplement to Volume 15, Number 4
Article
Renal Complications in Multiple Myeloma and Related Disorders: Survivorship
Care Plan of the International Myeloma Foundation Nurse Leadership Board
Beth M. Faiman, MSN,
APRN-BC, AOCN®, Patricia Mangan, APRN, BC,
Jacy Spong, RN, BSN, OCN®,
Joseph D. Tariman, PhD, APRN, BC, and
the International Myeloma
Foundation Nurse Leadership Board
Kidney
dysfunction is a common clinical feature of symptomatic multiple myeloma. Some
degree of renal insufficiency or renal failure is present at diagnosis or will
occur during the course of the disease and, if not reversed, will adversely
affect overall survival and quality of life. Chronic insults to the kidneys
from other illnesses, treatment, or multiple myeloma itself can further damage
renal function and increase the risk for additional complications, such as
anemia. Patients with multiple myeloma who have light chain (Bence Jones protein)
proteinuria may experience renal failure or progress to end-stage renal disease
(ESRD) and require dialysis because of light chain cast nephropathy. Kidney
failure in patients with presumed multiple myeloma also may result from
amyloidosis, light chain deposition disease, or acute tubular necrosis caused
by nephrotoxic agents; therefore, identification of patients at risk for kidney
damage is essential. The International Myeloma Foundation’s Nurse Leadership
Board has developed practice recommendations for screening renal function,
identifying positive and negative contributing risk and environmental factors,
selecting appropriate therapies and supportive care measures to decrease
progression to ESRD, and enacting dialysis to reduce and manage renal complications
in patients with multiple myeloma.
At a Glance
·
All patients with multiple myeloma have or are at risk for developing
kidney dysfunction.
·
Many inherent and acquired disorders can further place patients at risk
for renal disease.
·
Nurses should be aware of monitoring and assessments to preserve kidney
function in patients with multiple myeloma.
Renal
dysfunction is one of the common clinical features of symptomatic multiple
myeloma at presentation or throughout the course of the disease (Rajkumar &
Dispenzieri, 2008; Rajkumar & Kyle, 2005). Studies have shown that the
presence of renal failure indicates a higher tumor burden and, consequently,
more aggressive disease (Dimopoulos, Kastritis, Rosinol, Blade, & Ludwig,
2008). Therefore, patients who are diagnosed with renal insufficiency should be
treated aggressively because reversal of this condition results in survival
outcomes similar to those of patients who have normal renal function at
diagnosis (Rajkumar & Kyle, 2005; Tariman & Faiman, 2011).
Patients
may experience several types of renal failure. The National Kidney Foundation
(NKF) clinical practice guidelines (NKF, 2010) define renal failure as serum
creatinine levels of greater than 3 mg/dl. At least 20%–60% of patients will
present with renal insufficiency or renal failure at some point in their
disease (Blade et al., 1998; Tariman & Faiman, 2011), which in turn may
negatively affect survival if not reversed. In addition, chronic insults to the
kidneys (see Figure 1) from other illnesses,
treatment, or the myeloma itself may have further negative impact on renal
function.
The
cost of care for patients with multiple myeloma is enormous (Cook, 2008; van
Agthoven et al., 2004). Costs associated with patients in the United States who
require dialysis are difficult to quantify. However, an in-house evaluation of
patients requiring chronic dialysis at the Royal Preston Hospital in the United
Kingdom was performed, and results indicated that treatment of patients with
myeloma who have kidney dysfunction is 5%–33% more expensive than treatment of
those patients without myeloma (Coward, 1989). The extra cost is attributed
primarily to the greater number and longer duration of hospital admissions for
infection (Coward, 1989).
Conditions
that complicate the treatment of patients with multiple myeloma include older
age at presentation; in older adult patients, renal clearance may be reduced by
35%–50% in the absence of renal disease as a normal aspect of aging (Dimopoulos,
Alegre, et al., 2010). Other complicating factors include multiple coexisting
morbidities, such as hypertension, diabetes, or other chronic health conditions
(Rajkumar & Dispenzieri, 2008). Patients may experience renal failure or
progress to end-stage renal disease (ESRD) and dialysis because of light chain
cast nephropathy (i.e., damage to the kidneys as a result of the light chain
paraprotein). Kidney failure in patients with a presumptive diagnosis of
multiple myeloma also may be a result of damage similar to other disorders
where a monoclonal paraprotein is secreted. These include light chain
amyloidosis (AL), light chain deposition disease (LCDD), monoclonal
immunoglobulin deposition disease (MIDD), or acute tubular necrosis (ATN) from
the use of nephrotoxic agents in the setting of monoclonal gammopathy (Leung et
al., 2008). Because renal disease in patients with multiple myeloma is
heterogeneous, careful attention must be paid when selecting an appropriate
treatment to decrease progression to ESRD and dialysis, which are associated
with shortened overall survival (Blade et al., 1998; Blade & Rosinol,
2005).
Clinicians
have the ability to identify patients at risk for kidney damage as a result of
multiple myeloma and to institute preventive and therapeutic interventions;
despite this, long-term negative effects still may result. The authors’ goal is
to describe the impact of and screening for kidney disease, examine
contributing risk and environmental factors that may affect renal function, and
provide recommendations to reduce and manage renal complications in patients
with multiple myeloma. Adequate screening for acute or insidious development of
kidney dysfunction is essential to these patients for early intervention to
prevent long-term complications.
Clinical Presentations of Renal Insufficiency
Renal
insufficiency is characterized by an elevated serum creatinine (normal range:
0.7–1.4 mg/dl). Other associated signs and symptoms include anemia, fatigue,
fluid and electrolyte imbalances, and light chain proteinuria. In most studies,
a serum creatinine concentration of 2 mg/dl or greater is used to define the
presence of renal dysfunction in patients newly diagnosed with multiple myeloma
(Rajkumar & Dispenzieri, 2008). Reduced glomerular filtration rate (GFR) of
less than 60 ml per minute per 1.73 m2 of body surface area calculated using
the Modification of Diet in Renal Disease formula (Hallan, Asberg, Lindberg,
& Johnsen, 2004) is indicative of renal dysfunction and is considered a
clinically acceptable method of measurement (Dimopoulos, Terpos, et al., 2010;
Kooman, 2009). Hydration status should be taken into account as temporary
elevations in serum creatinine or decline in GFR may be seen in patients
experiencing acute dehydration as a result of nausea and vomiting, infection,
hypercalcemia, or nonsteroidal anti-inflammatory drugs (NSAIDs) (Knudsen,
Hjorth, Hippe, & the Nordic Myeloma Study Group, 2000).
Clinical
presentations largely depend on the pathogenesis of renal dysfunction. For
example, nephrotic range proteinuria without significant renal impairment,
orthostatic hypotension, and thickening of cardiac walls may indicate systemic
AL (Rajkumar & Dispenzieri, 2008). Immunofixation showing a monoclonal
protein is strong evidence of AL or LCDD in the presence of nephrotic syndrome
(Gertz, 2002; Leung et al., 2008).
Since
2004, a nephelometric assay for serum free light chains (sFLC) has been used as
a quantitative marker in the diagnosis and evaluation of patients with
nonsecretory multiple myeloma (Dispenzieri et al., 2009). In patients with
nonsecretory multiple myeloma, measurable amounts of monoclonal protein are not
secreted in the serum and/or urine, which provides a challenge for monitoring
disease status. The sFLC assay relies on an imbalance between kappa and lambda
light chains and is a surrogate marker for monoclonality (Bradwell et al.,
2009; Dispenzieri et al., 2009). Several studies have evaluated the validity of
the sFLC assay since its inception. One group was able to identify a light
chain imbalance in 19 of 28 patients with nonsecretory myeloma (Drayson et al.,
2001). In addition, abnormal sFLC ratios have been linked to a higher risk of
progression from smoldering or asymptomatic myeloma to active multiple myeloma
(Dispenzieri et al., 2008). A report by Kuhnemund et al. (2009) described 10
patients who appeared to have stable multiple myeloma as judged by conventional
monitoring of intact immunoglobulin levels. However, when followed over a
period of four years, these patients developed severe organ dysfunction as a
consequence of initially undetected light chain progression, termed free light
chain escape (Kuhnemund et al., 2009). Classic diagnostics, such as
electrophoresis and quantitative immunoglobulin measurement, proved futile to
detect light chain progression, whereas sFLC were reliable markers (Kuhnemund
et al., 2009).
Light
chain deposition disease is characterized by renal failure with nephrotic range
proteinuria and usually kappa light chains. Lambda light chain proteinuria
commonly is seen in AL (Rajkumar & Kyle, 2005). Fanconi syndrome is a
disorder of proximal tubular transport, leading to urinary excretion of amino
acids, glucose, bicarbonate, uric acid, phosphate, potassium, and low molecular
weight proteins. The presence of hypophosphatemia, hypokalemia, hypouricemia,
and glycosuria in a patient with normal serum glucose is strongly suggestive of
Fanconi syndrome (Bridoux et al., 2005).
The Long-Term Effects of Multiple Myeloma on Renal Function
Unfortunately,
by the time many patients have been diagnosed with multiple myeloma, mild to
moderate kidney damage may have already occurred. Therefore, nurses must be
aware of the pathogenesis of renal failure in myeloma, disorders similar to
multiple myeloma, and monitoring strategies to employ to prevent further kidney
damage.
Pathogenesis of Renal
Insufficiency in Myeloma
Cast
nephropathy is the most common cause of damage to the kidneys as a result of
myeloma cell deposition, also called myeloma
kidney. Protein casts appear on
microscopic evaluation and essentially clog the kidney tubes. The casts are
surrounded by multinucleated giant cells located in the distal and collecting
tubules. These large, dense, tubular casts can precipitate in the tubules and
obstruct and rupture the tubular epithelium. Tubulointerstitial damage may
occur in the form of flattened tubular cells, degeneration with necrosis, and
stripping away of the tubular basement membrane, leading to tubuloepithelial
cell atrophy and interstitial fibrosis (Dimopoulos et al., 2008; Leung et al.,
2008).
The
glomerulus is responsible for filtering immunoglobulin light chains before the
light chains are catabolized or excreted in the urine. Light chains present in
the urine may overwhelm the proximal tubules’ ability to catabolize the
proteins. As proteins reach the nephrons, light chains may combine with
Tamm-Horsfall mucoprotein, leading to cast formation (Dimopoulos et al., 2008).
The process is manifested as large casts obstructing the tubules, which may
lead to increased serum creatinine levels, decreased GFR, and increased risk
for further deterioration of renal function (Gertz, 2005).
Acute Tubular Necrosis
ATN
can be precipitated by dehydration in the presence of kappa or lambda light
chains that may deposit in the kidney, as described earlier. The use of loop
diuretics also may contribute to cast formation and increased serum creatinine
levels. Vasoconstriction as a result of hypercalcemia and decreased blood flow
from the kidneys as a result of the use of NSAIDs or aminoglycosides also may
damage the kidneys (Tariman & Faiman, 2011).
Amyloidosis
AL
is a disease characterized by the deposition of amyloid fibrils that consist of
monoclonal light chains in various tissues of the body, often leading to organ
dysfunction. Amyloid is a fibrillar structure that most commonly deposits in
the heart, kidneys, nervous system, or gastrointestinal tract (Gertz, 2002).
Symptoms
at presentation can be vague and depend on the affected organ, which often
makes this disease difficult to diagnose. Clinical presentation may include
nephrotic syndrome, congestive heart failure, peripheral neuropathy,
macroglossia, periorbital purpura, or hepatomegaly (Gertz, 2002). If AL is
suspected, a biopsy should be conducted to confirm the diagnosis. Subcutaneous
fat (fat pad biopsy), rectal, renal, heart, or liver biopsy with positive Congo
red staining confirms the diagnosis of AL (Haroun et al., 2003). In addition, a
bone marrow aspirate and biopsy should be performed to demonstrate the presence
of monoclonal plasma cells (Gertz, 2002).
In
the kidney, amyloid deposits are predominantly found within the glomeruli
(Dimopoulos et al., 2008). Patients usually present with significant
proteinuria, but not always with renal failure. Progression to renal failure
can be slow (Rajkumar & Dispenzieri, 2008).
Light Chain Deposition
Disease
In
LCDD, diagnosis is supported by immunofluorescence and electron microscopy.
Linear peritubular deposits of monotypic light chains usually are found, but
these deposits also are found along the basement membrane, mesangial nodules,
Bowman’s capsule, vascular structures, and in the interstitium (Dimopoulos et
al., 2008). In addition to the glomerular findings, the presence of
interstitial fibrosis is a frequent finding. The pathology of light chain
deposition disease differs from amyloid; these deposits have a granular rather
than fibrillar structure. LCDD usually consists of kappa light chains, which do
not stain with Congo red (Herrera, Poblet, Cabrera, Pedrero, & Alonso,
2008), and the deposits are typically found in the renal tubular basement
membranes (Gertz, 2005).
Clinical
presentation includes nephrotic syndrome, anemia, and, eventually in almost all
cases, renal failure. In LCDD, kidney involvement is frequently part of a more
diverse and complex clinicopathologic picture when compared with AL. Diagnosis
of LCDD requires a renal biopsy (Dimopoulos et al., 2008). Both LCDD and renal
AL have poor prognoses; however, newer therapies such as bortezomib and
lenalidomide in combination with dexamethasone or prednisone have demonstrated
efficacy in the treatment and maintenance setting. Autologous stem cell
transplantation also may be considered in patients with AL or LCDD (Dimopoulos
et al., 2008; Rajkumar & Dispenzieri, 2008).
Diagnosis of Renal Insufficiency
Renal
insufficiency is evidenced by serum creatinine levels greater than 2 mg/dl; it
may improve and even resolve in some patients if detected early and treated
appropriately. Electrophoresis and immunofixation of serum and urine (an
aliquot from a 24-hour urine collection) are necessary. Electrolytes and serum
creatinine should be measured. Complete blood count (CBC) testing may identify
anemia secondary to renal failure. Baseline and periodic monitoring of sFLC
assays in patients with free light chain escape is important (Dispenzieri et
al., 2008).
Impact of Kidney Dysfunction on Multiple Myeloma Therapeutics
and Risk Factors
Elevated
serum calcium levels (i.e., hypercalcemia) can lead to ATN and renal failure.
Therefore, reversal of hypercalcemia with hydration, corticosteroids, and
bisphosphonates is essential. Reducing tumor burden by initiating myeloma
treatment, such as bortezomib with or without high-dose dexamethasone pulses,
may be effective if renal insufficiency is related to myeloma (Rajkumar &
Dispenzieri, 2008).
The
efficacy of plasmapheresis in improving renal function has not been
demonstrated conclusively in the few small-scale studies that have been
conducted (Clark et al., 2005; Clark & Garg, 2008). Dialysis is indicated
if the patient’s GFR is critically low (estimated GFR 15 ml per min per 1.73 m2
or below) and if symptomatic uremia is present (Hutchison et al., 2009).
Extended hemodialysis using high-cutoff dialyzers may effectively remove sFLC
and can lead to improved renal function (Hutchison et al., 2009).
Factors to Consider in
Relapsed Myeloma
Despite
therapy advancements made since the early 2000s that have increased survival
rates, multiple myeloma remains incurable (National Comprehensive Cancer
Network [NCCN], 2010b). A malignant clone eventually will re-emerge and relapse
may occur along with renal insufficiency. As a result, nurses need to consider
the safety of novel agents in patients with renal insufficiency. Agents such as
bortezomib, thalidomide, and doxorubicin alone or in combination with steroids
generally are well tolerated (Chanan-Khan et al., 2007, 2009). Lenalidomide can
be given to patients with renal insufficiency or renal failure with dose modifications,
as discussed later in this article. Other agents such as cyclophosphamide and
melphalan also generally are well tolerated by patients with renal
insufficiency, but the dose of melphalan may be reduced based on the
clinician’s judgment (Celgene Corp., 2004).
Patients
with myeloma often experience renal insufficiency because of disease
progression. Although dexamethasone pulses may assist in reversing renal
failure from hypercalcemia or disease progression, the overall benefit often is
not sustained. Most practitioners will use bortezomib in combination with
dexamethasone (Kastritis et al., 2007). The advent of novel treatments, using
combination therapies to improve progression-free survival, offers options to
treat patients at the time of relapse even in the setting of decreased renal
function (NCCN, 2010b).
Additional Risk Factors
The
NKF (2010) identified persons at increased risk for chronic renal disease,
including those with diabetes, cardiovascular disease, hypertension, age
greater than 60 years, racial or ethnic minority status in the United States,
and those with a family history of chronic kidney disease. Patients with
myeloma are at an increased risk of renal failure not only from their myeloma,
but also from age and these other risk factors. Diabetes and hypertension are
the leading causes of ESRD, with diabetes mellitus as the number one cause of
kidney failure. About half of all new patients on dialysis have diabetes,
making it the fastest growing risk factor for kidney disease. Blood pressure
and blood sugar control can help prevent progression to ESRD (Firestone &
Mold, 2009; O’Seaghdha et al., 2009). Common risk factors for kidney
dysfunction in patients with myeloma are listed in Figure
2.
Hypertension
is both a cause and a complication of chronic kidney disease and should be
treated carefully and controlled in all patients. Penfield (2006) discussed how
weight control, exercise, smoking cessation, and medications for controlling
blood pressure may prevent or slow the progression to kidney failure in
patients with multiple myeloma.
Because
kidney function is reduced in older adults, the older the patient is, the
greater he or she is at risk for developing renal insufficiency (Faiman,
Bilotti, Mangan, Rogers, & the International Myeloma Foundation Nurse
Leadership Board, 2008). Renal clearance may be reduced by a third to a half in
older adult patients without other signs of renal disease, necessitating dose
reductions for renally cleared drugs (Dimopoulos, Alegre, et al., 2010). In
addition, patients with myeloma are at a higher risk for renal failure because
of diabetes or steroid side effects and may require close monitoring and
tighter control of their diabetes (Faiman et al., 2008). Some ethnic groups
such as African Americans and Hispanics are at an increased risk for renal
disease compared to Caucasians. All patients should be monitored for kidney
disease, particularly in these groups.
Bone Complications
Bone
loss associated with chronic renal disease is an osseous complication of
multiple myeloma, and bone changes can begin in adults many years before
symptoms appear. Older adult patients, postmenopausal women, and patients with
multiple myeloma in general are at increased risk for osteoporosis, which
progresses as renal function worsens (a result of renal osteodystrophy and
hyperparathyroidism secondary to chronic renal disease) (Malluche, Koszewski,
Monier-Faugere, Williams, & Mawad, 2006; Malluche, Mawad, &
Monier-Faugere, 2010). Patients, in turn, experience increased risk of bone
fractures and resultant joint and bone pain.
The
kidneys play an important role in maintaining healthy bone mass throughout life
by maintaining calcium and phosphorus levels in the blood. Normally, kidneys
remove excess phosphorus from the blood. When the kidneys fail, though, serum
phosphorus increases and combines with serum calcium, leading to lower
circulating levels of calcium in the blood. The resultant hypocalcemia
stimulates the parathyroid glands to release parathyroid hormone (PTH), which
draws calcium from the bones to raise blood calcium levels. This results in
osteopenia with weakening of the bones. Nurses should be aware that patients
with chronic kidney disease (CKD) require routine monitoring for serum PTH and
vitamin D (Levey et al., 2003). The International Myeloma Foundation’s Nurse
Leadership Board has addressed maintaining bone health as part of their
survivorship care plan (Miceli et al., 2011).
Immunomodulatory Agents
Thalidomide
and lenalidomide are immunomodulatory agents approved by the U.S. Food and Drug
Administration (FDA) for the treatment of myeloma. Dosage adjustments are not
needed with thalidomide in patients with renal insufficiency (Celgene Corp.,
2010b). Lenalidomide, in combination with dexamethasone, is FDA approved for
the treatment of myeloma in patients who have received at least one prior
therapy and its efficacy has been demonstrated in two pivotal phase III
registration trials (Dimopoulos et al., 2007; Weber et al., 2007). Because
lenalidomide is primarily excreted unchanged by the kidney, adjustments to the
starting dose of lenalidomide are recommended to provide appropriate drug
exposure in patients with moderate or severe renal impairment and in patients
on dialysis (Celgene Corp., 2010a). In a subanalysis of these trials,
lenalidomide plus dexamethasone was demonstrated to lead to improvement in
renal insufficiency in the majority of patients. With careful monitoring of
creatinine clearance levels and appropriate dose adjustments, lenalidomide plus
dexamethasone also is a highly effective and well-tolerated treatment for
patients with myeloma who have renal insufficiency (Dimopoulos, Alegre, et al.,
2010). Dose modifications for patients treated with lenalidomide based on renal
insufficiency must be followed because renal insufficiency has been linked to
increased myelosuppression (Dimopoulos, Alegre, et al., 2010) (see Table 1). In the absence of specific recommendations,
CBC and chemistry panels should be monitored carefully in any patient with
renal insufficiency who is receiving lenalidomide. Thalidomide requires no dose
adjustments in renal insufficiency (Celgene Corp., 2010b).
Bortezomib
is a proteasome inhibitor that is approved by the FDA for treatment of multiple
myeloma with no dosage reductions for patients with renal failure (Millennium:
The Takeda Oncology Company, 2010). A subset analysis of data from two key
clinical trials in patients with relapsed myeloma demonstrated a response rate
of 30% in patients with severe renal impairment (i.e., creatinine clearance of
less than 30 ml per minute) and 25% in those with moderate renal impairment. In
addition, patients with creatinine clearance values as low as 13.8 ml per
minute have been included in clinical trials. The pharmacokinetics of
bortezomib have been studied in patients with normal renal function and in
patients with varying degrees of renal impairment from moderate to severe,
including patients on dialysis (doses after dialysis). No differences were
noted in bortezomib exposure among those with and without renal impairment
(Millennium: The Takeda Oncology Company, 2010).
Chanan-Khan
et al. (2007) conducted a multicenter retrospective study on the safety and
efficacy of bortezomib in patients with multiple myeloma with renal failure
requiring dialysis. The median serum creatinine level in the study was 6.8
mg/dl. Patients were treated with bortezomib alone or in combination with other
agents (e.g., dexamethasone, liposomal doxorubicin, or thalidomide). The
overall response rate was 75% among the 20 patients with response data. Three
of four patients with impaired renal function had improved renal function
following bortezomib-based therapy. That included one patient who was spared dialysis,
and two patients who no longer required dialysis support after complete
response. These findings suggest that bortezomib is a safe and useful agent in
renal failure and dialysis-dependent patients (Chanan-Khan et al., 2007).
Newly Diagnosed Patients
Eligible for Transplantation
Frontline
therapy for the transplantation-eligible patient with decreased renal function
includes regimens that contain thalidomide, dexamethasone, vincristine,
doxorubicin, liposomal doxorubicin, cyclophosphamide, and bortezomib.
Alkylating agents such as melphalan may be administered to patients who are not
considered candidates for transplantation (NCCN, 2010b). The combinations of
lenalidomide and dexamethasone (Rajkumar et al., 2010) or bortezomib and
pegylated liposomal doxorubicin (Jakubowiak et al., 2009) have shown promising
results in treating the myeloma. Clinical trials suggest that bortezomib with
liposomal doxorubicin is a safe combination in the presence of renal
insufficiency (Blade et al., 2008).
Autologous
stem cell transplantation has been well documented as an effective treatment
for patients with newly diagnosed myeloma as well as for those with relapsed or
refractory disease (Attal et al., 1996, 2002, 2003, 2006, 2010; McCarthy,
Owzar, Anderson, Hofmeister, & Hurd, 2010). However, few experts agree on
the type of induction regimen, the use of single or tandem transplantation, and
the role, if any, of allogeneic transplantation. Transplantation may be
considered in patients receiving dialysis, but morbidity and mortality are
higher (Blade & Rosinol, 2005). In addition, the timing of transplantation,
whether at diagnosis or relapse, is uncertain. Novel agents such as
thalidomide, lenalidomide, and bortezomib should be considered for induction
therapy.
Bortezomib
is an effective treatment option for patients with renal insufficiency who are
eligible for transplantation. In a phase II open-label intergroup trial,
patients (N = 48) received a combination of bortezomib and dexamethasone prior
to an autologous stem cell transplantation. The pretransplantation response
rates included a complete response in 21% (n = 10) and 10% (n = 5) had very
good partial remission (defined as more than 90% reduction of the M-component).
Investigators concluded that the bortezomib plus dexamethasone regimen appeared
effective and well tolerated in patients newly diagnosed with myeloma
(Harousseau et al., 2006).
Newly Diagnosed Patients Not
Eligible for Transplantation
Thalidomide
and dexamethasone have been studied in older adult patients with myeloma. The
use of high-dose dexamethasone is toxic for older adult patients and is not
well tolerated (Palumbo & Rajkumar, 2009). Results of a clinical trial by
San Miguel et al. (2008) reported that a combination of melphalan, prednisone,
and bortezomib was superior to melphalan and prednisone (MP) in patients newly
diagnosed with myeloma, including those with renal impairment. In the clinical
trial, 682 patients were randomly assigned to receive either MP every six weeks
or bortezomib plus MP on a six-week cycle with two three-week cycles of
bortezomib and one cycle of MP. Bortezomib plus MP was superior to MP in time
to progression, overall survival, complete response, progression-free survival,
and time to next therapy.
The
immunofixation-negative complete response rate was 35% for bortezomib plus MP
compared with only 5% for MP, and a 52% reduction in risk of progression was
noted for the group that received bortezomib plus MP. In the 185 patients with
renal impairment (defined as creatinine clearance less than 60 ml per minute),
no significant difference was noted in complete response rates, time to
progression, or overall rate of survival compared with the 159 patients with
normal renal function (defined as creatinine clearance of 60 ml per minute or
higher). The data suggest that adding bortezomib to melphalan and prednisone is
an effective upfront therapy for patients with multiple myeloma, including
those with impaired renal function (San Miguel et al., 2008).
Supportive Care Recommendations
Bisphosphonates,
such as zoledronic acid and pamidronate, are potent inhibitors of bone
resorption that promote bone formation. However, bisphosphonates may be toxic
to the kidneys in patients with renal insufficiency or chronic kidney disease
(Miceli et al., 2011; Perazella & Markowitz, 2008). Pamidronate and
zoledronic acid both are indicated for the purpose of decreasing
skeletal-related events and fractures in patients with multiple myeloma, but
their effects on patients differ. Pamidronate is less nephrotoxic but more
likely to cause tubular injury and nephrotic syndrome (Kunin, Kopolovic,
Avigdor, & Holtzman, 2004; Markowitz, Fine, & D’Agati, 2002; Perazella
& Markowitz, 2008). That generally is seen with very prolonged use and/or
higher doses. Zoledronic acid is more nephrotoxic than pamidronate,
particularly in patients with uncontrolled myeloma, and is associated with
toxic ATN (Kunin et al., 2004; Markowitz
et al., 2002; Perazella & Markowitz, 2008). Clinicians need to be
particularly careful with baseline elevation in serum creatinine because
zoledronic acid can induce renal failure that may not be reversible (Perazella
& Markowitz, 2008).
Caution
must be exercised when using these drugs, which are FDA approved for patients
with hypercalcemia of malignancy (pamidronate) and multiple myeloma
(pamidronate and zoledronic acid) (Kyle et al., 2007). When renal function has
stabilized, serum creatinine levels should be evaluated at baseline and prior
to each infusion of bisphosphonates. Dose reductions of zoledronic acid and
pamidronate also may be needed, and longer infusion times of pamidronate
currently are recommended for patients with reduced creatinine clearance.
Patients who are receiving bisphosphonates also should be given 1,000 mg per
day of calcium and 400 IU per day of vitamin D. However, calcium
supplementation is contraindicated in patients with hypercalcemia (Faiman et
al., 2008).
Anemia,
defined in myeloma as a hemoglobin concentration 2 g/dl below the institutional
limits of normal, is present in patients with moderate to severe renal
dysfunction, but also may be caused by blood loss, cytotoxic therapy, or
increased disease activity. If blood loss is not found, and the anemia is not
considered to be related to treatment or disease progression, assessing serum
erythropoietin, iron, folic acid, and vitamin B12 levels may identify the type
of anemia. Erythropoiesis–stimulating agents (ESAs) (i.e., erythropoietins such
as epoetin alfa or darbepoetin alfa) may be used to manage anemia (NCCN,
2010a).
The
use of ESAs in renal disease is accepted; however, their use in myeloma remains
controversial. In addition, increasing concerns about ESA use abound, as
multiple studies show decreased survival in patients with CKD and other cancers
(Tariman & Faiman, 2011). The NCCN practice guidelines currently recommend
that darbepoetin can be initiated at a dose of 2.25 mcg/kg2 weekly, and 500 mcg
every three weeks is an appropriate fixed dose (NCCN, 2010a). In addition,
epoetin alfa can be given at a dose of 150 units three times weekly or up to
40,000 units weekly, subcutaneously. Long-term erythropoietin therapy may be
associated with a functional iron deficiency; therefore, serum iron, ferritin,
and serum total iron binding capacity should be assessed prior to initiating
oral iron therapy.
Results
of a study by Katodritou et al. (2008) suggested that ESAs may have a negative
effect on the survival of patients with myeloma. In the study, 323 Greek
patients with multiple myeloma were evaluated from 1988–2007. The median
survival was 31 months for patients who received ESAs, compared with 67 months
for those who were not exposed to ESAs. The median progression-free survival
for patients in the ESA group was 14 months versus 30 months for those without
ESA exposure (Katodritou et al., 2008).
Although
these results suggest that using ESAs could lead to disease progression, the
use of these drugs is recommended in NCCN guidelines for management of anemia
(NCCN, 2010a). Because of the increased risk for thrombus, particularly in
patients with multiple myeloma who are treated with ESAs, and the potential of
decreased survival, the NCCN (2010a) recommends that the severity of anemia be
assessed and the risks of ESA therapy versus blood transfusion be balanced with
the benefits of therapy. Some clinicians, however, have called for
re-evaluation of the use of ESAs in patients with cancer (Unger, Thompson,
Blank, & Temple, 2010).
Supportive
care considerations in the dialysis-dependent patient differ from those of the
nondialysis-dependent patient with chronic renal insufficiency. Individuals
undergoing dialysis can benefit from many of the available novel treatment
strategies, but doses of bortezomib, thalidomide, and lenalidomide should be
given after dialysis. Dose reductions for bortezomib are not required
(Millennium: The Takeda Oncology Company, 2010), but modifications for patients
receiving lenalidomide must be followed (Celgene Corp., 2010a).
Monitoring
Nurses
and clinicians must closely monitor patients’ myeloma and renal insufficiency
by blood chemistry and CBC testing (see Figure 3).
Additional assessment of myeloma parameters, such as serum and urine protein
electrophoresis, serum beta-2 microglobulin, 24-hour urine for protein
electrophoresis, and sFLC assay also is necessary. Although the frequency of
testing depends on the degree of renal failure as well as patients’ response to
therapy, testing CBC and chemistry laboratory parameters on a monthly basis is
reasonable. The nurse may use the Chronic Kidney Disease Staging System
outlined in Table 2 to monitor patients with renal
dysfunction.
Special Considerations in Patients With Multiple Myeloma on
Dialysis
About
20% of patients with multiple myeloma currently are receiving dialysis (Blade
& Rosinol, 2005). Clinicians must be cognizant of the following potential
issues and concerns surrounding patients requiring hemodialysis (Blade &
Rosinol, 2005; Cook, 2008; Finkelstein, Wuerth, & Finkelstein, 2009;
Penfield, 2006).
·
Finances: Dialysis and supportive
care associated with end-stage renal disease add to the cumulative costs of
treating patients with multiple myeloma. That includes additional expenses when
plasma exchanges are used to restore normal renal function.
·
Quality of
life: No
study has examined the quality of life (QOL) of patients with myeloma on
dialysis; however, research findings from QOL studies in chronic renal disease
consistently have shown that patients’ overall health-related QOL is
compromised (Finkelstein et al., 2009).
·
Stem cell
transplantation: Cases of toxic deaths were no different between patients with low and
normal GFRs, although patients with low GFR had more morbidity from mucositis,
diarrhea, and infections (Blade & Rosinol, 2005; Finkelstein et al., 2009).
·
Renal
transplantation in the setting of multiple myeloma: Although renal
transplantation generally is not considered for patients with multiple myeloma,
it has been performed and could be considered for patients with ESRD whose
myeloma is in remission (Taheri et al., 2007).
Conclusion
Renal
insufficiency in patients with myeloma should be assessed at initial diagnosis
and regularly throughout therapy. Preventive
measures should be initiated at diagnosis and throughout the course of the
disease. Nurses have the unique ability to play a key role in early
identification of renal insufficiency and to provide patient education on
preventive interventions such as liberal oral hydration and avoiding NSAID
therapy (Brater, 1999). In addition, by ensuring that patients undergo routine
laboratory evaluation with attention to serum calcium and creatinine levels,
nurses may help patients avoid acute renal failure. Prompt intervention with
hydration and identification of the underlying cause of renal failure may allow
a patient’s renal function to improve, provide patients with more therapeutic
options, and offer the potential for increased survival and improved QOL.
The authors gratefully
acknowledge Brian G.M. Durie, MD, and Robert A. Kyle, MD, for critical review
of the manuscript; Lynne Lederman, PhD, medical writer for the International
Myeloma Foundation, for preparation of the manuscript; and Lakshmi Kamath, PhD,
at ScienceFirst, LLC, Cedar Knolls, NJ, for assistance in preparation of the
manuscript.
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070596
Beth M. Faiman, MSN,
APRN-BC, AOCN®, is a nurse practitioner in the Hematology and
Medical Oncology Department at the Cleveland Clinic in Ohio; Patricia Mangan,
APRN, BC, is a nurse practitioner and the nurse lead of the Hematologic
Malignancies and Stem Cell Transplant Programs in the Hematology/Oncology
Department in Abramson Cancer Center at the University of Pennsylvania in
Philadelphia; Jacy Spong, RN, BSN, OCN®, is an RN in the
Hematology/Oncology Department at the Mayo Clinic in Scottsdale, AZ; and Joseph
D. Tariman, PhD, APRN, BC, is an advanced practice nurse in the myeloma program
at Northwestern University in Chicago, IL. The authors take full responsibility
for the content of this article. Publication of this supplement was made
possible through an unrestricted educational grant to the International Myeloma
Foundation from Celgene Corp. and Millennium: The Takeda Oncology Company.
Faiman is a consultant and on the speakers bureau for Celgene Corp. and
Millennium: The Takeda Oncology Company, Mangan is on the speakers bureau for
Celgene Corp. and Millennium: The Takeda Oncology Company, and Tariman is a
consultant for Millennium: The Takeda Oncology Company. The content of this
article has been reviewed by independent peer reviewers to ensure that it is
balanced, objective, and free from commercial bias. No financial relationships
relevant to the content of this article have been disclosed by the independent
peer reviewers or editorial staff. (Submitted January 2011. Accepted for
publication February 11, 2011.)
Author Contact: Beth M.
Faiman, MSN, APRN-BC, AOCN®, can be reached at faimanb@ccf.org, with copy to editor at CJONEditor@ons.org.
http://dx.doi.org/10.1188/11.CJON.S1.66-76