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The Changing Treatment Paradigm
in Patients With Newly Diagnosed Multiple
Myeloma: Implications for Nursing
Joseph D. Tariman, RN, APN, MN, APRN-BC, OCN®, and Stella Marie Estrella, BSN, RN
Key Points . . .
Purpose/Objectives: To review the changing treatment paradigm for
newly diagnosed multiple myeloma and its implications for nursing.
Data Sources: Journal articles, textbooks, published research data.
High-dose chemotherapy with autologous stem cell
Data Synthesis: The treatment approaches to newly diagnosed mul-
transplantation is the standard of therapy for patients newly
tiple myeloma are varied, and no consensus exists about the best choice
diagnosed with multiple myeloma who are younger than age
of induction therapy prior to high-dose chemotherapy with autologous
70 or have no comorbidities.
stem cell transplantation. Novel therapies that have shown strong clini-
cal activity in patients with relapsed or refractory myeloma currently are
Novel therapies currently being explored are reported to have
being explored as first-line therapy with associated higher incidence of
a higher incidence of potential serious complications.
serious complications.
Oncology nurses play vital roles in the safe and effective ad-
Conclusions: Novel approaches in the treatment of newly diagnosed
ministration of conventional and novel therapies for patients
multiple myeloma may lead to better overall patient survival. Research
with newly diagnosed multiple myeloma.
is ongoing to find ways to improve progression-free and overall survival
in patients with multiple myeloma.
Implications for Nursing: Oncology nurses play vital roles in the
assessment and monitoring of serious complications associated with
(RevlimidTM, Celgene Corporation), a thalidomide analog
various therapies for patients with newly diagnosed multiple my-
eloma. Key responsibilities include safe and effective administration
and an immunomodulatory derivative (IMiD), has shown
of complex chemotherapeutic regimens, management of side effects,
promising results in phase II clinical trials and now is enter-
patient and family education, and coordination of a multidisciplinary
ing phase III (Richardson, Jagannath, et al., 2002). Another
IMiD, CC-4047 (ActimidTM, Celgene Corporation), also has
shown promising results in phase I study (Schey et al., 2004).
Lenalidomide and Actimid currently are being investigated as
treatment for relapsed and refractory disease, but their use as
ultiple myeloma is a clonal B-lymphocyte ma-
front-line therapies is expected in the near future. New drugs
lignancy of the plasma cells. The hallmarks of
multiple myeloma include the classic triad of the
presence of a serum or urine monoclonal immunoglobulin
Joseph D. Tariman, RN, APN, MN, APRN-BC, OCN  ®, is a certified
(Ig) (commonly known as M protein or M spike), osteolytic
nurse practitioner in the Multiple Myeloma Program of the Depart-
lesions, and bone marrow plasmacytosis (> 30% plasma cell
ment of Medicine in the Division of Hematology/Oncology at North-
proliferation) (Lokhorst, 2002). Several novel agents recently
western University Medical Faculty Foundation and Stella Marie
have been introduced in the clinical setting and have shown
Estrella, BSN, RN, is a staff nurse in the Bone Marrow Transplant
promising results in improving patients' overall survival
Unit of Northwestern Memorial Hospital, both in Chicago, IL. Tari-
(Richardson et al., 2003; Tariman, 2003b). The role of angio-
man also is a consultant and a member of the speakers bureau for
genesis in the pathogenesis of multiple myeloma continues
Millennium Pharmaceuticals, Inc., which manufactures Velcade®, a
to evolve, and with promising results of thalidomide (Thalo-
drug mentioned in this article. (Submitted October 2004. Accepted
for publication February 28, 2005.) (Mention of specific products
mid®, Celgene Corporation, Warren, NJ) in newly diagnosed
and opinions related to those products do not indicate or imply
multiple myeloma (Rajkumar, Hayman, et al., 2002; Weber,
endorsement by the Oncology Nursing Forum or the Oncology
Rankin, Gavino, Delasalle, & Alexanian, 2003), this novel
Nursing Society.)
agent is being used increasingly in the clinical setting (Rajku-
mar, Blood, Vesole, Shepard, & Greipp, 2004). Lenalidomide
Digital Object Identifier: 10.1188/05.ONF.E127-E138
such as bortezomib (Velcade®, Millennium Pharmaceuticals,
Durie, Salmon, & Moon, 1980). The diagnostic criteria are
Inc., Cambridge, MA) and lenalidomide use a new treatment
displayed in Table 1. This staging system is based on M protein
paradigm that targets not only multiple myeloma cells directly
levels, the number of bone lesions, and the severity of anemia
but also their microenvironment. Use of these novel biologi-
or hypercalcemia (Durie & Salmon). Durie et al. identified a
cally based therapeutic agents alone or in combination with
process to quantitate the total-body myeloma cell mass. This
conventional chemotherapy can overcome drug resistance
number is calculated by dividing the total-body M component
and may result in better survival for patients with multiple
synthetic rate per myeloma cell. In examining a large series of
myeloma (Anderson, 2003; Barlogie et al., 2004). A changing
individuals with multiple myeloma, the authors identified three
treatment paradigm in patients with multiple myeloma will
stages of the disease.
have a significant effect on clinical practice. This article will
Stage I, or low cell mass, reflects counts of fewer than 0.6
explore new implications for nursing practice based on these
x 1012 cells/m2. Stage II, or intermediate cell mass, reflects
latest treatment approaches.
more than 0.6 ­1.2 x 1012 cells/m2. Stage III, or high cell
mass, reflects counts greater than 1.2 x 1012 cells/m2. Further
staging is done based on renal status at the time of diagnosis.
Diagnosis and Staging
Group A consists of individuals with a normal renal function
(creatinine level less than 2.0 mg/dl), and group B consists
The Durie and Salmon myeloma diagnostic criteria (see
of individuals with evidence of renal dysfunction (creatinine
Figure 1) are used widely in the United States and have been
level greater than 2.0 mg/dl).
validated by large multicenter trials. The parameters are easily
determined in the majority of rural or urban clinical practice
settings (Harousseau & Moreau, 2002). The diagnostic criteria
are divided into major and minor. In most cases, one major
Understanding the nature of plasma cells and the Igs se-
criterion together with one minor criterion is sufficient to
creted by them is important to elucidate the pathobiologic
diagnose multiple myeloma. Once the diagnostic criteria for
changes in multiple myeloma. The production of monoclonal
multiple myeloma are met, Durie-Salmon clinical staging can
Igs is directly proportional to myeloma cell activity, except in
be used to determine the stage of disease.
nonsecretory cases.
The Durie-Salmon clinical staging system incorporates the
Igs, or antibodies, are secretory products of plasma cells, and
diagnositic system proposed in 1975 and the labeling index pro-
each Ig molecule has two heavy and two light chains (Kyle &
posed by Durie and colleagues in 1980 (Durie & Salmon, 1975;
Lust, 1996). Under normal circumstances, they constitute the
humoral immune response to a foreign antigen. The five types
of heavy chains are denoted by the Greek letters µ, δ, γ, α, and
Multiple Myeloma
ε. The type of heavy chain present determines the class of the Ig:
Major criteria
1. Plasmacytoma on tissue biopsy
IgM, IgD, IgG, IgA, and IgE, respectively (Rajkumar & Greipp,
2. Bone marrow plasmacytosis with 30% plasma cells
2002). The two types of light chains are denoted by the Greek
3. Monoclonal globulin spike (M protein) on SPEP: IgG > 3.5 g/dl, IgA > 2.0
letters kappa and lambda. Each heavy chain Ig molecule has
g/dl, light-chain excretion on UPEP > 1 g per 24 hour in the absence of
either a kappa or a lambda subtype of light chain in association
with one of the types of heavy chain (i.e., IgG kappa or IgG
Minor criteria
lambda) (see Figure 2). Because multiple myeloma is a neo-
a. Bone marrow plasmacytosis with 10%­30% plasma cells
plastic, clonal process, the malignant cells and the secreted Igs
b. Monoclonal globulin spike present, but lower levels than defined in the
are either kappa- or lambda-restricted (restriction distinguishes
major criteria
normal plasma cells from malignant plasma cells). When
c. Lytic bone lesions
plasma cells become aberrant, they continue to produce Igs,
d. Normal IgM > 50 mg/dl, IgA > 100 mg/dl or IgG > 600 mg/dl
although about 3% of myeloma cases are nonsecretory (National
The diagnosis of myeloma requires a minimum of one major and one minor
Comprehensive Cancer Network [NCCN], 2004). Because the
criterion (although 1 + a is not sufficient) or three minor criteria that must
malignant proliferation of these plasma cells comes from one
include a + b.
clone, they produce a homogenous Ig, leading to overproduc-
tion of a monoclonal Ig (could be heavy chain or light chain),
Indolent Myeloma
known as M spike, either in the serum or urine. The M spike
Criteria as for myeloma with the following limitations:
value, which commonly is expressed in g/dl (serum) or mg per
a. Absent or only limited bone lesions (< 3 lytic lesions), no compression
24 hours (urine), is the monoclonal protein fraction of the total
Igs produced by myeloma cells that usually is obtained in serum
b. Stable paraprotein levels IgG level < 700 mg/dl, IgA < 500 mg/dl
c. No symptoms or associated disease features: Karnofsky performance sta-
and urine electrophoresis, respectively. M spike is a very impor-
tus > 70%, hemoglobin > 10 g/dl, normal serum calcium, normal serum
tant tumor marker in multiple myeloma because it is produced
creatinine, no infections
directly by myeloma cells. When the M spike value decreases
d. Plasma cell labeling index < 0.5%
while a patient is being actively treated, it directly correlates to
the degree of response to therapy (Blade et al., 1998).
Ig--immunoglobulin; SPEP--serum protein electrophoresis; UPEP--urine
protein electrophoresis
Heavy Chain Multiple Myeloma
Figure 1. Diagnostic Criteria by Durie and Salmon
The immunofixation test is the most sensitive and a more
specific test that identifies the type of Ig produced by the my-
Note. From "Clinical Features and Diagnostic Criteria" (p. 155), by H. Lokhorst
eloma cells. When monoclonal plasma cells produce heavy
in J. Mehta & S. Singhal (Eds.), Myeloma, 2002, London: Martin Dunitz. Copy-
chain Ig, multiple myeloma then is subtyped into either IgG
right 2002 by Martin Dunitz. Reprinted with permission.
Table 1. Multiple Myeloma Staging System
and may do well without treatment for many years (NCCN,
2004). A comprehensive review of randomized controlled
Estimated Myeloma
trials with a parallel design that compared early with
Mass (Cells x 1012/m2)
deferred treatment for patients with early-stage multiple
myeloma concluded that early treatment inhibited disease
Stage I
< 0.6
progression and may have reduced vertebral compression but
All of the following
(low burden)
no significant effects on response rate and overall survival
Hemoglobin value > 10 g/dl
existed (He et al., 2003).
Normal serum calcium
When disease progression is evident, demonstrated by a
Normal bone structure
Low M protein production
sustained 25% increase or greater in M protein in serum or
IgG value < 5 g/dl
urine or development of new sites of skeletal lytic lesion or hy-
IgA value < 3 g/dl
percalcemia, treatment should be started immediately (NCCN,
Urine kappa or lambda < 4 g/24 hr
2004). Systemic therapy with oral or IV chemotherapy is the
preferred initial approach to symptomatic multiple myeloma.
Stage II
0.6­ 1.2
Overall data fits in neither stage I nor stage III
(intermediate burden)
Alkylating agents (mustards such as melphalan and cyclo-
phosphamide) and nitrosoureas (carmustine or lomustine)
Stage III
> 1.2
typically are used. Radiation therapy use in multiple myeloma
One or more of the following
(high burden)
should be limited and reserved for symptomatic or painful
Hemoglobin value < 8.5 g/dl
discrete lesions, such as in cases of epidural extension with
Serum calcium value > 12 mg/dl
More than 3 lytic bone lesions
impending cord compression. In addition, radiation could
High M protein production
further deplete the bone marrow reserve for patients who may
IgG value > 7 g/dl
be eligible for stem cell transplantation (SCT).
IgA value > 5g/dl
Age older than 65 years and comorbid conditions such as
Urine kappa or lambda
renal compromise used to be negative factors in the selection
M component > 12 g/24 hr
of transplant candidates. Recently, studies have shown that
neither of these two factors is an important adverse parameter
A = creatinine value < 2.0 mg/dl
affecting the outcome of high-dose therapy and autotransplan-
B = creatinine value > 2.0 mg/dl
tation (Badros, Barlogie, Stiegel, Roberts, et al., 2001; Magag-
hr--hour; Ig--immunoglobulin
noli et al., 2003; Siegel et al., 1999; Sirohi et al., 2001; Terpos,
Note. From "A Clinical Staging System for Multiple Myeloma," by B.G. Durie
Apperley, et al., 2003). These reports have led to an increase
and S.E. Salmon, 1975, Cancer, 36, p. 852. Copyright 1975 by the American
in the number of patients who are eligible for autologous SCT
Cancer Society. Reprinted with permission from John Wiley and Sons, Inc.
for treatment for multiple myeloma (Zomas & Dimopoulos,
2002). Therefore, high-dose chemotherapy with autologous
kappa or lambda or IgA kappa or lambda. IgD and IgE types
SCT is recommended for patients 70 years of age or younger
of myeloma are rare and have an incidence of less than 1%.
who do not have severe comorbidities (Barosi et al., 2004;
IgM gammopathy (i.e., the presence of monoclonal IgM in the
Kyle, 2002; NCCN, 2004; Singhal, 2002). Ideally, hemato-
serum) usually is associated with Waldenstrom macroglobu-
poietic stem cells are collected before patients are exposed to
linemia rather than myeloma.
alkylating agents. The NCCN myeloma panel recommended
high-dose chemotherapy followed by autologous SCT as a
Light Chain Multiple Myeloma
primary treatment in patients with symptomatic multiple my-
When myeloma cells produce only light chain Igs (origi-
eloma with uniform consensus based on high-level evidence
nally described by Bence Jones, MD; hence, the name Bence
(category 1 consensus from the NCCN panel, the highest level
Jones protein is synonymous with light chain proteinuria),
of consensus among myeloma experts). Common induction
they are subtyped into kappa light chain or lambda light
therapies administered prior to high-dose chemotherapy
chain multiple myeloma. Most patients with myeloma have
include pulse dexamethasone; vincristine, doxorubicin, and
serum proteins with or without associated urinary proteins,
dexamethasone (VAD); and, most recently, thalidomide plus
but 20% of patients have urinary proteins only (Kyle et al.,
2003). For patients with light chain myeloma, a 24-hour urine
protein electrophoresis must be performed regularly as part of
Serum heavy chain immunoglobulins (77% of cases)
surveillance for disease progression because urine M protein,
· Immunoglobulin G kappa or lambda multiple myeloma
not serum M protein, is the tumor marker.
· Immunoglobulin A kappa or lambda multiple myeloma
Urinary light chain immunoglobulins or Bence Jones proteins (20% of cases)
· Kappa light chain multiple myeloma
· Lambda light chain multiple myeloma
The 2004 NCCN guidelines outline several conventional
therapies for newly diagnosed multiple myeloma. These
No serum or urine M proteins (3% of cases)
therapies are offered routinely outside the context of clinical
· Nonsecretory multiple myeloma
trials because their safety and efficacy have been validated
Figure 2. Subtypes of Multiple Myeloma Based on Specific
(see Figure 3).
Monoclonal Immunoglobulins or M Proteins Produced
Patients with monoclonal gammopathy of undetermined
by Myeloma Cells
significance (MGUS), indolent, or smoldering multiple
myeloma (see Figure 4) are observed initially for months
Note. Based on information from Kyle et al., 2003.
Older adult patients require close monitoring, particularly
Patients not eligible for autologous stem cell transplant
those with concurrent diseases such as congestive heart failure,
· Melphalan and prednisone
because steroid-associated sodium and water retention can
Patients eligible for autologous stem cell transplant
exacerbate symptoms (Gautier & Cohen, 1994). Monitoring
· Vincristine, doxorubicin, and dexamethasone
patients for weight gain and peripheral edema on a daily basis
· High-dose pulsed dexamethasone
will help in detecting pulmonary edema and cardiopulmonary
· Thalidomide and dexamethasone (insufficient data to recommend treatment
compromise. Inform patients and their family members to re-
port to their clinicians any weight gain greater than five pounds
· Liposomal doxorubicin, vincristine, and dexamethasone
in one day. Individuals with preexisting diabetes require close
Figure 3. Conventional Therapies in Patients With Newly
monitoring for signs and symptoms of steroid-induced hyper-
Diagnosed Multiple Myeloma
glycemia. Teaching patients and their families how to monitor
blood sugar and when to report side effects to clinicians is an
Note. Based on information from the National Comprehensive Cancer Network,
important aspect of treatment. Assess these patients for the
presence of polydipsia, polyuria, and polyphagia at each visit.
Homecare visits by an RN two to three times per week during
Induction Chemotherapy
the first cycle of high-dose dexamethasone may be needed to
High-dose pulsed dexamethasone: High-dose pulsed
monitor blood pressure, blood sugar levels, and other steroid-
related side effects. These visits may be continued through the
dexamethasone is a primary treatment regimen in patients
second and third cycles of therapy as clinically indicated. Dose
with multiple myeloma, with response and survival rates
reductions or change of treatment regimen may be required if
that are similar to those achieved with other standard regi-
steroid-related psychosis or diabetic ketoacidosis occurs or if
mens such as VAD (Alexanian, Dimopoulos, Delasalle, &
side effects are more pronounced and the risks outweigh the
Barlogie, 1992; Kumar et al., 2004). It has the convenience
benefits of treatment.
of oral administration. Dexamethasone 40 mg usually is
Vincristine, doxorubicin, and dexamethasone: Using
given on days 1­ 4, 9­12, and 17­20 with a one-week break
VAD as a treatment for myeloma was developed by the Uni-
(28-day cycle) or two-week break (35-day cycle). Because
versity of Texas M.D. Anderson Cancer Center in Houston in
dexamethasone is not associated with myelosuppression,
the early 1980s (Alexanian, Barlogie, & Tucker, 1990). The
this agent is indicated when radiotherapy is needed for the
response rate in chemotherapy-naive patients is reported to be
treatment of painful bone lesions or in patients with impend-
60%­80%, with 10%­15% complete remission (Alexanian
ing cord compression and may be the primary treatment of
et al., 1990; Samson et al., 1989). The VAD regimen may be
choice in patients who present with pancytopenia (Zomas &
preferable for patients in whom rapid tumor control is desired,
Dimopoulos, 2002).
such as those with hypercalcemia, renal failure, or widespread
The major drawbacks of dexamethasone therapy among
painful bone lesions. It is especially indicated in patients with
older adults are steroid-related toxicities (Gautier & Cohen,
plasma cell leukemia (myeloma associated with circulating
1994). Prophylactic antacid or proton pump inhibitors and
plasma cells greater than 20%) because standard alkylating
anti-infectives usually are administered concomitantly to
agents are ineffective (Dimopoulos, Palumbo, Delasalle, &
prevent common steroidal side effects, such as gastrointestinal
Alexanian, 1994). VAD also is useful in patients with renal
(GI) ulcers and infection. Monitoring of signs and symptoms
failure because none of its components is nephrotoxic or ex-
of ulcers, severe dyspepsia, fluid and sodium retention, cor-
creted renally. No more than three courses of VAD usually are
ticosteroid myopathy, acute pancreatitis, insulin-dependent
needed to confirm partial response (defined as a 50% reduc-
hyperglycemia, steroid psychosis, and infections is important.
tion of M protein) or resistance (continued rise in M protein)
Patient and family education should include instructions to
to this regimen (Alexanian et al., 1990). Monitoring the total
report signs and symptoms of gastritis, including nausea and
dose of doxorubicin and treating patients to a maximum toler-
vomiting with or without hematemesis, to clinicians to prevent
ated dose of 450 mg/m2 can prevent potential cardiotoxicity.
serious complications such as GI bleeding.
Major drawbacks of the VAD regimen are the need for
central line access (doxorubicin is a vesicant) and steroid-
related toxicities mentioned previously. The use of pegylated
Monoclonal gammopathy of undetermined significance
· Less than 10% plasmacytosis
liposomal doxorubicin (nonvesicant formulation) has been
· Absence of myeloma-associated signs and symptomsa
reported, and the treatment regimen appears to be as effective
Smoldering multiple myeloma
as treatment with standard doxorubicin (Hussein, 2003).
· Plasmacytosis greater than 10% but not greater than 30%
The dose of dexamethasone in the VAD regimen is the
· Absence of myeloma-associated signs and symptomsa
same as in the pulsed dexamethasone regimen; therefore,
Indolent multiple myeloma
similar steroid-related toxicities must be anticipated as well
· Plasmacytosis greater than 10% but not greater than 30%
as the added concerns of central line infection (where patients
· May have mild anemia, few lytic lesions (less than three)
are at risk for infection because the central line serves as a
· No other myeloma-associated signs and symptoms
portal of entry of pathogenic organisms). Deep vein thrombo-
Myeloma-associated signs and symptoms include anemia, bone pain, bone
sis is a risk if VAD is combined with thalidomide. Vincristine
lytic lesions, renal insufficiency, and hypercalcemia.
and doxorubicin are given on days 1­4 of each cycle of VAD,
Figure 4. Characteristics of Monoclonal Gammopathy
whereas dexamethasone is continued on days 9­12 and 17­20
of Undetermined Significance and Early-Stage Multiple
on each cycle. Patients and family members must receive clear
instructions from the healthcare team that dexamethasone is
the most important component of the VAD regimen. Strict
Note. Based on information from Kyle et al., 2003; Kyle & Greipp, 1980.
compliance to this somewhat complex schedule is crucial to
and positive selection of CD34+ progenitor cells (myeloma
the success of induction therapy to reduce myeloma tumor
cells do not express the CD34 antigen) has been done to
burden quickly.
obtain tumor-free stem cells and improve response rates and
Thalidomide and dexamethasone: Thalidomide was rein-
overall survival. A long-term follow-up of a randomized study
troduced into the oncology clinical setting in 1998 and since
(Vescio et al., 1999) showed no survival benefit from CD34+
then has demonstrated significant activity against relapsed and
selection; therefore, purging and positive selection of stem
refractory multiple myeloma (Singhal et al., 1999). Thalido-
cells remain questionable (Singhal, 2002).
Conditioning regimen: High-dose melphalan is considered
mide has immunomodulatory properties, such as stimulation
of the secretion of interleukin-2 (IL-2) and interferon-γ (IFN-
the standard regimen for ablating the bone marrow of patients
γ) by CD8+ T cells, thereby increasing antitumor immunity
with multiple myeloma (Anagnostopoulos et al., 2004). Other
(Raje & Anderson, 2002).Thalidomide has antitumor prop-
combination regimens containing busulfan or etoposide are
erties against relapsed or refractory multiple myeloma with
complex and have shown no obvious additional benefit (Anag-
response rates averaging 30%­35% (response rate is > 50%
nostopoulos et al.; Singhal, 2002). The most commonly used
reduction of M protein) (Barlogie, Tricot, & Anaissie, 2001;
regimens in clinical practice are high-dose melphalan at 200
Kyle & Rajkumar, 2001; Yakoub-Agha et al., 2002). The
mg/m2 given in one dose or at 100 mg/m2 on two consecutive
median duration of response to thalidomide is approximately
days followed by reinfusion of stem cells 24 hours after the
eight to nine months (ranges from 2 to more than 30 months)
completion of melphalan administration.
(Durie & Stepan, 2001).
The half-life of melphalan is believed to be 50­170 minutes
The most commonly reported side effects of thalidomide
(Singhal, 2002). The dose of melphalan sometimes is reduced
are constipation, somnolence, and fatigue. Fairly common
depending on the age of the patient (i.e., > 70 years) or if co-
to least common side effects include peripheral neuropathy,
morbid conditions are present. A reduced dose of melphalan
skin rash, and deep vein thrombosis (Tariman, 2003a). Tha-
at 140 mg/m2 for patients older than 70 years of age usually is
lidomide is highly teratogenic. Clinicians and patients must
employed (Badros, Barlogie, Siegel, Morris, et al., 2001).
adhere strictly to the System for Thalidomide Education and
Tandem Autologous Stem Cell Transplantation
Prescribing Safety program (Zeldis, Williams, Thomas, &
Elsayed, 1999). Therapeutic anticoagulation also may be
Tandem autologous transplantation, a sequential adminis-
essential during thalidomide therapy in newly diagnosed pa-
tration of two high doses of melphalan at least three months
tients (Rajkumar, Hayman, et al., 2002; Weber et al., 2003)
apart, each followed by SCT, has been used in an attempt to
and when combined with cytotoxic chemotherapy because
improve response rates and survival in patients with multiple
deep vein thrombosis incidence was reported to be as high as
myeloma. Evidence to support this treatment approach is in-
25% (Zangari et al., 2003).
sufficient because the only study showing benefit for tandem
A reasonable approach for use of thalidomide in multiple
transplants used a conditioning regimen known to be associ-
myeloma is to initiate therapy at 50­100 mg nightly and
ated with inferior outcome. However, tandem autologous SCT
escalate every two weeks in 50­100 mg increments as toler-
is recommended for patients who have responded to the first
ated. Efforts should be made to titrate the dose up to 600 mg
autologous SCT but are not in complete remission or are near
per day for patients with poor prognostic features such as in
a complete response (Attal et al., 2003). Studies on tandem
relapsed or refractory myeloma (Barlogie, Desikan, et al.,
autologous transplantation still are ongoing, and no other
2001; Thompson & Hansen, 2003).
single study has shown to date that it offers overall survival
advantage compared to one transplant (see Table 2).
Autologous Stem Cell Transplantation
Allogeneic Stem Cell Transplantation
Collection of peripheral blood stem cells: In general,
collection and cryopreservation of blood stem cells should
Allogeneic SCT has been used to treat some patients with
be initiated as soon as the best achievable response is con-
multiple myeloma, but to date patient outcomes have been
firmed (i.e., 50% reduction of M protein from baseline)
dismal (Mehta, 2002). Several factors may account for this
(Zomas & Dimopoulos, 2002). Chemomobilization, the use
poor outcome, such as the underlying disease, the patient's
of chemotherapeutic agent(s) prior to stem cell collection
condition, and the treatment regimen, including supportive
and cryopreservation, commonly is used. Use of growth
therapy. Among them are advanced Durie-Salmon stage, ex-
factor alone (i.e., granulocyte colony-stimulating factor or
tensive prior therapy, high b2M, high lactate dehydrogenase
granulocyte macrophage­colony-stimulating factor) without
serum values, a long diagnosis to transplant interval, low
chemotherapy prior to stem collection to mobilize stem cells
serum albumin, prior autograft, refractory disease, and renal
(growth factor mobilization) may be effective in a select
dysfunction. Poor patient selection (e.g., those with poor per-
group of patients. Sequential administration of VAD followed
formance status and terminal disease) has been responsible for
by high-dose cyclophosphamide and consolidated by the
these dismal results (Mehta). The role of nonmyeloablative al-
combination of etoposide, dexamethasone, cytarabine, and
logeneic transplantation (i.e., mini-allogeneic transplantation)
cisplatin has improved complete response rates and allowed
currently is being investigated because of a lower mortality
the collection of an adequate number of stem cells to support
rate and possible therapeutic benefit.
two autologous transplants (Barlogie et al., 1997). Other
Treatment Options for Patients Not Eligible
chemomobilization regimens prior to stem cell collection
for High-Dose Chemotherapy With Autologous
include high-dose cyclophosphamide and cyclophosphamide,
Stem Cell Transplantation
dexamethasone, etoposide, and cisplatin.
Melphalan and prednisone: For patients with symptomatic
Purging (removal of lingering malignant plasma cells) with
monoclonal antibodies or 4-hydroperoxycyclophosphamide
multiple myeloma who are older than 70 years or in younger
Table 2. Types of Responses for Single Versus Tandem
needs to be taken with meals. Patients may take H2-histamine
Autologous Stem Cell Transplant
receptor antagonists to prevent gastric distress associated with
steroids. Older individuals who are at risk for infectious or GI
complications must be monitored closely.
Novel Therapies
42% complete response or
50% complete response or
very good partial response
very good partial response
Bortezomib: Bortezomib is a novel, first-in-class protea-
10% seven-year event-free
20% seven-year event-free
some inhibitor agent that inhibits the 26S proteasome (Adams,
2003b). The mechanism of action of bortezomib in multiple
myeloma has been described and the potential effects of bor-
21% seven-year overall
42% seven-year overall
tezomib in myeloma and other types of cancer are outlined in
Figure 5 (Adams, 2003a).
Note. Based on information from Attal et al., 2003.
In May 2003, the U.S. Food and Drug Administration ap-
proved bortezomib as a treatment for relapsed and refractory
patients for whom transplant is not feasible, intermittent
myeloma. In a landmark phase II trial (protocol M34101-025,
systemic oral melphalan and prednisone (MP) has been the
also known as the Summit Protocol), 193 of 202 patients were
first line of therapy since the 1970s (Anderson, Hamblin, &
evaluable for response to bortezomib alone and the combined
Traynor, 1999; Kyle, 2002; Rajkumar, Gertz, Kyle, & Greipp,
complete and partial response rate was 28% regardless of the
2002). The relative importance of two active agents in the MP
number or type of previous therapies or baseline patient charac-
regimen has been debated because of conflicting results in
teristics, including performance status, myeloma type, b2M, or
either MP combination or intermittent melphalan alone. An
chromosome 13 deletion status. Predictors of a poor response
analysis clearly has shown the usefulness of steroids by corre-
included greater than 50% plasma cells in the bone marrow
lating survival with prednisone dose intensity and not with the
and abnormal bone marrow cytogenetics other than chromo-
total melphalan dose (Palmer, Belch, Hanson, & Brox, 1988).
some 13 deletion status. Median time to response was 38 days
In general, corticosteroids as part of primary treatment for
(two cycles). Median major response duration was 12 months,
multiple myeloma demonstrate high activity in plasma cells
and the overall response was as high as 35% when minimal
with concomitant sparing of normal hematopoietic elements.
responses were included. Grade 3 adverse events included
Corticosteroids may increase the speed of response without
thrombocytopenia (28%), fatigue (12%), and neutropenia
added myelosuppression while improving patients' sense of
(11%). Grade 4 adverse events, which included thrombocyto-
well-being (Zomas & Dimopoulos, 2002).
penia, diarrhea, vomiting, and peripheral neuropathy, occurred
Before high-dose chemotherapy and stem cell rescue, the
in 14% of patients (Richardson et al., 2003).
MP oral regimen was the most frequent treatment for newly
Although bortezomib has been approved for patients with
diagnosed multiple myeloma (Sonneveld & Segeren, 2003).
multiple myeloma who have failed at least two different types
With this regimen, the response rate is 50%­60% and the
of treatment (Colson, Doss, Swift, Tariman, & Thomas, 2004),
mean survival rate is about 24 ­36 months (Bataille & Ha-
it also has been used with patients with newly diagnosed mul-
rousseau, 1997). The survival rates at 5 and 10 years are 25%
tiple myeloma. In a phase II trial, patients received bortezomib
and 8%, respectively (Munshi, Desikan, & Barlogie, 2000).
1.3 mg/m2 on days 1, 4, 8, and 11 with a 10-day break (21-day
Standard MP chemotherapy consists of melphalan 8 mg per
cycle) for a maximum of six cycles. Dexamethasone 40 mg
day for seven days and prednisone 20 mg three times a day for
the day of and the day after bortezomib administration was
the same seven days every six weeks (Kyle, 2002). Melphalan
given after two cycles to patients whose M spike value was
also can be given at 8 mg/m2 daily for four consecutive days
less than half from baseline and after four cycles to patients
and prednisone at 60 mg/m2 daily by mouth, also for four
who did not achieve complete disappearance of M spike.
consecutive days.
Nineteen patients were accrued in this study, and 12 patients
White blood cells and platelets are checked every three
completed six cycles and were evaluable for response. Four
weeks after beginning each cycle of therapy. The dosage of
patients (33%) achieved near complete remission (defined
melphalan must be adjusted until modest midcycle cytopenia
as negative M spike value but still immunofixation positive),
occurs (Kyle, 2002). If the serum creatinine level is more than
and five patients (42%) had a partial response after six cycles
2 mg/dl, the dose of melphalan should be reduced by 25% to
(Jagannath et al., 2004). The most common adverse events
prevent severe myelosupression. If cytopenia does not occur,
(grade 1­3) were fatigue (67%); GI-related symptoms such as
the dose of melphalan should be increased in a stepwise esca-
diarrhea (58%), constipation (42%), nausea (42%), and vom-
lation by 2­3 mg/m2 (Kyle; Zomas & Dimopoulos, 2002).
A minimum of three courses of MP should be given before
therapy is discontinued because delayed responses are common.
· Increases apoptosis by inhibiting antiapoptotic factors
An objective response may not be seen for 6­12 months or even
· Decreases production of cellular adhesion molecules which confer resis-
longer in some patients. If pain is alleviated and no evidence of
tance to standard chemotherapies
progressive disease is present (i.e., no increase in serum or urine
· Inhibits interleukin-6 cytokine, a major proliferative factor of myeloma cells
M protein, no new bone lesions, no hypercalcemia), the regimen
· Decreases production of cyclins and cell cycle regulators
should be continued.
Figure 5. Potential Effects of Bortezomib in Multiple
Oral melphalan must be taken on an empty stomach at least
two hours before meals or three hours after eating because
food reduces its absorption by at least 50% (Alberts, Chang,
Note. Based on information from Chauhan et al., 1996; Mitsiades et al., 2002;
Chen, Evans, & Moon, 1979), unlike prednisone, which
Richardson et al., 2003.
iting (33%); and peripheral neuropathy (33%). Of particular
proximately 15,000-fold greater inhibition of TNF-a activity
note, subsequent to receiving bortezomib, one patient had
than thalidomide. It also inhibits IL-1 levels and multiple
undergone high-dose chemotherapy with SCT and attained
myeloma cell proliferation. Actimid and lenalidomide have
complete hematologic recovery (Jagannath et al.).
different tumor activity profiles and currently are being
Another study also reported using bortezomib in combi-
tested in different malignancies. These two novel thalidomide
nation with doxorubicin and dexamethasone for untreated
analogs display antiangiogenic activity independent of their
multiple myeloma (Cavenagh et al., 2004). Fifteen patients
immunomodulatory effect (Dredge et al., 2002). To date, most
with previously untreated multiple myeloma were enrolled.
studies on lenalidomide and Actimid have been done with
All patients received bortezomib 1.3 mg/m2 on days 1, 4, 8,
patients with relapsed or refractory myeloma.
and 11 and oral dexamethasone 40 mg on days 1­ 4, 8­11,
A phase I study of lenalidomide showed that it overcomes
and 15­18 cycle 1 (day 1­ 4 only during cycles4). For
conventional drug resistance and is well tolerated in patients
doxorubicin dosing, patients were divided into three cohorts.
with relapsed multiple myeloma. More importantly, no sig-
The first cohort (n = 3) received no doxorubicin, the second
nificant somnolence, constipation, or neuropathy (common
(n = 4) received doxorubicin 4.5 mg/m2 on days 1­4, and the
toxicities of thalidomide) was reported among four cohorts
third (n = 8) received 9 mg/m2 on days 1­4 of the cycle. All
of patients who received the drug at doses of 5, 10, 25, and
patients achieved at least a partial response (50% reduction of
50 mg per day (Richardson et al., 2001). Best responses in
M protein); two patients achieved a complete response (100%
M spike, with a reduction of greater than 25%, were seen in
reduction of M protein).
12 of 19 evaluable patients (63%) and less than 25% in an
Patients receiving bortezomib therapy need to be monitored
additional 3 patients; 4 patients had no response. This study
closely for any adverse effects. Failure to assess or institute
demonstrated that lenalidomide has antitumor activity and
appropriate early interventions may jeopardize patients'
acceptable toxicity and provides the framework for further
health. Peripheral neuropathy needs close monitoring, and
studies. Dose-limiting toxicities, including grade 3 and 4
appropriate dose or schedule modification based on patients'
leukopenia, neutropenia, and thrombocytopenia, were found
degree of neuropathy is recommended (Tariman & Lemoine,
in all except the 5 mg per day cohort.
2003). Complete blood counts before each dose and weekly
A similar phase I study with 15 patients (all patients had
chemistries are necessary to monitor any electrolyte imbalance
chemorefractory disease, having relapsed after at least one
or creatinine abnormality (Tariman & Lemoine). Transfusion
high chemotherapy dose, with a median of 10 prior cycles
support and use of growth factors may be clinically indicated.
of chemotherapy) enrolled concluded that three patients
Grade 4 hematologic toxicities will require dose modification.
(20%) showed a greater than 50% M spike reduction with a
The dose usually is held until symptoms return to a grade 3
concomitant reduction of plasma cell involvement in bone
level with or without transfusion or use of growth factors.
marrow biopsy (Zangari et al., 2003). However, responses
Antidiarrheals and antiemetics may be used as clinically in-
were observed only at the 25 and 50 mg doses. This study
dicated. Oncology nurses play a vital role in the assessment
also found the same significant myelosuppression reported
and monitoring of these adverse effects and in the initiatation
by Richardson et al. (2001), even in patients with adequate
of immediate interventions before serious health conditions
platelet counts and marrow cellularity. Furthermore, this
or irreversible damage occur (Colson et al., 2004).
particular study suggested that lenalidomide had the potential
Immunomodulatory drugs: As the use of thalidomide in
to cause cardiovascular problems such as thromboembolism
the treatment of patients with newly diagnosed, relapsed, or
(two patients) and syncope (one patient).
refractory myeloma has increased, so has interest in immu-
A follow-up phase II study supported phase I findings and
nomodulatory drugs that are potent thalidomide derivatives or
demonstrated that lenalidomide has an acceptable toxicity
analogs that markedly stimulate T-cell proliferation, as well
profile and the convenience of daily oral dosing (Richardson,
as IL-2 and IFN-a production (Corral et al., 1999). Lenalido-
Jagannath, et al., 2002). After successful phase I and II trials,
mide, an IMiD that is 50­2,000 times more potent than tha-
a phase III multicenter, international trial at 50 sites was con-
lidomide in stimulating T-cell proliferation triggered via the T-
ducted. It currently is closed for enrollment after successful
cell receptor and 50­100 times more potent than thalidomide
accrual of 302 patients with relapsed or refractory multiple
in augmenting IL-2 and IFN-a, thereby stimulating peripheral
myeloma. The primary objective of this study is to compare the
blood mononuclear cells and augmenting natural killer cells
efficacy of oral lenalidomide in combination with oral pulse
function (Richardson, Schlossman, et al., 2002). In addition,
high-dose dexamethasone to that of placebo and oral high-dose
lenalidomide triggers dose-dependent decreased secretion
pulse dexamethasone (Weber, 2003). Most recently, a Southwest
of tumor necrosis factor-a (TNF-a), IL-1, and IL-6, which
Oncology Group phase III multicenter study was initiated to
promote myeloma cell proliferation and trigger increased
study lenalidomide in newly diagnosed, untreated patients with
secretion of IL-10. Lenalidomide decreases multiple myeloma
multiple myeloma. This study expects to accrue 500 patients.
cell proliferation by reducing binding of multiple myeloma
The primary side effects of lenalidomide are myelosuppres-
cells to bone marrow stromal cells, inhibiting the production
sion and thromboembolic events. Appropriate and timely use
in the bone marrow milieu of cytokines (IL-6, vascular en-
of growth factors and blood product transfusions are crucial
dothelial growth factor, TNF-a) that mediate the growth and
to prevent serious complications such as sepsis and bleeding
survival of multiple myeloma cells, blocking angiogenesis,
from severe neutropenia and thrombocytopenia, respectively.
and stimulating host antimultiple myeloma natural killer cell
A thorough assessment for signs and symptoms of thrombo-
immunity (Davies et al., 2001; Gupta et al., 2001; Hideshima
embolic events is also unequivocally important to prevent
et al., 2000; Richardson, Schlossman, et al., 2002).
serious complications such as pulmonary embolism.
Other agents: Several other biologically based therapeutic
Another thalidomide analogue, Actimid, is the second IMiD
to enter clinical trials. In in vitro models, it demonstrated ap-
agents currently are under preclinical and clinical investigation
for multiple myeloma. These include NF-kB inhibitor (PS-
acid only for the prevention of skeletal events. The superiority
1145), 2-methoxyestradiol, tyrosine kinase inhibitor (PTK787),
of one agent over the other cannot be definitively established;
histone deacetylase inhibitor (NVP-LAQ824), farnesyl trans-
therefore, the choice of pamidronate or zoledronic acid will
ferase inhibitor (R115777), and osteoprotegerin (Alsina et
depend on choosing between the higher drug cost of zole-
al., 2004; Catley et al., 2003; Chauhan et al., 2002; Hayashi,
dronic acid, with its shorter, more convenient infusion time
Hideshima, & Anderson, 2003; Lin et al., 2002; Mitsiades et al.,
of 15 minutes, versus the less expensive drug, pamidronate,
2004; Mooberry, 2003; Ochiai et al., 2003; Santucci, Mackley,
with its longer infusion time of two hours (Berenson et al.,
Sebti, & Alsina, 2003; Vanderkerken et al., 2003). These novel
agents are mostly in phase I and phase II clinical trials and have
Common side effects from IV bisphosphonates include
shown promising activity against multiple myeloma. They are
bone pain, nausea, fatigue, fever, vomiting, diarrhea, and
potential additions to the treatment armamentarium for my-
myalgias (Rosen et al., 2003). Supportive care measures
eloma. Application of cytogenetics and molecular genetics, es-
include assessing dehydration and electrolyte levels and
pecially gene expression profiling, may soon aid in a molecular
administering antiemetics, antipyretics, antidiarrheals, and
classification of multiple myeloma potentially leading to new
analgesics as clinically indicated (Maxwell, Swift, Goode,
treatment strategy (Bumm et al., 2002; Claudio, Masih-Khan,
Doane, & Rogers, 2003). Blood chemistry results usually
& Stewart, 2004; Zhan et al., 2002).
are reviewed before IV bisphosphonate administration, and
serum creatinine is monitored on a regular basis. An increase
Adjunctive Treatment
in creatinine of 0.5 mg/dl in patients with normal baseline
Bisphosphonates: Bisphosphonates directly inhibit the os-
and 1.0 mg/dl in patients with abnormal baseline creatinine
teolytic activity of osteoclasts and reduce their survival. They
would require the dose to be held until the creatinine returns
have been shown to provide a meaningful supportive benefit
to within 10% of the baseline value. Patients who are receiv-
to patients with multiple myeloma and lytic bone disease
ing any bisphosphonate therapy for malignant bone disease
(Berenson et al., 2002). Pamidronate, a second-generation
are instructed to take daily calcium (500 mg) and vitamin D
aminobisphosphonate, has been evaluated in a randomized,
(400 IU) supplements (Maxwell et al.).
double-blind trial in patients with advanced multiple myeloma
Implications for Nursing
(Berenson et al., 1996). Bone pain and analgesic requirements
were significantly reduced in the pamidronate group. The total
number of occurrences of pathologic fracture and episodes of
Many advances have occurred in the care of patients with
hypercalcemia was reduced by half. Pamidronate currently is
newly diagnosed multiple myeloma. Improvement in supportive
used at a dose of 90 mg once a month given in a two-hour in-
care, high-dose chemotherapy with autologous SCT, and novel
fusion. Long-term indefinite use of this agent has been shown
therapeutic agents are among the most recent developments.
to be safe and efficacious (Ali et al., 2001). Pamidronate in
The changing treatment paradigm for newly diagnosed patients
comparison with ibandronate (a first-generation bisphospho-
with multiple myeloma eventually may lead to better quality
nate) was found to be superior in reducing osteoclast activity,
of life and improved overall survival. However, as discussed
bone resorption, IL-6, and, possibly, tumor burden in multiple
previously, new side effects and serious complications (deep
myeloma (Terpos, Viniou, et al., 2003).
vein thrombosis, pulmonary embolism, severe myelosuppres-
A more potent third-generation bisphosphonate, zoledronic
sion, and infection or sepsis and peripheral neuropathy) also
acid (Zometa®, Novartis Pharmaceuticals, East Hanover, NJ),
may come along with these advancements.
has proven superior to pamidronate in the treatment of hyper-
Nursing interventions are directed toward addressing the
calcemia and skeletal metastasis (Major et al., 2001). Similar
clinical issues that, in some cases, could be fatal. Nurses play
to pamidronate, prolonged use of zoledronic acid seems to be
an important role in maintaining patients' strict adherence
well tolerated and safe (Ali et al., 2001; Rosen et al., 2003).
to complex chemotherapy regimens, supportive therapies
Zoledronic acid currently is used at a dose of 4 mg once a
(growth factor support and bisphosphonates), and prophylactic
month in a 15- to 30-minute IV infusion, indefinitely. Con-
therapy for deep vein thromboses and infection prophylaxis.
cerns about the nephrotoxicity of zoledronic acid have been
When planning nursing care, the entire treatment team must
reported (Berenson et al., 2002), but one study reported that
understand a patient's therapeutic plan and potential com-
in patients with mildly to moderately reduced renal function,
plications associated with treatment. Careful monitoring of
dosage adjustment of zoledronic acid likely is not necessary
potential life-threatening complications is a pivotal role of
(Skerjanec et al., 2003). Zoledronic acid and pamidronate
oncology nurses. It also is critical to include patients and fam-
can reduce the risk of vertebral, wrist, and hip fractures by
ily members when discussing therapeutic goals, treatment op-
30%­50% (Body, 2003). Zolendronate is the first and only
tions, and adverse effects to watch. An ongoing, adequate pain
bisphosphonate to be proven effective in patients with all
assessment and effective management of the chemotherapy
types of bone lesions, from osteolytic (commonly found in
side effects such as the use of antiemetics, antidiarrheals, and
patients with multiple myeloma) to osteoblastic (bone damage
hydration are critical in maintaining patients' sense of well-be-
from metastases of solid tumor to the bones) and therefore
ing. Specific nursing interventions for pain include assessment
represents an important therapeutic advancement of bone
and documentation of an individual's severity of pain (0­10
metastases (Rosen, Harland, & Oosterlinck, 2002).
scale), proper positioning of affected limbs, use of supports
The American Society of Clinical Oncology has published
and braces (cervical collar, back brace, sling) to prevent ad-
its clinical practice guidelines for the use of bisphosphonates
ditional stress on bones, and consultation with physical or
in the prevention and treatment of lytic bone disease in pa-
occupational therapists. Effective pain control is possible in
tients with multiple myeloma (Berenson et al., 2002). The
patients with multiple myeloma using a three-step treatment
committee has recommended IV pamidronate or zoledronic
plan, the World Health Organization pain treatment ladder
("Cancer Pain Relief and Palliative Care," 1990), which has
Finally, oncology nurses play a key role in educating pa-
been used widely for the treatment of tumor pain. Pain man-
tients and their families regarding novel agents and help them
agement also should incorporate nonpharmacologic therapies
make informed decisions when determining whether patients
such as aromatherapy, massage, heat, cold, relaxation, and
should participate in clinical trials.
immobilization (Fellowes, Barnes, & Wilkinson, 2004).
The respiratory system is the most frequent site of infection in
patients with multiple myeloma. Nurses can teach patients and
their families how to decrease pooling of pulmonary secretions
Therapeutic options have increased, patient outcomes
and increase gas exchange (e.g., coughing and deep-breathing
have improved, and further insights have been gained into
exercises, use of incentive spirometers, avoiding contact with
the biology and genetics of multiple myeloma (Barlogie et
individuals with signs and symptoms of upper respiratory tract
al., 2004). Healthcare providers are witnessing increasing
infections). Patient and family instructions such as immediate
utilization of new technologies and biologically based novel
notification of the healthcare team when patients manifest
therapeutics (Hayashi et al., 2003). The use of tumor- and
fever, cough, sore throat, and sputum production are important
host-directed therapies may be an important adjunct in
(Tariman, 2005). Because of its defective humoral immunity,
effecting a traditional cure or return to a chronic benign
vaccination with live organisms is contraindicated in patients
state such as MGUS or smoldering myeloma (Barlogie et
with multiple myeloma and exposure to others who may have
al., 2004).
received live organism vaccines (e.g., children immunized
The nursing management of patients with multiple my-
with oral polio) should be avoided (Wong, 1995). All patients
eloma and their families offers nurses an opportunity to
with multiple myeloma, and in particular those older than age
care for patients experiencing both acute and chronic se-
65, should be immunized with a single dose of the 23-valent
quelae of the disease. Nursing care can have a direct effect
pneumococcal vaccine ("Prevention of Pneumococcal Disease,"
on early recognition of complications and management of
1997) and a yearly influenza vaccine.
treatment-related toxicity. Patient and family education re-
Oncology nurses play a vital role in ensuring that patients
garding the disease, conventional and novel treatments, and
receive the optimal psychological support necessary to
early recognition of signs and symptoms of complications
promote well-being and overall quality of life. Information
can contribute to an overall improvement in quality of life.
on support groups and multiple myeloma organizations is
Nurses play an important role not only as direct caregivers
beneficial for patients and families. Organizations such as
but also as patient advocates and educators. Oncology
the International Myeloma Foundation (www.myeloma
nurses must continue to keep abreast of recent changes and
.org) and Multiple Myeloma Research Foundation (www
advances in the care of patients with multiple myeloma
.multiplemyeloma.org) provide individual and group support.
(Tariman, 2005).
These organizations also have written patient educational
materials regarding multiple myeloma and current treatment
Author Contact: Joseph D. Tariman, RN, APN, MN, APRN-BC,
for the disease. Many of these organizations can be accessed
OCN, can be reached at jtariman@nmff.org, with copy to editor at
via the Internet.
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