Clinical Review & Education

JAMA | Review

Diagnosis and Management of Multiple Myeloma

A Review
Andrew J. Cowan, MD; Damian J. Green, MD; Mary Kwok, MD; Sarah Lee, MD; David G. Coffey, MD;
Leona A. Holmberg, MD, PhD; Sherilyn Tuazon, MD; Ajay K. Gopal, MD; Edward N. Libby, MD

Multimedia
IMPORTANCE Multiple myeloma is a hematologic malignancy characterized by presence of JAMA Patient Page page 497
abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth
causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple
myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161
people worldwide each year.

OBSERVATIONS Among patients with multiple myeloma, approximately 73% have anemia,
79% have osteolytic bone disease, and 19% have acute kidney injury at the time of
presentation. Evaluation of patients with possible multiple myeloma includes measurement
of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels;
serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis;
and full-body skeletal imaging with computed tomography, positron emission tomography,
Author Affiliations: Division of
or magnetic resonance imaging. The Revised International Staging System combines data
Medical Oncology, Department of
from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in Medicine, University of Washington,
conjunction with malignant plasma cell genomic features found on fluorescence in situ Seattle (Cowan, Green, Lee,
hybridization—t(4;14), del(17p), and t(14;16)—to assess estimated progression-free survival Holmberg, Gopal, Libby); Clinical
Research Division, Fred Hutchinson
and overall survival. At diagnosis, 28% of patients are classified as having Revised Cancer Research Center, Seattle,
International Staging stage I multiple myeloma, and these patients have a median 5-year Washington (Cowan, Green, Lee,
survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) Holmberg, Tuazon, Gopal, Libby);
Seattle Cancer Care Alliance, Seattle,
therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib),
Washington (Cowan, Green, Kwok,
an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated Lee, Holmberg, Gopal, Libby);
with median progression-free survival of 41 months, compared with historical reports Division of Hematology, Department
of 8.5 months without therapy. This induction therapy combined with autologous of Medicine, University of
Washington, Seattle (Kwok);
hematopoietic stem cell transplantation followed by maintenance lenalidomide is Sylvester Comprehensive Cancer
standard of care for eligible patients. Center, University of Miami Health
System, Miami, Florida (Coffey); Now
with Bristol Myers Squibb, Seattle,
CONCLUSIONS AND RELEVANCE Approximately 34 920 people in the US and 155 688 people
Washington (Tuazon).
worldwide are diagnosed with multiple myeloma each year. Induction therapy with an
Corresponding Author: Edward N.
injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone Libby, MD, University of Washington,
followed by treatment with autologous hematopoietic stem cell transplantation, Department of Internal Medicine,
and maintenance therapy with lenalidomide are among the treatments considered Division of Medical Oncology, 1144
Eastlake Ave E, LG-650, Seattle,
standard care for eligible patients.
Washington 98109 (elibby@
seattlecca.org).
JAMA. 2022;327(5):464-477. doi:10.1001/jama.2022.0003 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

M
ultiple myeloma is a hematologic malignancy charac-
terized by abnormal clonal plasma cells in the bone
marrow, with potential for uncontrolled growth
causing destructive osseous bone lesions, acute kidney injury,
anemia, and hypercalcemia. The median age at onset of multiple
myeloma is 69 years, and approximately 63% of patients diag-
nosed with multiple myeloma are older than 65 years.1 In 2021, an
estimated 34 290 new diagnoses of multiple myeloma and 12 410
deaths occurred in the US. In 2019, more than 155 688 people
were diagnosed with multiple myeloma worldwide.2 Approxi-
mately 100 000 deaths from multiple myeloma occur each year
worldwide.1 This review summarizes current evidence regarding
the epidemiology, clinical presentation, diagnosis, and manage-
ment of multiple myeloma.
Methods
A literature search of the PubMed database was performed
between January 1, 2000, through October 6, 2021, for English-
language studies of the epidemiology, diagnosis, clinical presenta-
tion, and treatment of multiple myeloma. Additional papers
were identified from review of the references from identified rel-
evant articles. A total of 111 reports were identified and reviewed.

464 JAMA February 1, 2022 Volume 327, Number 5 (Reprinted) jama.com

© 2022 American Medical Association. All rights reserved.

Diagnosis and Management of Multiple Myeloma
Table 1. National Comprehensive Cancer Network and International Myeloma Working Group Diagnostic Criteria for Monoclonal Gammopathy
of Undetermined Significance, Smoldering Multiple Myeloma, and Multiple Myeloma11,12
Monoclonal gammopathy Smoldering
Criteria of undetermined significance multiple myeloma
Monoclonal protein <3 g/dL ≥3 g/dLa
quantification
Bone marrow plasma cells <10% ≥10%a
by CD138 IHC
Urinary monoclonal protein <500 mg/24 h ≥500 mg/24 h
(Bence Jones protein)
Myeloma-defining events Absent Absent
Abbreviations: FLC, free light chains; MRI, magnetic resonance imaging;
PET-CT, positron emission tomography–computed tomography.
SI conversion factors: To convert calcium values to mmol/L, multiply by 0.25;
creatinine values to μmol/L, multiply by 88.4; creatinine clearance values to
mL/s/m2, multiply by 0.0167.
a
For smoldering multiple myeloma, either monoclonal protein level 3 g/dL or
greater or bone marrow plasma cells 10% or greater fulfills the diagnostic
criteria.
b
A monoclonal protein in the serum or urine, identified by serum protein
Randomized clinical trials, meta-analyses, and consensus guide-
lines were prioritized for inclusion. A total of 38 randomized clini-
cal trials, 8 nonrandomized clinical trials, 44 observational studies
(longitudinal and cross-sectional), 2 meta-analyses, and 6 con-
sensus guidelines were included.
Epidemiology
Multiple myeloma is most prevalent in people older than 65 years
in industrialized countries such as Australasia, North America, and
Western Europe.2 Year 2017 data from the Surveillance, Epidemi-
ology, and End Results program in the US document increasing in-
cidence with age, from 8.2 per 100 000 persons aged 50 to 54 years,
up to 50.6 per 100 000 persons aged 80 to 84 years.3
The cause of multiple myeloma remains unclear. Risk factors in-
clude male sex,3 occupation as a firefighter,4 obesity,5 dioxin/
Agent Orange exposure,6 and 9/11 first responder.7 In the US, inci-
dence is higher in people who are Black (14 per 100 000 persons)
compared with people who are White (6.1 per 100 000 persons).3
Pathophysiology
The clonal plasma cells that cause multiple myeloma are derived from
postgerminal center B cells. In a healthy individual, following anti-
gen exposure (eg, viral or bacterial infections), naive B cells nor-
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Review Clinical Review & Education
Multiple myeloma
Typically presentb
≥10%c
Typically presentb
End-organ damage attributable to the plasma cell
neoplasmd:
Hypercalcemia (serum calcium >1 mg/dL higher than
upper limit of normal or >11 mg/dL)
Kidney injury (serum creatinine >2 mg/dL or creatinine
clearance <40 mL/min/1.73 m2)
Anemia (hemoglobin >2 g/dL below lower limit of normal
or <10 g/dL)
Bone lesions (≥1 osteolytic lesions on osseous radiograph,
computed tomography, or PET-CT)
More than 1 of the following biomarkers of myelomad:
Clonal bone marrow plasma cells ≥60%
Ratio of involved to uninvolved serum free light chains
≥100 and involved FLC concentration 10 mg/dL or higher
>1 focal lesion on MRI ≥5 mm
electrophoresis or urine protein electrophoresis, is typically present in patients
with multiple myeloma; however, in 1% to 2% of patients it is absent (termed
“nonsecretory multiple myeloma”).
c
This requirement is not necessary for patients who have more than 1
biopsy-proven plasmacytoma, although bone marrow involvement is
common.
d
A diagnosis of multiple myeloma is confirmed in patients with 10% or greater
abnormal plasma cells in the bone marrow and at least 1 of the end-organ
events or myeloma-defining biomarkers shown.
mally proliferate and subsequently undergo somatic hypermuta-
tion of the IgH and IgL VDJ sequences.8 This process produces
long-lived plasma cells (a subset of plasma cells that provide long-
lasting, sustained antibody production)9 that reside in the bone mar-
row and are an important component of humoral immunity.8,10 The
development of an abnormal clonal plasma cell population mimics
these normal biological processes but results in excessive amounts
of intact immunoglobulin.
In almost all patients, multiple myeloma begins as monoclonal
gammopathy of undetermined significance (MGUS), a clonal plasma
cell dyscrasia present in 3% to 5% of people older than 65 years
(Table 1) and in 10% of those older than 80 years.13 MGUS is asso-
ciated with progression to active (symptomatic) multiple my-
eloma, at a rate of approximately 1% to 2% per year, with a 20-year
risk of progression to multiple myeloma of approximately 18%.14
Smoldering multiple myeloma (SMM) is a more advanced
plasma cell disorder, with 4100 patients diagnosed annually in
the US.15 Approximately 10% of patients with SMM progress to
multiple myeloma each year.15 Until recently, standard care for
management of SMM has been monitoring every 3 to 6 months of
hemoglobin, serum creatinine, serum calcium, and serum free
light chain levels; serum and urine protein electrophoresis with
immunofixation; and whole-body skeletal imaging, until disease
complications are identified. Treatment with lenalidomide should
be considered for patients with SMM who are at higher risk of
progression to symptomatic multiple myeloma, to delay or avoid
development of multiple myeloma complications.
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 Clinical Review & Education Review
Figure 1. Evaluation of Patients Suspected to Have Multiple Myeloma
Patient presents with symptoms, signs, and/or laboratory evidence
suggestive of multiple myeloma
Fatigue Hypercalcemia
Bone pain Increased total serum protein level
Anemia Lytic lesions on bone imaging studies
Kidney failure Compression or pathologic fractures on radiography
Diagnostic testing
Blood and urine testing
Complete blood cell count with differential
Comprehensive metabolic panel including calcium level
Serum protein electrophoresis with immunofixation
Serum free light chain testing
24-h urine for electrophoresis with immunofixation
β2 microglobulin, albumin, and lactate dehydrogenase
Imaging of the entire skeleton
Whole-body low-dose computed tomography
(preferred because of lower cost than other modalities)
or
Whole-body bone marrow magnetic resonance imaging
or
Whole-body positron emission tomography–computed tomography
or
Whole-body skeletal/osseous survey
(less desirable for screening because of lack of sensitivity)
Detection of monoclonal gammopathy and/or lytic or focal bone lesions
YES NO
Bone marrow aspiration and Evaluation for other causes
biopsy with cytogenic analysis of symptoms, signs, and/or
to finalize diagnosis laboratory findings
This algorithm has not been validated in clinical trials.
In 2013, the first randomized trial of treatment for patients
with SMM was reported.16 This trial randomized 119 participants to
lenalidomide + dexamethasone vs observation alone. At a median
follow-up of 40 months, 13 of 57 patients in the treatment group
(23%) developed multiple myeloma, vs 47 of 62 patients in
the observation group (76%). During the specified study period,
4 of 57 patients in the treatment group (7%) died, vs 13 of 62 (21%)
in the observation group. At a median follow-up of 40 months,
the hazard ratio (HR) for developing multiple myeloma with treat-
ment was 0.18 (95% CI, 0.09-0.32; P < .001). Compared with
observation, 3-year survival was better in the group receiving
lenalidomide + dexamethasone (HR for death, 0.31 [95% CI, 0.10-
0.91]; P = .03).
A second clinical trial17 randomized 182 patients with high-
risk SMM to either placebo or lenalidomide, continued until pro-
gression or intolerance of therapy occurred. At 3 years of follow-
up, 8 patients in the 90-patient treatment group had progressed
to multiple myeloma compared with 31 patients in the 92-patient
observation group. Overall mortality was low in both groups over
the 36-month study period; therefore, a statistically significant
difference in survival was not demonstrated. Two patients died in
the treatment group and 4 patients in the observation group.
466 JAMA February 1, 2022 Volume 327, Number 5 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Diagnosis and Management of Multiple Myeloma
Clinical Presentation
Among 1027 patients from Minnesota newly diagnosed with mul-
tiple myeloma, typical findings included anemia (defined as a
hemoglobin level <12 g/dL) in 73%, abnormalities (typically lytic
lesions) on conventional radiographs in 79%, and elevated serum
creatinine level in 19%.18 Additional characteristics included hyper-
calcemia (13%), lymphadenopathy (1%), leukopenia (20%), and
thrombocytopenia (5%).18
In patients newly diagnosed with multiple myeloma, approxi-
mately 3.3% present with extramedullary disease (defined as the
presence of 1 or more extraosseous plasmacytomas on cross-
sectional imaging), central nervous system involvement, or plasma
cell leukemia. Extramedullary disease is associated with a more ag-
gressive disease course, both at time of diagnosis and among pa-
tients with relapsed multiple myeloma.19 Central nervous system in-
volvement generally presents as either leptomeningeal disease or
cranial nerve involvement. Treatment consists of administration of
intrathecal chemotherapy with cytarabine, methotrexate, or both,
and survival is typically short (approximately 7 months).20 Plasma
cell leukemia is defined by presence of 20% or greater plasma cells
in the peripheral blood and is associated with a 4-year survival of
28%, even among patients receiving autologous hematopoietic stem
cell transplantation.21,22
Approximately 10% to 15% of patients with multiple myeloma
are diagnosed with concurrent immunoglobulin light chain amyloi-
dosis during the course of their disease.23 Light chain amyloidosis
is characterized by deposition of misfolded light chains (amyloid) in
vital organs. Impaired vital organ capacity due to amyloid cardio-
myopathy or nephropathy is a well-known complication of light chain
amyloidosis. Light chain amyloidosis should be considered in pa-
tients with multiple myeloma who have nephrotic range protein-
uria, macroglossia, periorbital ecchymoses, submandibular gland en-
largement, or unexplained cardiomyopathy. In patients with multiple
myeloma who have these features, both the bone marrow and an
abdominal fat pad biopsy should be stained with Congo red to search
for amyloid.
Diagnosis
Laboratory Evaluation in Multiple Myeloma
Initial laboratory evaluation for multiple myeloma should include
a complete blood cell count with differential; measurement of se-
rum creatinine, serum calcium, albumin, lactate dehydrogenase,
serum free light chains, and β2 microglobulin levels; and serum and
24-hour urine protein electrophoresis with immunofixation
(Figure 1). In approximately 86% of people with multiple my-
eloma, the serum protein electrophoresis reveals a monoclonal pro-
tein, defined as the presence of an atypical antibody in the blood.18
A 24-hour urine protein test to quantify Bence-Jones protein is im-
portant to document the presence of baseline proteinuria and evalu-
ate for evidence of secondary light-chain amyloidosis, which often
manifests as nephrotic range proteinuria. The serum free light chain
assay should be performed because it quantifies kappa and lambda
free light chain levels that may be elevated and that contribute to
end-organ damage. Documenting the abundance of monoclonal
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Diagnosis and Management of Multiple Myeloma
protein and serum free light chains at baseline is important for as-
sessing the extent of baseline disease and response to therapy. Moni-
toring the monoclonal protein and free light chain levels over time
will determine whether therapy is successful. Approximately 1% to
2% of patients present with absence of measurable serum or urine
markers, termed “nonsecretory” multiple myeloma.24
Flow cytometry to identify abnormal circulating plasma cells
should be considered if plasma cell leukemia is a possible diagno-
sis. A unilateral bone marrow aspirate and biopsy should be per-
formed in all patients suspected of having multiple myeloma; analy-
sis of the marrow includes morphology of plasma cells; quantification
of CD138+ plasma cells in the core biopsy by immunohistochemis-
try, flow cytometry, fluorescence in situ hybridization (FISH), and
conventional cytogenetics. Either baseline whole-body low-dose
computed tomography (CT), whole-body magnetic resonance
imaging (MRI), or whole-body positron emission tomography CT
(PET-CT) should be performed in all new diagnoses of multiple my-
eloma. Imaging may document compression fractures, lytic le-
sions, or pathologic fractures. In resource-limited settings without
access to advanced imaging modalities, an osseous survey may be
performed instead.
Until 2014, the following criteria were necessary for diagnosis
of multiple myeloma: 10% or greater clonal plasma cells in the bone
marrow, and demonstrable end-organ damage as evidenced by at
least 1 of the classic laboratory or radiographic findings of multiple
myeloma (hypercalcemia, kidney involvement, anemia, and bone le-
sions [“CRAB”]) (Table 1). In 2014, the criteria for diagnosing active
or symptomatic multiple myeloma requiring treatment were ex-
panded by the International Myeloma Working Group to include “my-
eloma defining biomarkers,” eg, 60% or greater bone marrow plasma
cells, ratio of involved to uninvolved free light chains 100 or greater,
or more than 1 focal lesion on magnetic resonance imaging (MRI) that
measures at least 5 mm.11 Thus, a diagnosis of multiple myeloma is
confirmed in patients with 10% or greater abnormal plasma cells in
the bone marrow and at least 1 of the end organ events (CRAB cri-
teria) or myeloma-defining biomarkers shown in Table 1.
Imaging in Multiple Myeloma
Osseous end-organ damage, consisting of osteolytic bone lesions
that can lead to pathologic fractures, is common and contributes
to substantial morbidity and mortality. Bony end-organ damage is
detected in 70% of patients with multiple myeloma at diagnosis.18
Osseous and extraosseous plasmacytomas (tumor-like growth of
plasma cells) are also detectable from baseline imaging. Imaging
is important to evaluate the extent of osteolytic bone disease and
plasmacytomas in patients with newly diagnosed or relapsing mul-
tiple myeloma.
Several modalities can be used for imaging in multiple my-
eloma. The conventional whole-body radiograph (osseous survey)
detects lytic lesions only when at least 30% to 50% of the cortex is
eroded. By that time, patients are already at risk for pathologic frac-
tures. Therefore, whole-body radiography has been replaced by more
sensitive imaging techniques.25 Specifically, CT or PET-CT are pre-
ferred for diagnosis of multiple myeloma and should be used to evalu-
ate patients with SMM when the clinical suspicion for multiple my-
eloma is high.26 CT scanning is used to detect lytic lesions in people
with multiple myeloma, SMM, and MGUS. In a study of 212 patients
without lytic lesions on plain radiographic survey, CT identified lytic
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© 2022 American Medical Association. All rights reserved.
Review Clinical Review & Education
lesions in 20% of patients. PET-CT evaluates the presence, extent,
and metabolic activity of osseous and extraosseous manifesta-
tions of multiple myeloma. In 1 study, PET-CT was compared with
whole-body radiography for detection of bony lesions in 46 pa-
tients with newly diagnosed multiple myeloma. Nine of the 46
patients (19%) had negative findings for osteolytic lesions on whole-
body radiography but were found to be positive by PET-CT.27
MRI is an alternative imaging modality in multiple myeloma that
includes evaluation of the bone marrow.25 Current consensus guide-
lines for differentiating SMM from multiple myeloma requiring
therapy recommend CT as the initial diagnostic tool in people with
SMM; if findings are negative, CT should be followed by MRI to look
for more than 1 focal lesion in the marrow.28 In a study of 149 pa-
tients with SMM, when more than 1 focal lesion was present by MRI,
progression to multiple myeloma requiring active treatment oc-
curred at a median follow-up of 13 months, compared with those
without focal lesions on MRI, in whom median time to progression
was not reached at 43 months.29 These imaging modalities are also
used to follow up patients receiving active therapy to identify dis-
ease relapse or to monitor response to treatment.28
Prognosis
Overall Survival
Since 2000, survival from the time of diagnosis of multiple my-
eloma has improved.30 A recent long-term follow-up analysis of 1000
patients with newly diagnosed multiple myeloma treated between
2007 and 2016 with lenalidomide + bortezomib + dexametha-
sone (RVd [or VRd]) induction therapy reported a median overall sur-
vival of 126.6 months (median follow-up, 67 months).31 Prior to the
year 2000, median overall survival of multiple myeloma was closer
to 30 months.32 Despite improved survival for newly diagnosed mul-
tiple myeloma, approximately 20% of people newly diagnosed have
substantially worse outcomes. In patients with multiple myeloma,
serum biomarkers of disease burden and genetic risk factors are com-
bined in an algorithm, the Revised International Staging System, to
estimate prognosis (Table 2).
Genetic Risk Stratification of Multiple Myeloma
In patients with multiple myeloma, genetic analysis of the malig-
nant plasma cell can be performed using FISH, in which fluorescent
probes bind to chromosomal changes of concern in the myeloma
cell, thereby identifying genetic factors to risk stratify patients. Limi-
tations include variability of diagnostic thresholds between differ-
ent laboratories and lack of standardization of FISH panels used for
multiple myeloma.34 Conventional cytogenetics (karyotyping) are
routinely performed but lack sensitivity to routinely detect chro-
mosomal abnormalities relevant in multiple myeloma.35
The following FISH findings at diagnosis are associated with
worse progression-free survival and overall survival in multiple
myeloma (also referred to as high-risk chromosomal changes): 1q+,
t(4;14), t(14;16), t(14;20), and del(17p) (TP53 mutation).36-39 The
presence of multiple high-risk features, such as the combination of
del(17p) and 1q+, confer additional risk.40 The t(4;14) change
results in overexpression of the fibroblast growth factor receptor 3
(FGFR3) gene, occurs in approximately 7% to 8% of patients newly
diagnosed with multiple myeloma, and is associated with worse
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 Clinical Review & Education Review
Table 2. Revised International Staging System Staging for Multiple Myeloma
β2 microglobulin, mg/dL
Albumin, g/dL
Lactate dehydrogenase
High-risk chromosomal abnormalities—del (17p), t(4;14),
t(14;16)
5-y survival rate, %
Abbreviation: R-ISS, Revised International Staging System.
a
Either albumin level less than 3.5 g/dL, or β2 microglobulin level 5.5 mg/L or
lower but greater than 3.5 mg/L, meets R-ISS stage 2 criteria.
progression-free and overall survival.36 Del(17p) is due to loss of
p53, a tumor suppressor gene, on the long arm of chromosome
17.41-43 Del(17p) occurs in 5% to 20% of patients and is associated
with worse outcomes in patients with multiple myeloma.37 Other
changes, such as t(14;16), result in overexpression of the c-MAF
oncogene focus and are identified in 3% to 5% of patients newly
diagnosed with multiple myeloma.44
In patients with relapsed multiple myeloma, new FISH findings
may arise, which suggests clonal evolution, defined as progressive
acquisition of an increasing number of mutations contributing to
more advanced disease. Presence of a secondary deletion (17p),
biallelic inactivation of tumor suppressor genes, or both is associ-
ated with poor outcomes.45
Additional chromosomal changes may include hyperdiploidy, de-
fined as trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and/or 21 or the
translocation t(11;14) seen in 15% to 20% of patients (causes over-
expression of cyclin-D1), but these are not associated with poorer
prognosis.46
Treatment of Newly Diagnosed Multiple Myeloma
General Principles of Therapy
The primary treatment goal for patients with multiple myeloma is
to increase survival and quality of life by mitigating disease-related
complications through suppression of the malignancy over the long
term. Therapies typically aim to reduce the abundance of malig-
nant plasma cells in the bone marrow, which is measured in part by
the level of the monoclonal protein and serum free light chains.
Greater reduction in these malignant plasma cells correlates with
more durable disease control.47 The most significant advance-
ments in multiple myeloma therapy have been the introduction
of proteasome inhibitors (eg, bortezomib, ixazomib, and carfil-
zomib), immunomodulatory agents (eg, thalidomide, lenalido-
mide, and pomalidomide), monoclonal antibodies directed against
myeloma cell surface antigens (eg, daratumumab, elotuzumab, and
isatuximab), and autologous hematopoietic stem cell transplanta-
tion (Figure 2). Standard first-line therapy in the US for newly diag-
nosed multiple myeloma in both transplant-eligible and non–
transplant-eligible patients is RVd—the combination of lenalidomide
(immunomodulatory drug), bortezomib (proteasome inhibitor), and
steroids (dexamethasone). Other primary therapies are described
in Table 3. Major clinical trials of treatments for newly diagnosed
multiple myeloma are summarized in Table 4 and Table 5.
468 JAMA February 1, 2022 Volume 327, Number 5 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Diagnosis and Management of Multiple Myeloma
Risk stratification for multiple myeloma33
R-ISS stage 1 R-ISS stage 2 R-ISS stage 3
<3.5 <5.5a >5.5
≥3.5 <3.5a Any
Within upper limit of normal Any Greater than upper limit of normalb
Absent Present or absent Presentb
77 62 47
b
Either lactate dehydrogenase level greater than upper limit of normal or
presence of high-risk chromosomal abnormalities is necessary, in addition to
β2 microglobulin level greater than 5.5 mg/L, to meet R-ISS stage 3 criteria.
Once the diagnosis of multiple myeloma is confirmed, initial
(induction) therapy should be initiated, and eligibility for autolo-
gous (donor and recipient are the same person) hematopoietic
stem cell transplantation should be evaluated. Patients are consid-
ered eligible for autologous hematopoietic stem cell transplanta-
tion if they have adequate organ function and good functional sta-
tus. Approximately 25% of all US patients newly diagnosed with
multiple myeloma in 2015 underwent transplant.89 Older age is not
a contraindication to transplant, although most patients undergo-
ing the procedure are younger than 70 to 75 years.90 Significant
cardiac, pulmonary, or hepatic disease often excludes patients, but
transplant may still be performed safely in patients with kidney
compromise or failure.
Transplant-Eligible Patients
Induction, Consolidation, and Maintenance Therapy
Transplant-eligible patients typically receive 3 to 6 months of
induction therapy prior to transplant. Although not standard prac-
tice, consolidation, referring to additional treatment cycles after
transplant, may be given and is currently undergoing evaluation in
clinical trials. Maintenance therapy refers to low-dose antimyeloma
therapy, with the goal of prolonging remission after initial therapy.
Currently, the standard initial therapy for patients eligible for trans-
plant is RVd. A US national cooperative group clinical trial S0777 led
by the Southwest Oncology Group randomized 525 patients with
newly diagnosed multiple myeloma to RVd or to doublet therapy
with lenalidomide + dexamethasone (Rd). Progression-free sur-
vival was significantly better in those randomized to RVd, com-
pared with Rd (41 months compared with 29 months).57 Based on
these results and additional clinical trial evidence, RVd is the cur-
rent standard of care.12,57
Recently, results from the GRIFFIN and CASSIOPEIA clinical trials
have studied combining the anti-CD38 antibody, daratumumab, with
proteasome inhibitor + immunomodulatory agent + glucocorti-
coid regimens for patients with newly diagnosed multiple
myeloma.58,66 GRIFFIN randomized 207 patients in the US with
newly diagnosed multiple myeloma to either daratumumab with
RVd or RVd alone. The primary outcome of complete response rate
at the end of consolidation after transplant was significantly higher
in the combined therapy group, compared with RVd alone (42.4%
vs 32%; odds ratio, 1.57 [95% CI, 0.87-2.82]). In the CASSIOPEIA trial,
1085 patients in Europe with newly diagnosed multiple myeloma
were randomized to daratumumab with bortezomib + thalido-
mide + dexamethasone (VTd) or to VTd alone before and after
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Diagnosis and Management of Multiple Myeloma
Figure 2. Treatment of Newly Diagnosed Multiple Myeloma
Established diagnosis of untreated multiple myeloma
Assessment of patient performance status
Estimate baseline physical capacity to perform activities of daily
living to assess ability to tolerate chemotherapy
In patients with poor performance status or general frailty, consider
using chemotherapy regimens with less risk of adverse effects
Transplant eligibilty and induction therapy determination
Transplant eligiblea
Adequate organ function
Good performance status
Induction therapy
Three- or 4-drug combination including a proteasome inhibitor,
immunomodulatory drug, and glucocorticoid with or without
an anti-CD38 antibodyb
Autologous hematopoietic stem cell transplant performed
YES NO
Maintenance therapy
Immunomodulatory drug, proteasome inhibitor, or combination therapy (for select high-risk patients)b
This algorithm has not been validated in clinical trials. LDH indicates lactate
dehydrogenase.
a
It may be necessary to postpone transplant until later in the disease course for
patients recovering from complications of multiple myeloma such as fractures
requiring orthopedic surgery, compression fractures with chronic severe pain,
complications of induction therapy, physical and emotional setbacks related to
transplant.58 At a median follow-up of 18.8 months, complete re-
sponse rates were significantly higher in the daratumumab + VTd
group, compared with VTd alone (29% vs 20%; odds ratio, 1.60 [95%
CI, 1.21-2.12]). These data suggest that combining daratumumab with
proteasome inhibitors, immunomodulatory agents, and glucocor-
ticoids as initial treatment for multiple myeloma may improve out-
comes in transplant-eligible patients.
The primary toxicities of induction therapy drugs include pe-
ripheral neuropathy (up to 33% of patients treated with RVd), vari-
cella reactivation, venous thromboembolic events, neutropenia, in-
fections, and teratogenicity with immunomodulatory agents
(Table 3).91 Monoclonal antibodies are associated with infusion-
related reactions, consisting of dypnea, cough, chills, rash, allergic
rhinitis, sore throat, and nausea, typically with the first dose, in up
to 45% of patients.91
Autologous Hematopoietic Stem Cell Transplantation
for Multiple Myeloma
For patients undergoing stem cell transplantation, colony-
stimulating factor, chemotherapy (typically cyclophosphamide), or
both is used to stimulate and mobilize peripheral blood stem cells,
which are collected using apheresis. After stem cell collection, pa-
tients receive intravenous high-dose melphalan (a potent antimy-
eloma agent), followed by reinfusion of stem cells. The Inter-
groupe Francophone du Myélome 2009 clinical trial randomized
700 patients with newly diagnosed multiple myeloma treated with
RVd induction and consolidation to either transplant or no trans-
jama.com
© 2022 American Medical Association. All rights reserved.
Review Clinical Review & Education
Evaluation of prognosis using the Revised International Staging System (R-ISS)
R-ISS stage reflects prognosis and may help with decisions regarding choice
of chemotherapy regimen
Calculated using serum β2 microglobulin, albumin, and LDH levels with genetic risk
classifiers del(17p), t(4;14), and t(14;16). (see Table 2)
Transplant ineligible Transplant ineligible
with high performance statusa with poor performance status
Adequate organ function Inadequate organ function
Good performance status Poor performance status
Induction therapy Induction therapy
Three- or 4-drug combination including a Two- or 3-drug combination including 1 or 2
proteasome inhibitor, immunomodulatory of the following: proteasome inhibitor,
drug, or anti-CD38 antibody, plus a immunomodulatory drug, anti-CD38
glucocorticoid (required)b antibody; plus a glucocorticoid (required)b
Maintenance therapy
Immunomodulatory drug or proteasome inhibitorb
multiple myeloma, or patient choice.
b
Examples of proteasome inhibitor: bortezomib (subcutaneous), ixazomib
(oral), and carfilzomib (intravenous). Immunomodulatory drug: oral
thalidomide, lenalidomide, or pomalidomide. Anti-CD38 antibody:
daratumumab or isatuximab (intravenous or subcutaneous). Glucocorticoid:
dexamethasone or prednisone (oral or intravenous).
plant, followed by maintenance lenalidomide for 1 year. At 14-
month follow-up, progression-free survival was significantly better
in people who received transplant (50 months vs 36 months; ad-
justed HR for disease progression or death, 0.65 [95% CI, 0.53-
0.80]). A separate clinical trial conducted in Europe, the EMN02/
HO95 trial, randomized 1197 patients to either transplant or
bortezomib + melphalan + prednisone consolidation after induc-
tion with bortezomib + cyclophosphamide + dexamethasone.81 The
median progression-free survival was significantly better with trans-
plant (56.7 months vs 41.9 months; HR, 0.73 [95% CI, 0.62-0.85]).
These randomized clinical trials support continued benefit for trans-
plant after induction for eligible patients with multiple myeloma. In
patients with high-risk multiple myeloma, studies have suggested
that a tandem autologous stem cell transplant (performance of a sec-
ond transplant approximately 3 months after the first) may im-
prove overall survival and progression-free survival. The role of tan-
dem transplantation for multiple myeloma is under study.92
Mortality rates from transplant are less than or equal to 1%.88
The most common adverse effects of transplant include mucositis,
nausea/vomiting, anorexia, and myelosuppression (associated with
higher risk of infection).85 There is a small increase in secondary ma-
lignancies, particularly myelodysplastic syndrome and acute my-
eloid leukemia, in patients receiving long-term lenalidomide main-
tenance therapy after transplant.93
Reduced-intensity allogeneic (donor and recipient are not the
same person) hematopoietic stem cell transplantation using donor
stem cells is not widely used for treatment of multiple myeloma, and
(Reprinted) JAMA February 1, 2022 Volume 327, Number 5 469
 470
Table 3. Approved Drugs Used in Treatment of Multiple Myeloma
Class Mechanism of action
Immunomodulatory agents Bind to an E3 ubiquitin ligase
(IMiDs)48-53 complex with cereblon, resulting in
modulation of substrate specificity,
causing proteasome degradation of
disease-related proteins54-56
Typical administration
Drug name schedule Eligibility and efficacy rates Adverse effects
Lenalidomide + Oral (usually given on Eligibility: newly diagnosed, relapsed/refractory Myelosuppression (neutropenia): 80%
pomalidomide + days 1-14 of a 21-d Efficacy: lenalidomide + dexamethasone for Venous and arterial thromboembolic events:
thalidomide cycle or days 1-21 newly diagnosed multiple myeloma—overall 4%-5%
of a 28-d cycle) response rate, 71.5%57
Hypersensitivity reaction (dermatologic):
Pomalidomide + dexamethasone for relapsed 20%-30%
multiple myeloma—overall response rate, 30%53 Gastrointestinal toxicity (constipation or
diarrhea): 40%-50%
Clinical Review & Education Review

Proteasome inhibitors57-65
Inhibition of the 20S proteasome
(reversible [bortezomib + ixazomib];
irreversible [carfilzomib])
Fatigue: 30%-40%
Neuropathy: 10%-15%
Embryo/fetal toxicity: rare, requires REMS
program
Bortezomib Subcutaneous/ Eligibility: newly diagnosed, relapsed multiple Peripheral neuropathy: 30%-40%
intravenous, usually myeloma Gastrointestinal toxicity (diarrhea, nausea,
once weekly or twice Efficacy: lenalidomide + bortezomib + vomiting): 15%-20%
weekly dexamethasone for newly diagnosed multiple Thrombocytopenia: 30%
myeloma—overall response rate, 81.5%57

JAMA February 1, 2022 Volume 327, Number 5 (Reprinted)

Monoclonal antibodies66-72
CD38 monoclonal antibody; CD38
expressed on all myeloma cells;
mechanism appears to be through
induction of antibody-dependent
cellular cytotoxicity, apoptosis,
complement-dependent cytotoxicity
Ixazomib Oral, weekly Eligibility: relapsed multiple myeloma
Efficacy: ixazomib + lenalidomide +
dexamethasone for relapsed multiple
myeloma—overall response rate, 78%64
Carfilzomib Intravenous, twice or Eligibility: relapsed multiple myeloma Cardiomyopathy: 8%-10%
once weekly Efficacy: carfilzomib + lenalidomide + Acute kidney injury: 2%
dexamethasone for relapsed multiple Thrombocytopenia: 32%
myeloma—overall response rate, 87.1%62
Carfilzomib + dexamethasone for relapsed
multiple myeloma—overall response rate, 77%59
Daratumumab Subcutaneous or Eligibility: newly diagnosed and relapsed Infusion-related reactions: 10%-50%
intravenous multiple myeloma Infections (typically URI/bronchitis/pneumonia):
Efficacy: daratumumab + lenalidomide + 15%-40%
dexamethasone for newly diagnosed multiple
Hepatitis reactivation: uncommon
myeloma—overall response rate, 92.9%72
Isatuximab Intravenous Eligibility: Relapsed multiple myeloma
Efficacy: isatuximab, pomalidomide, and

© 2022 American Medical Association. All rights reserved.

Antibody-drug conjugates74-76
SLAMF7 monoclonal antibody; cell
surface glycoprotein CS1 is found to
be universally expressed at high
levels on myeloma cells
Monoclonal antibody targeting
BCMA (a cell surface protein
expressed routinely on plasma cells)
with a drug conjugate, MMAF
dexamethasone for relapsed multiple
myeloma—overall response rate, 60%70
Elotuzumab Intravenous Eligibility: Relapsed multiple myeloma
Efficacy: elotuzumab + lenalidomide +
dexamethasone—overall response rate, 79%73
Belantamab mafodotin Intravenous, Eligibility: relapsed multiple myeloma
every 21 d Efficacy: overall response rate, 30%74
Infusion-related reactions: >50
Elevated liver enzyme levels: 2%-3%
Keratopathy: 50%-60%, REMS required
Cytopenias:
Anemia, 32%
Decreased neutrophils, 28%
Thrombocytopenia, 62%)

(continued)

jama.com
Diagnosis and Management of Multiple Myeloma
 Table 3. Approved Drugs Used in Treatment of Multiple Myeloma (continued)
Typical administration

jama.com
Class Mechanism of action
Selective inhibitors of nuclear export Through blocking of exportin 1,
(SINE)77,78 inhibition of nuclear export of tumor
suppressor proteins and growth
factors; leads to apoptosis of
myeloma cells
Chimeric antigen receptor (CAR) Autologous T cells are collected from Idecabtagene
T cells79,80 a patient, transduced using a viral
vector with a chimeric antigen
receptor targeting BCMA, then
expanded and formulated prior to
administration; lymphodepleting
chemotherapy is administered,
followed by infusion of CAR T cells,
Drug name schedule Eligibility and efficacy rates Adverse effects
Selinexor Oral, once or twice Eligibility: relapsed multiple myeloma Nausea: 50%
weekly Efficacy: Selinexor + bortezomib + Anorexia: 35%
dexamethasone—overall response rate, 76.4%78
Cytopenias: 40%-50%
Administered as a Eligibility: relapsed multiple myeloma Cytokine release syndrome: 80%-90%
vicleucel single infusion of CAR T Efficacy: overall response rate, 73%79 Immune effector cell–mediated neurologic
cells after syndrome: 10%-20%
lymphodepleting
chemotherapy Cytopenias: 80%-90%
Hypogammaglobulinemia infections: 70%-80%
Diagnosis and Management of Multiple Myeloma

and the formulated CAR T product in

the patient recognizes and kills
tumor cells, leading to expansion of
the CAR T cells in a patient
Alkylators Nitrogen mustard compounds; Melphalan + Oral or intravenous, Eligibility: newly diagnosed and relapsed Cytopenias
alkylators act by crosslinking DNA, cyclophosphamide may be weekly to every multiple myeloma Nausea
leading to DNA damage and cellular 28 d Efficacy: bortezomib + melphalan + prednisone
death Diarrhea
for newly diagnosed multiple myeloma—overall
response rate, 77%81 Fatigue
Glucocorticoids82,83 Indirectly repress target genes via Dexamethasone Intravenous or oral, Muscle atrophy
interaction with NF-κB and AP-1, usually weekly Hyperglycemia
important factors in MM
pathogenesis Irritability
Insomnia
Abbreviations: AP-1, activator protein 1; BCMA, B-cell maturation antigen; MMAF, monomethyl auristatin F; NF-κB, nuclear factor kappa B; REMS, Risk Evaluation and Mitigation Strategies; SLAM7, surface antigen CD319;
URI, upper respiratory infection; XPO1, exportin 1.

© 2022 American Medical Association. All rights reserved.

(Reprinted) JAMA February 1, 2022 Volume 327, Number 5
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471
 Clinical Review & Education Review Diagnosis and Management of Multiple Myeloma

Table 4. Selected Randomized Clinical Trials of Induction Chemotherapy With or Without Transplant for Newly Diagnosed Multiple Myeloma
Southwest Oncology Group Eastern Cooperative Oncology Group
S0777 trial57 E1A11 trial84 IFM 200985
Study groups RVd vs Rd KRd vs RVd, 36 wk RVd ×7 cycles + transplant with 1 y
lenalidomide maintenance vs RVd ×8
cycles with 1 y lenalidomide maintenance
Population Newly diagnosed multiple myeloma Newly diagnosed multiple myeloma; Newly diagnosed multiple myeloma
ineligible for, or not intended for
immediate AHSCT
Median follow-up, mo 84 9 44
Results
Progression free survival, mo 41 vs 29 (P = .003) 34.6 vs 34.4 (P = .74) 50 vs 36 (P < .001)
Overall survival Not reached vs 69 mo (P = .71) 3 y: 86% vs 84% (P = .92) 4 y: 81% vs 82% (P = .87)
Duration of response, mo 50 vs 39 (P = .02)
Overall response rate, % 90.2 vs 78.8 (P = .001) 87 vs 84 (P = .26)
Abbreviations: AHSCT, autologous hematopoietic stem cell transplantation; dexamethasone; Rd, lenalidomide + dexamethasone; RVd,
IFM, Intergroupe Francophone du Myélome; KRd, carfilzomib + bortezomib + lenalidomide + bortezomib + dexamethasone.

Table 5. Selected Randomized Clinical Trials of Transplant With or Without Consolidation With or Without Maintenance
for Newly Diagnosed Multiple Myeloma
Cancer and Leukemia Group
B 100104 trial86
Study groups Posttransplant maintenance with
lenalidomide (10 mg daily) vs placebo
Population Patients with stable disease or better
after transplant, up to day 100 after
transplant
Median follow-up, mo 91
Location US
Outcomes
Time to progression/ Median time to progression, 57.3 mo
progression-free survival (lenalidomide) vs 28.9 mo (placebo)
(P < .001)
Overall survival Median, 113.8 mo lenalidomide vs 84.1
mo placebo (P < .001)
Secondary malignancy rate 8% hematologic malignancy and 6% solid 7% (bortezomib) vs 7% (thalidomide)
tumor in (lenalidomide) vs 1%
hematologic malignancy and 4% solid
tumor (placebo)
European HOVON-65/
GMMG-HD4 trial87
Bortezomib vs cytotoxic chemotherapy
induction and bortezomib vs thalidomide
maintenance in transplant patients
Newly diagnosed multiple myeloma
96
75 centers in Germany, the Netherlands,
Belgium
Median progression-free survival, 34 mo
(bortezomib) vs 28 mo (thalidomide)
(P < .001)
96-mo overall survival, 45%
(bortezomib) vs 48% (thalidomide)
(P = .24)
Blood and Marrow Transplant
Clinical Trials Network 0702 study88
Single transplant vs single transplant with
RVd consolidation vs tandem transplant
all with lenalidomide maintenance until
progression
Symptomatic multiple myeloma within
12 mo of starting therapy
US
ITT 6-y progression-free survival, 43.9%
(tandem transplant + lenalidomide) vs
39.7% (transplant + RVd + lenalidomide)
vs 40.9% (P = .60)
ITT 6-y overall survival, 73.1% (tandem
transplant + lenalidomide) vs 74.9%
(transplant + RVd + lenalidomide) vs
76.4% (transplant + lenalidomide)
(P = .80)
At 38 mo: 5.6% (tandem
transplant + lenalidomide) vs 5.7%
(transplant + RVd + lenalidomide)
vs 4.1% (transplant + lenalidomide)

Abbreviations: ITT, intention to treat; RVd, lenalidomide + bortezomib + dexamethasone.

clinical trial data are conflicting regarding benefit.94 Allogeneic he-
matopoietic stem cell transplantation for multiple myeloma is pri-
marily used for younger patients (usually younger than 50 years) who
have high-risk disease and should be conducted within clinical trials
whenever possible.
After transplant, the standard of standard care is maintenance
therapy (defined as long-term continuous low-dose administration
of an active antimyeloma agent) with either lenalidomide or
bortezomib to prolong remission. Maintenance therapy with
lenalidomide improved survival in a single large trial and was associ-
ated with improved survival in a meta-analysis86,95 (Table 5). Con-
solidation was not supported by randomized trial data.88 For
patients with high-risk features—eg, 1q+, del(17p), t(4;14), t(14;16),
t(14;20), or plasma cell leukemia—the foundation of maintenance
therapy is a proteasome inhibitor–based regimen. Triplet mainte-
nance therapy with an RVd-like combination should be considered
in selected patients.96
Transplant-Ineligible Multiple Myeloma
For patients ineligible for transplant, recommended treatment con-
sists of either 3-drug combination regimens such as RVd, or dara-
tumumab + lenalidomide + dexamethasone, followed by mainte-
nance with lenalidomide. The Southwest Oncology Group S0777 trial
randomized 525 patients with multiple myeloma for whom trans-
plant was not immediately intended; 264 were randomized to RVd
and 261 to Rd. Forty-three percent of patients were 65 years or
older,57 and these patients received therapy doses adjusted for age
and chronic medical conditions; RVd was superior to Rd in patients
older than 65 years (progression-free survival HR, 1.27 [95% CI 1.00-
1.61]). Older patients who cannot tolerate RVd may receive therapy

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Diagnosis and Management of Multiple Myeloma
with lenalidomide or bortezomib combined with a glucocorticoid as
an alternative.97
Treatment Response
Assessment
Response to therapy in multiple myeloma is measured by moni-
toring the complete blood cell count, serum and urine electro-
phoresis, serum free light chain levels, bone marrow biopsy, and
imaging. Disappearance of the monoclonal protein, and improve-
ment in blood counts, kidney function, and pain, are indicative of
successful treatment.
Minimal Residual Disease in Multiple Myeloma
New technologies are available to evaluate patients for minimal re-
sidual disease (ie, very low levels of multiple myeloma in the bone
marrow after therapy). Next-generation sequencing of the immu-
noglobulin gene within myeloma cells allows detection of malig-
nant plasma cells present at 1 abnormal cell per million normal cells
(10−6) and is now approved by the US Food and Drug Administra-
tion (FDA) for multiple myeloma.98 Minimal residual disease as-
sessed by next-generation sequencing can be used to predict long-
term outcomes, and its potential application in treatment is under
study (ClinicalTrials.gov identif iers NCT03901963 and
NCT04071457).
Treatment of Relapsed Multiple Myeloma
Many therapeutic options are available for patients with relapsed
and refractory multiple myeloma (Table 3). If not previously re-
ceived, treatment with daratumumab or isatuximab—both anti-
CD38 monoclonal antibodies—combined with a steroid and either
an immunomodulatory drug or a proteasome inhibitor, can be highly
effective, with overall response rates of 60% to 85%.67-70,99,100
Carfilzomib, a second-generation proteasome inhibitor, may be
combined with an immunomodulatory agent or alkylating agent
(cyclophosphamide).59-62,84 Elotuzumab, an anti-SLAMF7 (sur-
face antigen CD319) monoclonal antibody, is effective when admin-
istered in combination with dexamethasone and either lenalido-
mide or pomalidomide.71,73 Selinexor, an exportin 1 inhibitor, was
approved in 2019 to treat patients with relapsed multiple my-
eloma. In 2020, belantamab mafodotin, a monoclonal antibody–
drug conjugate that targets a protein on the surface of plasma cells,
B-cell maturation antigen, was approved by the FDA.74,75,77 Benda-
mustine has both alkylating and antimetabolite activity and is ef-
fective for some patients.101 Multiagent cytotoxic chemotherapy
(eg, cyclophosphamide + doxorubicin + cisplatin + etoposide
[PACE], or other similar regimens) can be administered for short-
term disease control or as a bridge to more durable therapies in some
patients with rapidly progressive disease.102
Transplant should be considered at the time of disease relapse
in patients with stored autologous stem cells who have achieved a
durable remission from their first transplant; patients who post-
poned transplant at diagnosis should be strongly considered for this
procedure at first relapse.103
In April 2021, the first chimeric antigen receptor (CAR) T-cell
therapy targeting the B-cell surface maturation antigen for mul-
tiple myeloma, idecaptagene vicleucel (Ide-cel/Abecma), was ap-
jama.com
© 2022 American Medical Association. All rights reserved.
Review Clinical Review & Education
proved by the FDA for patients with relapsed multiple myeloma.79,80
In CAR T-cell therapy, T cells are collected from a patient’s blood-
stream and then genetically engineered to target a surface protein
on the myeloma cell membrane. The engineered CAR T cells are then
administered back to the patient after immunosuppressive chemo-
therapy (to prevent the immune system from destroying the new
T cells). Bispecific T-cell engagers, engineered molecules that bind
and activate T cells to stimulate their targeting of malignant cells,
are being tested in advanced clinical trials with success in relapsed
multiple myeloma.104 In addition, new derivatives of immunomodu-
latory drugs, known as cereblon E3 ligase modulators (CELMoDs),
have been tested in early phase studies and shown early evidence
of efficacy and safety in relapsed and refractory multiple myeloma.105
Supportive Care for Multiple Myeloma
Bone Health
Patients with multiple myeloma have a 40% to 50% risk of devel-
oping fractures or bone pain requiring palliation (together, typi-
cally called skeletal-related events).106 In randomized clinical trials,
bisphosphonates and receptor activator of nuclear factor kappa-B
ligand inhibitors reduced the risk of skeletal-related events in pa-
tients with multiple myeloma.106-108 Common adverse effects of
these drugs included hypocalcemia (pooled relative risk, 2.19 vs pla-
cebo) and osteonecrosis of the jaw (pooled relative risk, 4.61) of
patients.108 For patients with pathologic fractures, vertebroplasty
or intramedullary nail fixation may be necessary to improve pain and
functional status.109
Infections
Patients with multiple myeloma have an increased rate of infec-
tions, due to myeloma-related immunodeficiency (B-cell and T-cell
dysfunction) and the routine use of immunosuppressive
treatments.110 Antiviral medications such as acyclovir and valacy-
clovir should be prescribed to prevent reactivation of varicella zos-
ter and shingles in patients receiving proteasome inhibitors such as
bortezomib, carfilzomib, and ixazomib; anti-CD38; or anti-SLAM7
monoclonal antibody therapy, such as daratumumab, isatuximab,
and elotuzumab.111 In select patients, such as those with multiple
comorbidities, antibiotic prophylaxis with levofloxacin should be
considered to prevent bacterial infections.112 Growth factors such
as filgrastim and erythropoietin are often necessary to treat
therapy-related neutropenia and anemia.
Venous Thromboembolic Events
Patients with multiple myeloma are at increased risk of venous and
arterial thromboembolism, particularly when receiving immuno-
modulatory drugs such as thalidomide, lenalidomide, or pomalido-
mide. Thromboembolic prophylaxis with aspirin, low-molecular-
weight heparin, or a direct-acting oral anticoagulant is recommended
for all patients with multiple myeloma who receive an immuno-
modulatory drug depending on underlying risk.111
Palliative Radiation
For patients with painful lytic or extramedullary lesions, a short
course of involved-field radiation therapy may be considered to pal-
liate symptoms. The International Lymphoma Radiation Oncology
(Reprinted) JAMA February 1, 2022 Volume 327, Number 5 473
 Clinical Review & Education Review Diagnosis and Management of Multiple Myeloma

Group guidelines on radiation therapy recommend doses of 8 Gy

in 1 fraction, 20 Gy in 5 fractions, or 20 to 30 Gy in between 10
to 20 fractions, for palliation of painful myeloma bone lesions
or plasmacytomas.113
Limitations
This review has several limitations. First, the review discusses many
drugs that may not be widely available throughout the world. Sec-
ond, a formal review of the quality of the literature was not con-
ducted. Third, some relevant references may have been missed.
Conclusions
Approximately 34 920 people in the US and 155 688 people world-
wide are diagnosed with multiple myeloma each year. Induction
therapy with an injectable proteasome inhibitor, an oral immuno-
modulatory agent and dexamethasone followed by treatment with
autologous hematopoietic stem cell transplantation, and mainte-
nance therapy with lenalidomide are among the treatments con-
sidered standard care for eligible patients.

ARTICLE INFORMATION
Accepted for Publication: January 4, 2022.
Author Contributions: Drs Cowan and Libby had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Cowan, Gopal, Libby.
Acquisition, analysis, or interpretation of data:
Cowan, Green, Kwok, Lee, Coffey, Holmberg,
Tuazon, Libby.
Drafting of the manuscript: Cowan, Tuazon, Libby.
Critical revision of the manuscript for important
intellectual content: All authors.
Supervision: Cowan, Kwok, Gopal, Libby.
Conflict of Interest Disclosures: Dr Cowan
reported receiving grants from Janssen, Abbvie,
Bristol Myers Squibb, Nektar, Harpoon, and Sanofi
and receiving personal fees from Cellectar, Janssen,
Abbvie, GlaxoSmithKline, and Secura Bio. Dr Green
reported receiving personal fees from Janssen
Biotech, Juno Therapeutics, GlaxoSmithKline,
Neuleukin Therapeutics, Seattle Genomics, Legend
Biotech, Celgene, and Bristol Myers Squibb;
receiving clinical trial support from Janssen Biotech,
Seattle Genetics, Bristol Myers Squibb, Cellectar
Biosciences, and Sanofi-Aventis; receiving grants
from Juno Therapeutics and Spring Works
Therapeutics; and having a patent 20210171651
pending and holding patent 20200289565, with
royalties paid from Juno Therapeutics, a Bristol
Myers Squibb Company. Dr Holmberg reported
receiving study funding from Seattle Genetics,
Sanofi, Millennium-Takada, Bristol Myers Squibb,
Merck, and Janssen and holding a patent for
Up-To-Date, with royalties paid. Dr Tuazon reported
receiving grants from the Conquer Cancer
Foundation and National Institutes of Health/
National Cancer Institute (P30 CA015704). Dr
Gopal reported receiving research funding and
study drug from IgM, Agios, Bristol Myers Squibb,
and Teva; receiving personal fees from Epizyme,
Incyte, Kite, ADC, Karopharm, Nurix, and Cellectar;
and receiving consulting fees, research funding,
study materials, and/or other personal fees from
Merck, Takeda, Gilead, A-Z, Janssen, SeaGen, and
Pfizer. Dr Libby reported receiving research funding
and study drug from Celgene, Janssen,
GlaxoSmithKline, Genentech, BeiGene, and
Millenium and receiving consulting fees from
Alnylam, Abbvie, Pharmacyclics, Adaptive
Biotechnologies, and Akcea. No other disclosures
were reported.
Additional Information: Dr Tuazon was employed
at the Fred Hutchinson Cancer Research Center for
most of the time the manuscript was being
developed.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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