Concise Review
of the Disease and Treatment Options
International Myeloma Foundation
12650 Riverside Drive, Suite 206
Multiple Myeloma
North Hollywood, CA 91607-3421
Hotline (USA & Canada): (800) 452 CURE (2873)
Cancer of the Bone Marrow
Tel: (818) 487-7455
Fax: (818) 487-7454
Email: TheIMF@myeloma.org
Website: myeloma.org
Dedicated to improving the quality of life
of myeloma patients while working
towards prevention and a cure.
International Myeloma Foundation
2011/2012 Edition
Published by the International Myeloma Foundation
Prepared by Brian G.M. Durie, MD
© 2011, International Myeloma Foundation

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TABLE OF CONTENTS
INTRODUCTION . . . . . . . . . . . . . . . . 1
WHAT IS MYELOMA? . . . . . . . . . . . . . . . 1
PRODUCTION OF MONOCLONAL PROTEIN . . . . . . 2
ANNOTATED HISTORY . . . . . . . . . . . . . . 4
EPIDEMIOLOGY . . . . . . . . . . . . . . . . . 8
PATHOPHYSIOLOGY . . . . . . . . . . . . . . 10
BONE DISEASE . . . . . . . . . . . . . . . . 10
ANEMIA
. . . . . . . . . . . . . . . . . . 11
KIDNEY DYSFUNCTION . . . . . . . . . . . . . 12
OTHER ORGAN DYSFUNCTION . . . . . . . . . . 12
TYPES OF MYELOMA . . . . . . . . . . . . . . 13
CLINICAL SYMPTOMS
. . . . . . . . . . . . . 14
STAGING AND PROGNOSTIC FACTORS . . . . . . . 15
DEFINITION OF CLINICAL RESPONSE
. . . . . . . 17
TREATMENT . . . . . . . . . . . . . . . . . 18
SYSTEMIC ANTI-MYELOMA TREATMENT . . . . . . 20
TRANSPLANTATION . . . . . . . . . . . . . . 27
RADIATION . . . . . . . . . . . . . . . . . 31
MAINTENANCE THERAPY . . . . . . . . . . . . 32
SUPPORTIVE CARE
. . . . . . . . . . . . . . 33
MANAGEMENT OF RELAPSING
OR REFRACTORY DISEASE . . . . . . . . . . . . 35
NEW AND EMERGING TREATMENTS . . . . . . . . 37
REFERENCES . . . . . . . . . . . . . . . . . 38

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INTRODUCTION
PRODUCTION OF MONOCLONAL PROTEIN
The IMF Concise Review of the Disease and Treatment Options is an overview
BY MYELOMA CELLS
of myeloma, with a discussion of the pathophysiology, clinical features, and
treatment options. It is hoped that the information wil be helpful to health
The characteristic property of myeloma cells is the production and release
professionals and patients alike.
(or secretion) of monoclonal protein into the blood and/or urine. The amount
of monoclonal protein produced by myeloma cel s varies considerably from
patient to patient. In assessing myeloma, it is very important to know if a
WHAT IS MYELOMA?
patient's myeloma cel s are high producers or low producers or even non-secre-
Myeloma is a cancer of the plasma cel s in the bone marrow. Myeloma is
tors, with no protein released into the blood or urine. Once the relationship
synonymous with multiple myeloma and plasma cel myeloma. The malignant
between the protein level and the amount of myeloma in the bone marrow is
plasma cel s (see Figure 1) or myeloma cel s accumulate in the bone marrow.
known, it is possible to interpret and understand the relationship between a
The major features of myeloma result from the abnormal accumulation of
particular protein level and the myeloma tumor burden. Monoclonal protein
myeloma cel s within the bone marrow causing:
is also cal ed M-protein, M-component, myeloma protein, paraprotein, or the
protein spike. The monoclonal protein is cal ed a spike because of the way it
· Disruption of normal bone marrow function reflected by anemia and/or
appears on protein electrophoresis, a laboratory technique used to separate and
low white counts or platelet counts
identify proteins (see Figure 2).
· Destruction and invasion of bone surrounding the bone marrow cavity
FIGURE 2: MONOCLONAL SPIKE
· Production and release of monoclonal protein (M-Protein) from the
myeloma cel s into the blood stream and/or into the urine
· Reduction of normal immune function, reflected by reduced levels of
normal immunoglobulins and increased susceptibility to infection. Infection
is also more likely if the white blood cel count is low.
Plasmacytomas are localized "tumors" composed of plasma cel s, which can
grow inside bone (intramedul ary) or outside bone (extramedul ary or soft
tissue). When there are multiple plasmacytomas inside or outside bone, this
condition is also cal ed multiple myeloma.
myeloma cells producing M-protein
The monoclonal protein is an immunoglobulin or a component/fragment
of an immunoglobulin. Figure 3 il ustrates the structure of a normal immu-
FIGURE 1: MYELOMA CELLS
noglobulin molecule. In myeloma cel s, one or more mutations have occurred
in the genes responsible for immunoglobulin production. Myeloma pro-
teins therefore have an abnormal amino acid sequence and protein structure.
Typical y, the normal antibody function of the immunoglobulin is lost and the
three-dimensional structure of the molecule may be abnormal.
Increased production of abnormal immunoglobulin has a number of
consequences:
· Excess M-protein accumulates in the bloodstream and/or is excreted in
the urine as a monoclonal spike.
· The abnormal monoclonal molecules can adhere to each other
and/or other tissues such as blood cel s, blood vessel wal s, and other
1
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FIGURE 3: IMMUNOGLOBULIN MOLECULE STRUCTURE
· Free Bence Jones proteins can also adhere to each other and/or to other
tissue (just as the whole immunoglobulin molecule can). In this case the
end result is either:
1. Amyloidosis ­ A disease entity in which the Bence Jones light chains
crosslink in a highly symmetric, -pleated fashion and become depos-
ited in tissue around the body, including, for example, kidney, nerves,
and heart tissue; or
2. Light Chain Deposition Disease (LCDD) ­ The light chains are
deposited in a more haphazard fashion, but most especial y in smal
blood vessels of the eyes and kidneys; or
3. Monoclonal Immunoglobulin Deposition Disease (MIDD) ­
A disease in which there is deposition of fragments of both heavy and
light chains.
blood components. This can reduce blood flow and circulation, causing
It is important to be aware that routine blood testing can give very strange
hyperviscosity syndrome (discussed below).
results because of "stickiness" or hyperviscosity of myeloma blood samples in
automated chemical analyzers and/or interference with chemical reactions.
· Approximately 30% of the time, more light chains are produced than
are needed to combine with the heavy chains to create a whole immuno-
globulin molecule. These excess light chains are cal ed Bence Jones proteins
ANNOTATED HISTORY
(see History section). Free Bence Jones proteins have a molecular weight of
22,000 daltons and are smal enough to pass freely into the urine.
Dr. Henry Bence Jones was the first to investigate a strange protein in the urine
· The abnormal monoclonal proteins can also have a wide range of other
of a patient with myeloma. What caught his attention was a urine protein that
properties including:
dissolved on boiling, but re-precipitated on cooling: what are now cal ed "Bence
· Binding to normal blood clotting factors, resulting in increased bleed-
Jones" light chains. This patient also had a very strange bone disease that we now
ing tendency, enhanced blood clotting, or phlebitis
cal myeloma. The fol owing is a brief annotated summary of progress in research
and treatment for multiple myeloma and related diseases from that time forward.
· Binding to nerves to cause neuropathy or to circulating hormones to
cause metabolic dysfunction.
1844 -1850
First case descriptions of myeloma referred to as "mol ities and fragilitas ossium"
(soft and fragile bones). The first documented patient, Thomas Alexander
McBean, was diagnosed in 1845 by Dr. Wil iam Macintyre in London. The
unusual urine problem he discovered was ful y investigated by Dr. Henry Bence
FIGURE 4: DISEASE PHASES
Jones, who published his findings in 1848. In 1846, Mr. John Dalrymple, a
surgeon, determined that the diseased bones contained cel s subsequently
shown to be plasma cel s. Dr. Macintyre published the ful details of this case
of Bence Jones myeloma in 1850. Dr. Samuel Sol y published a similar case of
myeloma (Sarah Newbury) in 1844, but without any detailed urine studies.
1873
Rustizky introduced the term "multiple myeloma" to designate the presence of
multiple plasma cel lesions in bone.
1889
Otto Kahler published a detailed clinical description of multiple myeloma,
"Kahler's disease."
1890
Ramon y Cajal provided the first accurate microscopic description of
plasma cel s.
1900
Wright discovered that multiple myeloma cel s are plasma cel s.
1903
Weber noted that myeloma bone disease (lytic lesions) is detectable
using X-rays.
3
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1909
Weber suggested that plasma cel s in the bone marrow cause the myeloma
1996
First randomized study indicating possible benefit of high-dose therapy with
bone destruction.
bone marrow transplant support versus standard chemotherapy (Attal).
1930s
The routine diagnosis of myeloma remained dif icult until the 1930s, when
Randomized study of the bisphosphonate pamidronate (Aredia®) versus
bone marrow aspirates were first used on a larger scale. The development of
placebo indicates reduction in bone problems ("skeletal related events").
the ultracentrifuge and serum/urine protein electrophoresis improved both
1997
Evidence that viruses may be involved in triggering myeloma. Myeloma more
screening and diagnosis.
common in patients with HIV and hepatitis C. Human herpes virus-8 (HHV-8)
1953
Immunoelectrophoresis al owed exact identification of the monoclonal
found in bone marrow dendritic cel s. RNA found in blood with specificity for
myeloma proteins. Immunofixation has since been introduced as a more
SV40 cancer-causing monkey virus.
sensitive method.
1998
Continued research on the role of high-dose chemotherapy with autologous
1956
Korngold and Lipari noted that Bence Jones (BJ) proteins are related to normal
and al ogeneic transplant. The magnitude of benefit and patient population(s)
serum gamma globulin as wel as abnormal serum proteins. In their honor, the
likely to benefit remain uncertain. Transplant performed as part of initial
two types of Bence Jones proteins are cal ed kappa (), and lambda ( or L ).
(induction) therapy is shown to produce results similar to transplant done at
1958
Discovery of sarcolysin in the USSR. From this, melphalan (Alkeran®) was
first relapse.
derived. For the first time, treatment was possible.
Chromosome13deletionsshowntobepoorprognosticfactorfortransplantation
1961
Waldenström emphasized the importance of the dif erentiation between
as wel as some other therapies.
monoclonal and polyclonal gammopathies. He associated IgM monoclonal
New study reconfirms prednisone as a helpful maintenance therapy with
proteins with macroglobulinemia, as distinct from myeloma.
prolongation of remission. Alpha interferon also shown again to have some
1962
First report of successful treatment of myeloma with melphalan (Alkeran®) by
benefit in prolonging remission.
Bergsagel.
1999
Thalidomide shown to be an ef ective anti-myeloma therapy in patients with
1964
First report of successful treatment of myeloma with cyclophosphamide
relapsing/refractory disease.
(Cytoxan®) by Korst. Results with cyclophosphamide proved to be similar to
"Mini al ogeneic" transplant introduced as less toxic method to achieve a "graft-
results with melphalan.
vs-myeloma" ef ect.
1969
Melphalan combined with prednisone was shown by Alexanian to produce
Randomized French study shows no major benefit of double autologous
better results than melphalan alone.
transplant versus single transplant.
1975
Durie/Salmon staging system for myeloma introduced. Patients classified to
Longer-term fol ow-up shows that Aredia® treatment continued for 2 years
assess benefits of chemotherapy at dif erent disease stages (I, II, III, A or B).
is helpful.
1976-1992
Various combinations of chemotherapy agents tried, including the M2 regimen
2000
For the first time, there are several promising new approaches for myeloma
(VBMCP), VMCP-VBAP, and ABCM, with some indication of superiority
therapy. New clinical trials include thalidomide analogues (e.g., Revlimid®),
versus MP. However, in 1992, a comparative meta-analysis (Gregory) showed
long-acting Adriamycin® analogues (e.g., pegylated doxorubicin or Doxil®),
equivalent results for al combinations.
arsenic trioxide (Trisenox®), anti-angiogenesis agents (e.g., VEGF tyrosine
1979-1980
Labeling index (growth fraction analysis) first introduced as a test in myeloma
kinase inhibitor), agents to block cel adhesion, and proteasome inhibitors
and related diseases. Stable remission or plateau phase of myeloma identified.
(e.g., VELCADE®).
Plateau phase is a period when the growth fraction (LI%) of residual bone
2001
New classification system proposed for myeloma and related diseases
marrow plasma cel s is zero.
(see Table 1 below).
1982
Twin transplants performed by Fefer and Osserman as treatment for myeloma.
IFM (French Study Group) defines 3 risk groups based upon serum 2
1983
First use of serum 2 microglobulin as a prognostic test (Batail e, Child,
microglobulin and presence/absence of abnormalities of chromosome 13 by
and Durie).
FISH analysis.
1984
Barlogie and Alexanian introduce VAD chemotherapy.
2002
Evidence of ef icacy of new agents in clinical trials including VELCADE® (Phase
III, Mil ennium) and Revlimid® (Phase III, Celgene).
1984-1986
First reports of al ogeneic transplants in multiple myeloma by various
investigators.
Thalidomide combined with dexamethasone as frontline therapy for myeloma
produces response rate of approximately 70%.
1986-1996
Large numbers of studies evaluating high-dose therapy with autologous bone
marrow or stem cel rescue by various investigators. Both single (McElwain) and
MRC in U.K. reports autotransplant results at ASH (American
double (Barlogie) transplant procedures introduced.
Society of Hematology) annual meeting. Overal benefit noted,
especially for patients with high serum 2 microglobulin
(>7.5 mg/L).
5
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2003
VELCADE® (bortezomib; formerly PS-341) approved by the FDA as treatment
New agents in development include: HSP-90 inhibitors, new proteasome
for actively relapsing myeloma fol owing at least 2 prior therapies.
inhibitors, and new immunomodulatory agents. Evidence emerges that some
MRC autotransplant results provide the second randomized data set indicating
novel therapies may overcome some high-risk factors.
benefit of autotransplant versus standard-dose chemotherapy.
2008
Thalidomide approved by the EMEA in Europe as part of the "MPT" regimen
Results of IFM study comparing single with double transplant published
(melphalan/prednisone/thalidomide) for frontline therapy.
showing overal benefit with the double transplant after more than four years
VELCADE® approved by the FDA in the US as part of the "VMP" regimen
of fol ow-up. However, no apparent added benefit for patients already in
(VELCADE®/melphalan/prednisone) for frontline therapy.
complete remission with the first transplant.
Many new drugs in development and trials ongoing. The second-generation
Little Rock group (Shaugnessy/Barlogie) shows that bone disease in myeloma
proteasome inhibitor carfilzomib (PR-171) shows promise in early trials.
is associated with production of a particular protein cal ed DKK-1.
· Mozobil® (plerixafor) approved in combination with G-CSF for col ection of
2004
Results of ECOG randomized trial comparing thalidomide plus dexamethasone
stem cel s for autologous transplantation in patients with myeloma.
versus dexamethasone alone for previously untreated myeloma indicate a 59%
2009
· Development of new drugs continues, including encouraging results from
response rate with the combination versus 41% with dexamethasone alone
trials of second-generation proteasome inhibitors carfilzomib and NP-0052;
(ECOG Criteria).
HDAC inhibitors vorinostat and panobinostat; HSP-90 disrupter tanespimycin;
Results of multi-institutional randomized trial comparing VELCADE® with
monoclonal antibody elotuzumab; and third-generation immunomodulatory
dexamethasone show superiority of VELCADE® (details discussed in text).
agent pomalidomide.
Early results with VELCADE® in the frontline setting show excel ent results:
· IMWG analysis shows cytogenetic and FISH abnormalities combined with ISS
83% response rate for VELCADE®/dexamethasone and 94% with VELCADE®/
stage are prognostic; some novel therapies overcome poor risk factors.
Adriamycin®/dexamethasone and the ability to harvest stem cel s with
2010
· US FDA approves a risk evaluation and mitigation strategy (REMS) to ensure
successful transplantation and engraftment.
the safe use of erythropoiesis-stimulating agents (ESAs), which may promote
New myeloma staging system introduced, the ISS (International Staging
tumor growth, shorten survival, and increase the risk of cardiovascular
System). See page 17.
adverse events.
2005
Two large Phase III trials show that Revlimid® (lenalidomide) plus
· Preliminary identification of Epo receptors on myeloma cel s.
dexamethasone is superior to dexamethasone alone in relapsed myeloma
· Development of new drugs continues, including more encouraging results
(time to progression >15 months vs. 5 months).
from trials of second-generation proteasome inhibitor carfilzomib; HDAC
VELCADE® receives ful FDA approval for treatment of patients with myeloma
inhibitors vorinostat and panobinostat; monoclonal antibody elotuzumab; and
after 1 prior therapy.
third-generation immunomodulatory agent pomalidomide.
International Staging System (ISS), developed by the International Myeloma
· Several studies suggest a role for lenalidomide maintenance therapy.
Working Group (IMWG) of the International Myeloma Foundation (IMF), is
· Frontline therapy with novel agents may be as ef ective as transplantation in
published (see page 17).
eligible patients.
Numerous new agents in early development. Heat shock protein (HSP)-90
· Zometa® (zoledronic acid) may have an anti-myeloma ef ect; ef ective dental
inhibitors enter Phase I-II trials.
hygiene has reduced occurrence of ONJ.
Addition of thalidomide to standard melphalan/prednisone regimen shows
remarkable added benefit. Several upfront trials are ongoing.
2006
New response criteria for assessing treatment benefit are developed and
EPIDEMIOLOGY
published.
The average incidence of myeloma is 3-4/100,000 in the US, representing
Revlimid® receives FDA approval for treatment of myeloma in combination
with dexamethasone in patients who have received at least 1 prior therapy.
approximately 1.3% of al types of cancer. The American Cancer Society esti-
mated that in 2010, approximately 20,180 Americans would be diagnosed
Numerous new agents continue to be developed.
with myeloma, and 10,650 people would die from the disease. (Estimates for
2007
FDA accepts a supplemental NDA for use of VELCADE® plus Doxil® to treat
2011 are not available at the time of this writing.) There are currently approxi-
relapsed or refractory myeloma in patients who have not previously received
mately 100,000 Americans undergoing treatment for the disease. Myeloma
VELCADE® and have received at least 1 prior therapy. Combination thalidomide/
is more common in African Americans than Caucasians. For example, in
dexamethasone plus Doxil® compared with thalidomide/dexamethasone in a
phase III trial for newly diagnosed myeloma.
Los Angeles County the incidence of myeloma in African American men is
7
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TABLE 1
PATHOPHYSIOLOGY
Definitions of Myeloma and Related Monoclonal Gammopathies
NAME
DEFInItIon
The uncontrol ed growth of myeloma cel s has many consequences, including
MGUS
skeletal destruction, bone marrow failure, increased plasma volume and
(Monoclonal Gammopathy
· Monoclonal protein present
viscosity, suppression of normal immunoglobulin production, and renal
of Undetermined Significance)
· No active plasma cell disorder
insufficiency. Nonetheless, the disease can remain asymptomatic for many
years, as noted in the discussion of MGUS. In the symptomatic phase, the
ASYMPTOMATIC or
· Higher level of disease than MGUS,
SMOLDERING MYELOMA
but still no symptoms or organ damage
most common presenting complaint is bone pain. The serum and/or urine
· Can be classified into low or high risk based
M-protein is elevated and typical y rising at the time of diagnosis. (Please
upon lesser or greater chance of transition
note: M is used for Monoclonal, Myeloma, Monoclonal immunoglobulin and
to active myeloma
M-component, which are not quite identical, but are used synonymously).
The overal pattern of disease phases for patients with myeloma is il ustrated in
SYMPTOMATIC or
· Monoclonal protein present, and
ACTIVE MYELOMA
· One or more "CRAB" features
Figure 4. It is important to note that there can be multiple periods of response
of organ damage present*
and remission. The pathophysiology of myeloma is summarized in Table 2 in
schematic form.
*Organ damage classified as "CRAB"
C ­ calcium elevation (>10 mg/L)
R ­ renal dysfunction (creatinine >2 mg/dL)
BONE DISEASE
A ­ anemia (hemoglobin <10 g/dL or 2 g/dL decrease from patient's normal)
B ­ bone disease (lytic lesions or osteoporosis)
Ever since the first recognition of myeloma in 1844, there has been awareness
ONE OR MORE required for diagnosis of SYMPTOMATIC MYELOMA.
of an unusual and unique type of bone disease. It has taken until quite recently
Other less common features can also be criteria for an individual patient, including:
to determine the mechanisms involved. The first clue was that both myeloma
· Recurrent severe infections
cel s and increased numbers of osteoclasts are present at sites of bone destruc-
· Neuropathy linked to myeloma
tion. Understanding of the mechanisms has evolved from the observation that
· Amyloidosis or M-component deposition
· Other unique features
myeloma cel s produce osteoclast-activating factors (OAFs) to the identifica-
tion of local cytokines such as IL-1, IL-6, and TNF- and -; chemokines
such as MIP-1; and cel -cel adhesion processes involving av 3 integrin, al
9.8/100,000 versus 4.3/100,000 for Caucasian men. The incidence varies
of which are involved in producing increased numbers and activity of osteo-
from country to country from a low of <1/100,000 in China to approximately
clasts. More recently a substance cal ed RANK ligand (RANKL) has been
4/100,000 in most Western industrialized countries. The male:female ratio is
identified as a critical mediator of osteoclast activation. Many details of the
1.25:1 in the US. The incidence rises with age. Better diagnostic techniques
mechanisms of bone disease in myeloma are now understood. Several targets
and the higher average age of the general population may, in part, explain the
for treatment approaches have been identified.
rising incidence over the last several decades. A trend toward more frequent
Besides activation of osteoclasts, the other characteristic feature of myeloma
myeloma in patients under age 55 implies important environmental causative
bone disease is inhibition of osteoblasts, which are responsible for new bone
factors in the past 60 years. Several recent studies have evaluated the causation
production and bone healing. "Coupling" between osteoclast and osteoblast
of, or predisposition to myeloma, MGUS, and related disorders. Firefighters
function is responsible for normal bone remodeling and repair. The mecha-
and individuals in a variety of other occupations with toxic exposure as wel
nisms responsible for "un-coupling" in myeloma are also under investiga-
as individuals who are obese are at increased risk of myeloma. Eating seafood
tion. An important new observation is that the cholesterol-lowering statins
contaminated with heavy metals and/or chemicals may be a risk factor for
(HMG-CoA reductase inhibitors, e.g., Lipitor®, Mevacor®), can enhance
myeloma. Other medical conditions including immune system disorders and
osteoblast activity and promote bone healing. In addition, both VELCADE®
infections can be underlying and/or trigger factors. Several studies are focused
and lenalidomide (Revlimid®) have been shown to promote bone healing, in
on the genetic risk factors for myeloma.
addition to exerting a potent anti-myeloma activity. Studies to further investi-
gate the benefit of several new bone therapies are ongoing.
9
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Improvement in anemia occurs with successful treatment of the myeloma.
ANEMIA
Recombinant erythropoietin (Epo) (e.g., Epogen® or Procrit®) should be
used with caution in the light of recent reports of the association of Epo with
Anemia is a characteristic feature of myeloma. Although simple physical
increased tumor growth and reduced survival in patients with cancer, and the
displacement of marrow red blood cel precursors is undoubtedly a factor, the
identification of Epo receptors on myeloma cel s.
specific inhibition of red cel production by micro-environmental cytokine and
adhesion molecule effects is a more functional explanation. The exact causes of
myeloma-related anemia are being investigated by several research teams.
KIDNEY DYSFUNCTION
Impairment of kidney function is a common complication in patients with
TABLE 2
Schema of Pathophysiology
myeloma. However, this does not mean that every patient wil have this prob-
lem. In some patients, myeloma proteins, especial y Bence Jones light chains,
Skeletal Findings
cause renal injury by a variety of mechanisms ranging from tubular damage
· Solitary or multiple osteolytic lesions
from large accumulations of precipitated light chains, to effects of myeloma
· Diffuse osteoporosis (osteopenia)
proteins deposited as amyloid, to selective tubular damage resulting in the
Associated Effects Of Bone Destruction
metabolic effects of an entity cal ed Fanconi syndrome. Fanconi syndrome
· Elevated serum calcium
is a type of selective kidney tubular damage with leakage of amino acids and
· Hypercalciuria (calcium increase in urine)
phosphates into the urine, which can cause metabolic bone disease.
· Bone fractures
· Loss of height (vertebral collapse)
Other important factors related to kidney dysfunction in multiple myeloma
Extraskeletal Myeloma (Rare)
patients are increased levels of calcium and/or uric acid, infection, and the
· Soft tissue involvement, most commonly in head/neck area
effects of drugs such as nephrotoxic antibiotics, nonsteroidal anti-inflamma-
(e.g., nasopharynx); also in liver, kidney, and other soft tissue sites
tory drugs (NSAIDS), or contrast agents or dyes used for diagnostic studies.
Peripheral Blood
An important new observation is the potential y toxic effect of gadolinium-
· Anemia
based contrast agents used with MRI. Patients with kidney problems should
· Abnormal clotting
discuss the use of gadolinium with their physicians. Awareness of potential
· Leukopenia
kidney damage and maintaining sufficient fluid intake are especial y impor-
· Thrombocytopenia
tant for patients with myeloma to help avert the damaging effects of these
· Plasma cell leukemia
various factors.
· Circulating monoclonal B lymphocytes (precursors of myeloma cells)
Plasma Protein Changes
· Hyperproteinemia (elevated protein)
OTHER ORGAN DYSFUNCTION
· Hypervolemia (expanded volume)
· Monoclonal immunoglobulins
Myeloma cel s can accumulate in bone marrow and/or in a variety of tissue
(IgG, IgD, IgA, IgM, IgE, or light chains only)
sites and produce a broad range of potential complications.
· Narrowed anion gap (low serum sodium)
· Elevated serum
· Neurologic Effects ­ Nerve tissue is often affected in myeloma patients
2-microglobulin
· Decreased serum albumin
either by the direct antibody effects of myeloma proteins against nerves
· Elevated serum IL-6 and C-reactive protein (CRP)
(e.g., myelin sheaths) or deposition of amyloid fibrils on nerves, thus
impairing function. These effects result in peripheral neuropathies that
Kidney Abnormalities
· Proteinuria, casts without leukocytes or erythrocytes
must be distinguished from other causes of neuropathy such as diabetes
· Tubular dysfunction with acidosis
mel itus or primary nerve disorders such as multiple sclerosis, Parkinson's
· Uremia (kidney failure)
disease, and many others. Because of myeloma patients' susceptibility to
· Amyloidosis and renal dysfunction
infection, viral infections of nerve tissue are quite common, most par-
ticularly varicel a zoster (shingles), herpes zoster (cold sores), Epstein-Barr
11
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virus (mononucleosis), or cytomegalovirus, which may result in Bel 's palsy
(partial facial paralysis) or other complications.
CLINICAL SYMPTOMS
· Plasmacytomas ­ Both in bone and soft tissue, plasmacytomas can result
About 70% of patients with myeloma present with pain of varying intensity,
in compression or displacement of nerves, the spinal cord, or even brain tis-
often in the lower back or ribs. Sudden severe pain can be a sign of fracture
sue. These pressure effects often represent a medical emergency and require
or col apse of a vertebral body. General malaise and vague complaints are fre-
immediate treatment with high doses of corticosteroids, radiation therapy,
quent. Significant weight loss is rare.
or neurosurgery.
· Infections ­ The predisposition to infections is perhaps the single most
Both neutropenia and hypogammaglobulinemia increase the likelihood of
characteristic feature of myeloma patients besides the strong tendency for
infections. Although pneumococcal pneumonia is the classic infection associ-
bone disease. The mechanisms responsible for infection susceptibility are
ated with myeloma at presentation, other bacteria, such as streptococci and
not ful y understood. The presence of active myeloma in the bone marrow
staphylococci, are now frequently isolated. Haemophilus infection and herpes
results in impairment of normal immune function, including inhibition
zoster infections also occur.
of normal antibody production (reflected by hypogammaglobulinemia),
Hypercalcemia, historical y found in 30% of patients at diagnosis, causes
impaired T lymphocyte function, and activated but aberrant monocyte/
tiredness, thirst, and nausea. Precipitation of calcium salts can result in dete-
macrophage function. Some studies indicate that a factor issuing from
rioration of kidney function. Of note, in recent years the incidence of hyper-
the activated macrophages both enhances the activity of the myeloma and
calcemia in newly diagnosed patients has dropped to 10-15%, most likely
inhibits normal immunoglobulin production and T lymphocyte function.
because of earlier diagnosis. In Latin America and some parts of Asia where late
Myeloma patients are susceptible to both viral infections and infections with
diagnosis is common, hypercalcemia remains more common. Hyperviscosity
"encapsulated" bacteria such as pneumococcus. However, in the face of neu-
resulting from high myeloma protein levels can cause problems such as bruis-
tropenia and the effects of high-dose chemotherapy, and with the added local
ing, nose bleeding, hazy vision, headaches, gastrointestinal bleeding, sleepi-
effects of implanted catheters (e.g., Hickman and Groshon catheters or PICC
ness, and a variety of ischemic neurological symptoms caused by reduced
lines), the whole range of bacterial, fungal, and opportunistic infections can
blood and oxygen supply to the nerve tissue. Hyperviscosity occurs in <10%
occur in patients with myeloma undergoing therapy.
of patients with myeloma and in about 50% of patients with Waldenström's
macroglobulinemia (IgM paraprotein or M-component). Increased bleeding
In summary, key aspects of infections in myeloma patients are:
· Reduced immunity because of myeloma
tABLE 3
· Low white blood cell counts because of myeloma build-up in bone mar-
Types of Monoclonal Protein (%)*
row and/or the impact of treatment.
1. Serum
%
Totals
Infection, or any question of infection, should not be ignored. Prompt review
IgG
52
is required to assess the need for immediate antibiotic and/or antiviral therapy.
IgA
21
75%
Many patients learn to have therapy on hand for any emergency.
IgD
2
IgE
<0.01
2. Urine (Bence Jones or
TYPES OF MYELOMA
light chains only) types and
11%
3. Two or more monoclonal paraproteins
<1%
The type of monoclonal protein produced varies from patient to patient. The
Heavy chains (G or A) only
<1%
2%
most common is IgG and the least common is IgE. Table 3 shows the per-
No monoclonal paraprotein
1%
centages of different types of myeloma. Each type is associated with slightly
4. IgM (rarely myeloma; typically associated
different patterns of disease. For example, IgA myeloma is more commonly
with Waldenström's macroglobulemia)
12%
associated with disease outside bone (extramedul ary disease), whereas IgD
myeloma is more commonly associated with plasma cel leukemia and
TOTAL
100%
renal damage.
*This includes different types of MGUS and myeloma as well as Waldenström's.
Source: Data on 1,827 myeloma patients collected and analyzed by Pruzanski and Ogryzlo, 1970.
13
14

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is often exacerbated by thrombocytopenia as wel as by binding of monoclonal
tABLE 4
proteins to clotting factors and/or platelets.
Durie and Salmon Staging System
Neurologic involvement can result in specific problems depending on the
CrItErIA
MEAsurED MyELoMA CELL MAss
location of affected nerves. Particularly common problems are spinal cord
(myeloma cells in billions/m2)*
compression, meningitis, and carpal tunnel syndrome. Although the first two
STAGE I (low cell mass)
600 billion myeloma cells*
are due to plasma cel tumor formation or infiltration, carpal tunnel syndrome
All of the following:
is usual y due to amyloid deposition (deposition of Bence Jones proteins in a
· Hemoglobin value >10 g/dL
special -pleated form).
· Serum calcium value normal or <10.5 mg/dL
· Bone X-ray, normal bone structure (scale 0)
or solitary bone plasmacytoma only
STAGING AND PROGNOSTIC FACTORS
· Low M-component production rates
IgG value <5.0 g/dL
Prognosis in myeloma is determined by both the number and specific proper-
IgA value <3.0 g/dL
ties of myeloma cel s in a given patient. These specific properties include the
Urine light chain M-component on
growth rate of myeloma cel s, the production rate of monoclonal proteins,
electrophoresis <4 g/24h
and the production or non-production of various cytokines and chemicals
that damage or significantly impair other tissues, organs, or bodily functions.
STAGE II (intermediate cell mass)
600 to 1,200 billion myeloma cells*
In 1975, the Durie/Salmon staging system was developed (see Table 4). This
Fitting neither stage I nor stage III
system brings together the major clinical parameters in correlation with mea-
STAGE III (high cell mass)
>1,200 billion myeloma cells*
sured myeloma cel mass (the total number of myeloma cel s in the body).
One or more of the following:
The Durie/Salmon staging system continues to be used worldwide, primarily
· Hemoglobin value <8.5 g/dL
because it provides the best direct correlation with individual patient clinical
· Serum calcium value >12 mg/dL
features. Stage I patients have smoldering disease; Stage II and III patients
· Advanced lytic bone lesions (scale 3)
have active myeloma. In 2005, a new staging system was developed by the
· High M-component production rates
IMF-sponsored International Myeloma Working Group (IMWG). Clinical
IgG value >7.0 g/dL
and laboratory data were gathered on 10,750 previously untreated symptom-
IgA value >5.0 g/dL
atic myeloma patients from 17 institutions, including sites in North America,
Urine light chain M-component on
Europe, and Asia. Potential prognostic factors were evaluated using a variety
electrophoresis >12 g/24h
of statistical techniques. Serum 2 microglobulin (S2M), serum albumin,
SUBCLASSIFICATION (either A or B)
platelet count, serum creatinine, and age emerged as powerful predictors of
· A: relatively normal renal function
survival and were then further analyzed.
(serum creatinine value) <2.0 mg/dL
A combination of serum 2 microglobulin and serum albumin provided
· B: abnormal renal function
(serum creatinine value) >2.0 mg/dL
the most, powerful, simple, and reproducible three-stage classification. This
International Staging System (ISS) was ful y validated and is shown in Table
Examples: Stage IA (low cell mass with normal renal function)
5. The ISS was further validated by demonstrating effectiveness in patients
Stage IIIB (high cell mass with abnormal renal function)
*myeloma cells in the whole body
in North America, Europe, and Asia; in patients younger and older than age
65 years; with standard therapy or auto transplant; and in comparison with
the Durie/Salmon system. The ISS is simple, based upon easy-to-use variables
one of the fol owing genetic mutations: t(4;14), t(14;16), t(14;20), deletion
(serum 2M and serum albumin), and has been introduced for widespread
of 17p by FISH, or deletion of chromosome 13 or hypodiploidy by conven-
use.
tional metaphase cytogenetics. It is crucial to be aware that genetic risk is very
Myeloma can be further classified based upon genetic risk using molecular
much influenced by the treatment selected. For example, the deletion of 17p
fluorescence in situ hybridization (FISH) and cytogenetic features identified
by FISH is the only factor that consistently correlates with poorer outcomes
in bone marrow myeloma cel s. Such classification can have important impli-
with al therapies available in 2011. Conversely, the presence of t(4;14), which
cations for treatment. Higher-risk disease is defined as the presence of any
has been noted as a poor risk factor in the past, has largely been overcome with
15
16

---

the introduction of VELCADE® (bortezomib) combination regimens. There
As treatments have improved, it has become more important to assess response
is also a positive impact of lenalidomide- (Revlimid®) containing regimens
to treatment as accurately as possible. Besides the depth of response, which is
in patients with t(4;14) in several Revlimid® trials. A recent report from the
indicated by PR (50% improvement) or VGPR (90%) (see Table 7), one
French IFM group indicated that the presence of t(14;16) was also no longer a
must consider duration or length of response.
predictive prognostic factor in their trials. It is anticipated that new and better
Two important terms are:
risk classification systems wil be introduced over time and it wil become pos-
· TTP ­ Time To Progression: the time from start of treatment until
sible to offer treatment selection based upon documented treatment outcomes
relapse occurs.
with new combination approaches.
· PFS ­ Progression-Free Survival: the length of survival during which the
TABLE 5:
patient is stil in remission*.
International Staging System (ISS)
* Remission is generally considered to be a response (at least PR. i.e., 50% improvement)
which lasts for at least 6 months.
STAGE
VALUES
STAGE 1
2M <3.5
ALB
TREATMENT
3.5
STAGE 2
OVERVIEW
2M <3.5
ALB <3.5
Please see the History section for an overview of the evolution of currently
or
used treatments. Since melphalan was first introduced in 1962, various com-
2M 3.5 ­ 5.5
bination chemotherapy regimens have been utilized and attempts have been
made to improve outcomes using high-dose chemotherapy regimens with bone
STAGE 3
2M >5.5
marrow transplant (BMT) or peripheral blood stem cel transplant (PBSCT).
Note:
In the standard type of BMT or PBSCT, the "transplant" is a "rescue" with
2M = Serum 2 microglobulin in mg/L
ALB = Serum albumin in g/dL
normal bone marrow stem cel s when the stem cel s in the body have been
destroyed by high-dose chemotherapy (usual y melphalan).
In the decades of the `80s and `90s, high-dose melphalan with stem cel rescue
DEFINITION OF CLINICAL RESPONSE
was one of the few techniques/treatments available to reduce myeloma tumor
burden and achieve better outcomes. With the introduction of thalidomide
The new International Myeloma Working Group (IMWG) uniform response
for myeloma treatment in 1997, the options suddenly changed. Complete
criteria are recommended to classify response (see Table 7). Improvements
responses could be achieved with a simple oral agent. Additional new agents
in M-component must be associated with evidence of clinical improvement
fol owed in rapid succession: first VELCADE®, then Revlimid®, and now
(such as reduced bone pain and/or improved red blood cel counts). It is
carfilzomib and pomalidomide, which are poised for early approval by the
important to keep in mind that a higher percent regression does not automati-
FDA. Other agents such as elotuzimab, vorinostat, panobinostat, and others
are showing promising results.
cal y confer longer survival. When there is residual disease, the characteristics
of the remaining drug-resistant myeloma cel s determine the outcome. These
There is no single answer to the question of "the best" treatment options
remaining myeloma cel s may, or often may not, have any tendency for imme-
available in 2011. Fortunately, there are numerous regimens that produce
diate regrowth (relapse). If there is no re-growth, this is what is cal ed "plateau
very deep responses (more than 90% reduction of M-component [VGPR]),
phase": residual, but stable disease. The fraction of resistant myeloma cel s is
durable responses (remissions lasting 2 years), and improved overal survival.
primarily dependent upon the intrinsic molecular features of the individual
The best choice for each patient depends upon individual factors such as age,
myeloma and the pre-treatment tumor burden or stage. Responding patients
stage, genetic features, kidney status, and of course personal preference. It has
go from a high-risk to a lower-risk status until, ideal y, no signs of myeloma are
become an open question whether immediate auto transplant as a part of first
left, or they reach a stable plateau phase, but with measurable residual disease.
treatment is required or whether it can be offered as an option at first relapse,
The time required to reach the plateau phase is variable, ranging from 3 to 6
for example.
months (rapid response), to 12 to 18 months (slow response). Please refer to
It is important that myeloma patients be aware of the need for careful discus-
Figure 4 on page 3.
sions with their physicians.
17
18

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EXCLUDE MGUS OR ASYMPTOMATIC MYELOMA
myeloma protein. These indications for the need to start treatment can be
The first and most important decision is to determine if treatment is required.
summarized as CRAB features: Calcium elevation; Renal problems; Anemia;
Patients with MGUS and asymptomatic myeloma (Table 1) should be observed
or Bone issues. The overal goals of treatment are to address specific problems
closely rather than treated. There are currently no therapies that can enhance
and to achieve general control of the disease. A summary of types of treat-
the immune regulation of early myeloma or reduce the likelihood of disease
ments is provided in Table 6, and most commonly used chemotherapeutic
activation. However, several research trials are ongoing to assess if early treat-
drugs are detailed in Table 8.
ment is helpful in certain patients. A large cooperative group trial (combined
1. systEMIC AntI-MyELoMA trEAtMEnt:
ECOG/SWOG) was started in Fal , 2010. Patients with high-risk smoldering
myeloma are randomized to Revlimid® vs. placebo. Bisphosphonate therapy
INTRODUCTION
can be used for patients with early bone disease. Erythropoietin could be
The first specific treatment for myeloma was melphalan, introduced in 1962.
considered for treatment of isolated anemia, keeping in mind the caveats con-
Although the use of the simple oral combination of melphalan plus predni-
cerning this agent.
sone is stil a valid approach, several factors now influence the choice of this
Specific anti-myeloma treatment is recommended when symptomatic
type of therapy.
myeloma has developed, as reflected by an increasing M-component and/
· Melphalan can damage normal bone marrow stem cel s and is therefore
or emerging or imminent clinical problems or "CRAB" features (Table 1).
avoided in patients planning stem cel harvest.
Problems sufficient to require treatment include bone destruction (lytic
· Since older age (>70 years) is not an absolute deterrent to stem cel harvest
lesions and/or osteoporosis), renal insufficiency, progressive reduction in
and transplant, the role of stem cel transplant must be assessed for each
blood counts (e.g., anemia, neutropenia), elevated blood calcium, nerve
patient on an individual basis.
damage, or other significant organ or tissue damage caused by myeloma or
TREATMENT RECOMMENDATIONS IF STEM CELL HARVEST
TABLE 6
IS NOT A PLANNED OPTION
Myeloma Treatment Options
The approach to treatment has changed substantial y with the introduction
1. Chemotherapy
of the novel agents thalidomide, bortezomib (VELCADE®), and lenalido-
2. High-dose chemotherapy with hematopoietic stem cell transplant
mide (Revlimid®). Although melphalan/prednisone (MP) is stil an option
3. Radiation
for elderly patients, two new combinations with MP (Table 9) have emerged
4. Maintenance therapy
that are superior to MP for patients who are not eligible for transplantation:
5. Supportive care:
melphalan/prednisone/thalidomide (MPT), and bortezomib (VELCADE®)/
· Erythropoietin*
· Pain medication
melphalan/prednisone (VMP). In addition, thalidomide plus dexametha-
· Bisphosphonates
· Growth factors
· Antibiotics
· Brace/corset
sone (Thal/Dex) and lenalidomide (Revlimid®) plus low-dose dexamethasone
· Exercise
(RevloDex) are available for use in the non-transplant setting.
· Emergency care (e.g., dialysis, plasmapheresis, surgery, radiation)
Melphalan/Prednisone/Thalidomide (MPT): NCCN (National Compre-
6. Management of drug-resistant or refractory disease
hensive Cancer Network) category 1 choice* ­ Three randomized trials have
7. New and emerging treatments:
compared MP with MPT. Each has shown a higher response rate, longer remis-
· Thalidomide, Revlimid®, and next-generation IMiD, pomalidomide, in
sion, and longer progression-free survival (PFS) with MPT. Venous throm-
clinical trials
botic event risk requires appropriate prophylaxis, depending upon individual
· VELCADE® (proteasome inhibitor) and next-generation proteasome
inhibitors, e.g., carfilzomib, NPI-0052, in clinical trials
patient characteristics. (See the International Myeloma Working Group's
· Doxil® (pegylated liposomal doxorubicin) to substitute
for Adriamycin® infusion
* NCCN Categories of Evidence and Consensus are: Category 1: the recommendation is
· Mini-allo (non-myeloablative) transplant
based on high-level evidence (e.g. randomized controlled trials) and there is uniform
· Histone deacetylase (HDAC) inhibitors, e.g. vorinostat, panobinostat
NCCN consensus; Category 2A: the recommendation is based on lower-level evidence and
in clinical trials
there is uniform NCCN consensus; Category 2B: the recommendation is based on lower-
· Monoclonal antibodies in clinical trials, e.g., elotuzumab
level evidence and there is nonuniform NCCN consensus (but no major disagreement);
*with caveats
and Category 3: the recommendation is based on any level of evidence but reflects major
disagreement.
19
20

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guidelines for the prevention of thalidomide- and lenalidomide-related throm-
bosis in myeloma.)
TABLE 8
Most Commonly Used Chemotherapy Drugs
Melphalan/Prednisone/Revlimid® (MPR): NCCN category 2A choice ­
DRUG NAME
OTHER TREATMENT NAME
COMMENTS
Results of the ongoing Italian MM-015 study have shown that MPR confers a
TRADITIONAL AGENTS
significant advantage in progression-free survival over MP. However, concerns
Melphalan*
Alkeran®
First single agent for treatment
have emerged about untoward toxicities, including a smal risk of develop-
(M)**
(by mouth or IV)
of myeloma
ment of second primary cancers.This risk is currently under investigation.
Cyclophosphamide*
Cytoxan®
Similar efficacy to M but with more
(C or CY )**
(by mouth or IV)
GI and GU toxicity and less bone
marrow stem cell injury
TABLE 7
International Myeloma Working Group Uniform Response Criteria:
Prednisone
Prednisolone®
Directly active, works well with
CR and Other Response Categories
(P)**
(similar)
M, C, and B. Does not produce
RESPONSE
RESPONSE CRITERIAa
(usually by mouth)
suppression of bone marrow
SUBCATEGORY
Dexamethasone
Decadron®
Similar to prednisone but more potent;
sCR
CR as defined below plus
(D)**
(by mouth or IV)
more severe side effects
· Normal FLC ratio, and
· Absence of clonal cells in bone marrowb by immunohistochemistry
Vincristine
Oncovin®
No longer commonly used as part of
or immunofluorescencec
(V or O)**
(IV)
the VAD induction regimen, which was
shown to be inferior to VELCADE® +
CR
· Negative immunofixation on the serum and urine, and
Adriamycin® + dex
· Disappearance of any soft-tissue plasmacytomas, and
· 5% plasma cells in bone marrowb
Doxorubicin
Adriamycin®
Modest activity, used in combinations
(A)**
(IV)
(e.g., VAD, ABCM, VMCP-VBAP)
VGPR
· Serum and urine M-protein detectable by immunofixation but not on
electrophoresis, or
Busulphan*
Myleran®
Similar activity to M and C, usually part
· 90% or greater reduction in serum M-protein plus urine M-protein level
(B or BU)**
(by mouth or IV)
of high-dose therapy with transplant
<100 mg per 24h
(e.g., BU/CY regimen)
PR
· 50% reduction of serum M-protein and reduction in 24h urinary
VP - 16
Etoposide®
Modest activity, used alone
M-protein by 90% or to <200 mg per 24h
or in combination
· If the serum and urine M-protein are unmeasurable, a 50% decrease in
the difference between involved and uninvolved FLC levels is required in
Cisplatin
Platinol®
Minimal activity alone, but used
place of the M-protein criteria
(CP or P)**
(IV)
with VP-16 (E) as part of combinations
· If serum and urine M-protein are unmeasurable, and serum free light
(e.g., EDAP and DT-PACE)
chain assay is also unmeasurable, 50% reduction in plasma cells is
required in place of M-protein, provided baseline bone marrow plasma
NOVEL AGENTS
percentage was 30%
Pegylated, liposomal
Doxil®
In combination, promising activity,
doxorubicin*
In addition to the above listed criteria, if present at baseline, a 50%
(IV)
less toxicity than A
reduction in the size of soft tissue plasmacytomas is also required
Bortezomib
VELCADE®
Directly active, used alone or in
SD
Not meeting criteria for CR, VGPR, PR, or progressive disease
(B, V, or P)**
(IV)
combination
(not recommended for use as an indicator of response, stability of disease is
best described by providing the time to progression estimates)
Thalidomide
Thalomid®
Directly active, approved for use in
(T)
(by mouth)
combination with dexamethasone,
used in other combinations
Abbreviations: CR = complete response; FLC = free light chain; PR = partial response; SD = stable disease;
sCR = stringent complete response; VGPR = very good partial response.
a ­ All response categories require two consecutive assessments made at anytime before the institution of any new
Lenalidomide
Revlimid®
Directly active, approved for use in
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies
(R or L)
(by mouth)
combination with dexamethasone,
were performed. Radiographic studies are not required to satisfy these response requirements.
used in other combinations
b ­ Confirmation with repeat bone marrow biopsy not needed.
c ­ Presence/absence of clonal cells is based upon the / ratio. An abnormal / ratio by immunohistochemistry
* Alkylating agents
** Common abbreviations
and/or innumofluoresence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting
presence of an abnormal clone is a / ratio of >4:1 or <1:2.
21
22

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Bortezomib (VELCADE®)/Melphalan/Prednisone (VMP): NCCN category
in increased response and progression-free survival compared with VMP, with
1 choice ­ A large, randomized trial (VISTA) involving 682 patients with a
reduced rates of peripheral neuropathy and discontinuation of therapy.
median age of 71 years showed improved outcomes with VMP versus MP and
Thalidomide/dexamethasone (Thal/Dex): NCCN category 2B choice and
resulted in FDA approval for VELCADE® in this front-line setting. Response,
lenalidomide (Revlimid®)/Low-Dose Dex (RevloDex): NCCN category 1
length of remission, and overal survival were al superior with VMP. The most
choice ­ Although not tested exclusively in the nontransplant setting, both
important caveat is that 13% of the patients receiving VMP had severe (Grade
Thal/Dex and RevloDex can be considered for those who may not proceed to
3 or 4) neuropathy with the VELCADE® combination. Although the neu-
immediate transplant, as wel as for those who are eligible for transplant.
ropathy reversed in a majority of patients, this is an important concern.
With the approval of lenalidomide/dexamethasone (Rev/dex) in the relapse
Bortezomib (VELCADE®)/Melphalan/Prednisone/Thalidomide (VMPT):
setting and with very promising trials ongoing in the frontline setting, the
Not yet listed by NCCN ­ Weekly VELCADE® plus a reduced dose of tha-
RevloDex combination has become a popular option for induction therapy.
lidomide in combination with MP has been shown (GIMEMA trial) to result
An important ECOG trial (E4A03) showed excel ent results with Revlimid®
plus low-dose (weekly) dexamethasone versus Revlimid® plus conventional-
TABLE 9
dose (4-day pulse) dexamethasone. The percentages of early side effects were
Frequently Used Combinations
very low with RevloDex, as was the chance of early mortality, which was only
MP
First standard combination used for initial therapy
0.5% (within first 4 months). RevloDex thus became an excel ent option for
induction. The only major caution is for patients wishing to retain the option
CP
Alternative to MP
for stem cel harvesting. Researchers at the Mayo Clinic have noted lower stem
ABCM
Combination used in Europe, especially UK.
cel yields post-Rev/dex induction with a smal percentage of patients not col-
Little extra benefit versus MP
lecting adequate stem cel s for transplantation using Neupogen® growth factor
alone for harvesting.
VAD
Once the most commonly used alternative to MP,
now increasingly replaced with more active combinations
At the present time, 98% of patients in the U.S. receive induction therapy
including the novel therapies
that includes at least one novel agent. A recent registry survey showed that
RevloDex and VELCADE®-based combinations are used in approximately
D or MD
D alone or combined with M or C can be used as alternative
or CD
to VAD. Avoids need for four-day infusion.
equal numbers in the front-line setting, with thalidomide/dex now less fre-
quently used.
TD
(thal/dex) frontline combination, now largely replaced
by Rev/dex in the US
Revlimid®/Bortezomib(VELCADE®)/Dexamethasone (RVD): NCCN cat-
egory 2B choice ­ Trials thus far have shown very promising results for this
MPT
(MP+thal) To increase efficacy of MP
combination. Phase III trials in the newly diagnosed and relapsed settings are
(MP+Revlimid®) To increase efficacy of MP
ongoing. While not yet FDA approved in either the frontline or relapsed set-
MPR
ting, this regimen is not infrequently prescribed in the United States.
VMP
(MP+VELCADE®) FDA approved for frontline use
A recent development of note was the French-led randomized phase III trial
VMPT
(MP+reduced-frequency VELCADE® and reduced-dose
of subcutaneous (subq) versus IV VELCADE®, in which efficacy and toxic-
thalidomide) To increase efficacy of MP with less neuropathy
ity were assessed. The trial determined that efficacy was equal in both trial
arms, and that peripheral neuropathy of grade 2 or greater was reduced in the
RD or Rd
(Rev/dex) Popular frontline combination (NCCN category 1)
D= full-dose dex; d=low-dose dex, one day per week
subq arm.
OVERVIEW OF INITIAL THERAPY RECOMMENDATIONS
BD or VD
(VELCADE®/dex) FDA approved for frontline use
FOR PATIENTS NOT ELIGIBLE FOR TRANSPLANTATION
RVD
(Revlimid®+VELCADE®+dex) Promising combination in late
Both MPT and VMP have excel ent Phase III trial support as recommended
clinical trials for both newly diagnosed and relapsed myeloma
options. Further fol ow-up is required to assess the longer-term outcomes with
(Cytoxan®+VELCADE®+dex) Promising combination
both MPT and VMP. Initial data suggest that VMP can overcome the nega-
CVD
("CyborD")
in trials for both newly diagnosed and relapsed myeloma
tive impact of chromosomal poor prognostic features (see above). DVT risk
23
24

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is a concern with MPT, but not with VMP. MPT is completely oral, whereas
results in Phase II-III trials including: VCD (VELCADE®/Cytoxan®/Dex,
VMP incorporates the I.V. VELCADE® component. Both MPT and VMP
also known as CyborD) ­ NCCN category 2A choice; VELCADE®/Doxil®
have an associated neuropathy risk. The painful neuropathy with VMP is pos-
± Dex ­ NCCN category 2B choice; VRD (VELCADE®/Revlimid®/Dex)
sibly a greater concern, although reducing the frequency of VELCADE® to
­ NCCN category 2B choice. A recent Mayo trial of VRD vs. VCD vs.
once weekly may al eviate this problem.
VCRD (VELCADE®/Cytoxan®/Revlimid®/Dex) indicated that al regi-
mens had similar efficacy, but that the four-drug combination caused more
Alternatively, the simple two-drug options MP, Thal/Dex, RevloDex, or
toxicity and more frequently required dose reductions. Long-term fol ow-
Vel/dex can be considered depending upon the clinical situation.
up data is stil being col ected and assessed. Mayo anticipates conducting a
trial comparing VCD and VRD.
IF STEM CELL HARVEST IS PLANNED
The approach to frontline or induction therapy has evolved and changed
In addition, bortezomib is part of several new drug combinations in which
considerably over the last two decades.
synergy is anticipated (see Relapse/New Drug sections on pages 35-37).
VAD Chemotherapy: NCCN category 2B choice ­ The VAD protocol, first
introduced in 1984, became a popular alternative to MP or CP induction.
Significant disadvantages, including possible infection and blood clotting
tABLE 10
problems, as wel as superior response rates with thalidomide/dexamethasone,
Tests Required To Monitor Therapy Responses
Revlimid®/dexamethasone, and bortezomib with or without dexamethasone,
Blood Tests
· Routine blood counts
have now made VAD a less common option worldwide.
· Chemistry panel
· Liver function tests
Thalidomide/dexamethasone (Thal/Dex): NCCN category 2B choice ­
· Myeloma protein measurements (serum protein
Thal/dex is a standard option for front-line therapy, with a response rate of
electrophoresis plus quantitative immunoglobulins)
64%. Improved response rates and far lower incidence of peripheral neuropa-
· Serum Free Light Chain Assays (FreeliteTM)
thy with RevloDex have made this newer combination a preferable option,
· Serum 2 microglobulin
where and when available.
· C-reactive protein
· Peripheral blood labeling index (LI)
VELCADE®: NCCN category 1 choice ­ In June 2008, VELCADE® was
· Serum erythropoietin level
approved for use in the frontline setting. Although it is a very active single
Urine
· Routine urinalysis
agent, it is expected that it wil be used mostly in combination therapy, add-
· 24-hour urine for measurement of total protein,
ing to the arsenal of options available to newly diagnosed patients as wel
electrophoresis, and immunoelectrophoresis
as to those with refractory and/or relapsed disease. A variety of bortezomib
· 24-hour urine for creatinine clearance
(VELCADE®) combinations is now available:
if serum creatinine elevated
· Bortezomib/thalidomide/dexamethasone (VTD): NCCN category 1
Bone Evaluation
· Skeletal survey by X-ray
choice ­ Cavo et al. recently compared thalidomide/dexamethasone to
· MRI/CT scan for special problems
VTD in a randomized control ed trial involving 256 patients. The CR plus
· Whole body FDG/PET scan if disease status unclear
VGPR rate after 3 courses of 21 days was significantly higher for VTD
· Bone density measurement (DEXA scan) as baseline
and to assess benefit of bisphosphonates
(60%) compared with thalidomide/dexamethasone (27%).
· Bortezomib/dexamethasone (NCCN category 1 choice) versus VAD ­
Bone Marrow
· Aspiration and biopsy for diagnosis and periodic
Several studies have shown initial overal response rates (ORR) of 70%-
monitoring
· Special testing to assess prognosis looking for multiple
90% with bortezomib/dexamethasone (Vel/dex) as first therapy. In a
potential karyotypic and FISH abnormalities
recently reported trial, Harousseau et al. compared Vel/dex with VAD as
(number of chromosomes, translocations, deletions ­
pre-transplant induction. The CR + VGPR rates were: Vel/dex 47% versus
e.g., FISH 13q-, t[4:14], 1q21, etc.)
VAD 19% pre-transplant, and Vel/dex 62% versus VAD 42% post-autol-
ogous stem cel transplant, both significant differences.
Other Testing
· Amyloidosis
(special circumstances)
· Neuropathy
· Other bortezomib combinations ­ Numerous bortezomib (VELCADE®)
· Renal or infectious complications
combinationsarecurrentlybeingevaluated.Severalhaveproducedpromising
25
26

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Revlimid® Combinations in a Pre-Transplant Setting ­ The results with
· The added benefit of incorporating (or not) autotransplantation is under
lenalidomide (Revlimid®)/dexamethasone have been noted already. In essence,
ongoing review.
Rev/Dex can be used for induction when there is intent to proceed with har-
· Morbidity and mortality ­ With current growth factor, antibiotic, and
vest and stem cel transplantation, even though that has not been the priority
other supportive care, the procedure-related mortality with HDT is very
in trials conducted thus far. The induction results are excel ent and comparable
low: <5%. The majority of centers use intravenous high-dose melphalan
to the bortezomib combinations. Stem cel harvesting may require growth fac-
alone at a dose of 200 mg/m2 as the preparative regimen. Since the use of
tor plus cyclophosphamide or plerixafor (Mozobil®) versus growth factor (e.g.,
total body irradiation (TBI) adds toxicity without clear survival benefit,
Neupogen®) alone. Further studies are required to explore the use of Revlimid®
few centers recommend TBI as part of the preparative regimen.
in the pre-transplant setting.
· Both quality of life and cost-benefit analyses have been conducted for
Induction Therapy Recommendations for Transplant Candidates ­
HDT compared to standard-dose chemotherapy. The Nordic Myeloma
The options with Phase III randomized trial support are:
Study showed both improved quality and length of survival (median sur-
· Thal/Dex (TD)
vival of 62 months versus 44) but with added expense.
· VELCADE®/Dex (VD)
Current Recommendations
· VELCADE®/Thalidomide/Dex (VTD)
HDT with autologous stem cel support should be strongly considered as
· Revlimid®/Low-Dose Dex (RevloDex - Rd)
part of the frontline therapy for newly diagnosed patients with symptomatic
myeloma.
Al four regimens can produce rapid response and have high response rates. TD
and Rd are exclusively oral; VTD and VD have the intravenous VELCADE®
a. The standard conditioning regimen is melphalan 200 mg/m2. Total body
component. TD and Rd both carry an increased risk of blood clots (deep vein
irradiation is not recommended.
thrombosis, or DVT) and require aspirin or other anticoagulant treatment.
b. Stem cel purging is not recommended because of added expense without
Neuropathy is a concern with the thalidomide and VELCADE® regimens.
additional clinical benefit.
It is a chal enge to select the best treatment for each patient. One must con-
c. Peripheral blood stem cel s are recommended over bone marrow both
sider the early risks of treatment, responses and length of remission, DVT
because of ease of col ection and more rapid engraftment.
and neuropathy risks, convenience, and costs. Presence of genetic high-risk
d. The pre-transplant regimens are discussed above.
features and/or renal compromise may sway the choice toward VELCADE®
e. Several novel therapy combinations are being introduced as pre-transplant
combinations. Open dialogue to discuss the "pros and cons" is crucial.
regimens.
2. trAnsPLAntAtIon
ROLE OF AUTO TRANSPLANTATION AT TIME OF FIRST RELAPSE
HIGH-DOSE THERAPY (HDT) WITH AUTOLOGOUS
Part of the decision process for autotransplant involves knowledge of the
STEM CELL TRANSPLANTATION (ASCT)
impact of waiting, with a view to transplant at relapse. Data from two French
randomized trials indicate no reduction in overal survival from waiting to
· The role of autologous transplantation has been extensively reviewed.
do the transplant at relapse. Quality of life becomes an important consid-
· HDT with autologous stem cel transplantation has been shown to improve
eration. On the one hand, if transplant is not performed as a planned pri-
both response rates and survival in patients with myeloma. However, this
mary strategy, then typical y additional therapy, including maintenance, is
approach is not curative. With the introduction of novel combination
required, with corresponding toxicity and side effects. On the other hand,
approaches, in addition to ASCT, some investigators are introducing the
the major impact of the transplant is deferred, which for some patients is a
notion that a subgroup of patients ("good risk") may have extended sur-
better personal choice. Combination therapies that include the novel agents
vival and may achieve "functional cure" (defined as complete remission for
Revlimid®, thalidomide, and VELCADE® as front-line treatment are resulting
4 years).
in response and progression-free survival rates comparable to that of ASCT,
· Complete remission rates with HDT as a planned part of frontline therapy
al owing patients and their physicians the choice of postponing ASCT without
can now be 90% with new pre- and post-transplant strategies.
sacrificing efficacy. A large, randomized US-French trial of frontline VRD vs.
VRD + ASCT wil help to determine if the addition of ASCT to novel therapy
provides additional benefit or not.
27
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HARVESTING AND STORING STEM CELLS FOR LATER USE
c. Delayed transplant is a viable treatment option. A second transplant in
There is a strong reluctance in many centers to harvest stem cel s without a
a patient is a viable option, especial y if a first remission of >2 years has
clear plan for use, typical y immediate use. This reluctance arises from proto-
occurred. (See discussion below of "double" transplantation.)
col priorities, cost/utilization constraints for harvesting and storage, as wel as
THE ROLE OF DOUBLE OR TANDEM TRANSPLANTATION
numerous other factors. Nonetheless, many patients request and want their
· At present the added benefit of double or tandem transplantation versus a
stem cel s harvested, even though they may not be enthusiastic about immedi-
single autologous transplant is unclear.
ate high-dose therapy.
· The results with planned primary tandem transplant (Total Therapy 1, 2, 3,
Current Recommendations
4, and 5 at the University of Arkansas) have been good. The median over-
a. Harvesting with storage for future use is recommended with review on a
al survival has been 68 months, with some sub-groups having even lon-
case-by-case basis.
ger survival. Total Therapy 3, which incorporates the use of VELCADE®,
b. There is medical and scientific rationale for saving stem cel s for later use.
appears to offer earlier response and increased response rates, although
patients with certain risk factors, including older age, higher LDH, abnor-
mal cytogenetics, or advanced disease, are not as likely to achieve extended
TABLE 11
benefit.
High-dose Therapy
T YPE
ADVANTAGES
DISADVANTAGES
· Recent comparative studies, including the French randomized studies, have
shown benefit predominantly for a subgroup of patients (those who are not
Single
· 50% excellent remissions
· Relapse pattern similar to standard
Autologous
· At least as good as standard
chemotherapy
in CR). It is possible that longer fol ow-up wil show added benefit.
Transplant
therapy regarding overall survival · More toxic and expensive
Current Recommendations
and probably better for patients
· Patients who decisively benefit from
with high S2M.
transplant not clearly identified
a. At the present time, planned tandem transplant continues to be a clini-
· Basis for strategies to produce
· Maintenance therapy may still be
cal trial option and should be carried out at centers specialized in this
true remission or long-term cure
required/recommended
approach. A planned second transplant can be considered in patients
· New preparative regimens may
produce true complete remission
achieving <VGPR with a first auto transplant.
b. A second transplant in a patient who has responded wel with a first trans-
Double
· 2002 update of French data
· Role of double vs. single still unclear
Autologous
indicates survival benefit for
· Much more toxic and expensive
plant and relapsed after >2 years is a helpful and viable option (Sirohi,
Transplant
subset of patients not in CR
versus single
2001).
or VGPR
· No survival benefit if in CR or VGPR
·Excellent results with tandem
after first transplant
c. Saving and storing enough stem cel s for a second or additional transplant,
transplant (see text)
if appropriate, is strongly recommended.
Traditional
· No risk of contamination of
· Even for HLA identical siblings,
THE ROLE OF ALLOGENEIC TRANSPLANTATION
Allogeneic
marrow/stem cells with myeloma
significant risk of early complications
Transplant
· Possible graft versus myeloma
and even death (25-30%)
· Despite medical improvements over the past two decades, ful al ogeneic
effect to prolong remission
· Risk of complications unpredictable
transplant, even with a perfectly matched sibling donor, is a high-risk pro-
· Restricted to age <55
cedure in the management of multiple myeloma. The initial treatment-
· More toxic and expensive versus
autologous
related morbidity and mortality is high. Even at centers with the greatest
experience, and in the best risk settings, initial mortality is at least 15%
Mini-Allo
· Less toxic form of allo
· No anti-myeloma chemotherapy
to 20%. In other centers, 20% to 30% or higher mortality is frequently
Transplant
· Preparative chemotherapy
given
usually well tolerated
· Still produces graft-vs-host disease
reported. The pulmonary complications are usual y the most critical for
· Results in anti-myeloma
· Full benefits still unclear
patients with myeloma.
immune graft
· Risk of initial mortality
approximately 17%
· The potential advantages of al ogeneic transplantation are myeloma-free
stem cel s and graft versus myeloma effect. But, despite these factors, long-
Identical Twin
· No risk of myeloma contamin-
· No graft-vs-myeloma effect
term cure is rare. Relapse continues at a rate of approximately 7% per year
Transplant
ation in transplanted cells
· Need identical twin <55
· Much less risky than allogeneic
with long-term fol ow-up. Graft versus host disease can also be an ongoing
transplant
problem, requiring therapy and reducing quality of life.
29
30

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· The graft versus myeloma effect can be enhanced by using donor lympho-
4. MAIntEnAnCE tHErAPy
cyte infusions and has been clinical y beneficial in some series.
Alpha Interferon ­ For over 15 years, many investigators have evaluated the
· A recent cooperative group trial evaluating 710 patients randomized to
efficacy of interferon, an agent shown to prolong remission achievable with
non-myeloablative or "mini" al ogeneic transplant vs. tandem autologous
standard or high-dose therapy. Conflicting results have been obtained, but
transplant was presented at ASH 2010 (Krishnan et al.). Unfortunately, this
a smal benefit of 10% to15% in the prolongation of remission and survival
trial showed rather decisively that planned addition of mini-al o transplant
has been observed. Differences of 10% to 15% (i.e., 6 to 9 months) are hard
as part of an upfront double-transplant approach introduced significant
to prove in clinical studies. Although some investigators think that alpha
added risk with no survival benefit over tandem autologous transplant.
interferon may stil have a definite although smal role in the management
Thus, routine consideration of this approach is no longer recommended.
of myeloma, the associated side effects can have an adverse impact on patient
Current Recommendations
quality of life.
a. Conventional ful -match al ogeneic transplantation is rarely recommended
Prednisone ­ It has been difficult to find therapy that can prolong remissions
as a primary strategy because the risks are too high.
and survival in myeloma without compromising quality of life, as is the case
b. "Mini" al ogeneic transplantation is only recommended in a clinical trial
with alpha interferon. However, new studies have supported earlier observa-
setting.
tions from the 1980s that prednisone is an effective maintenance agent, and
c. Identical twin, or syngeneic, transplantation is a rare option, which is a
probably superior to alpha interferon. Prednisone administered three times
safe procedure with good outcome and is recommended as a consideration
per week (e.g., starting dose of 50 mg) has acceptable toxicity and can pro-
when an identical twin is available.
long both remission and survival. A particular advantage is that patients can
take prednisone for several years without developing resistant myeloma cel s.
3. rADIAtIon
However, caution is required because of longer-term side effects, and dose
radiation therapy is an important modality of treatment for myeloma.
reductions are usual y necessary.
For patients with severe local problems such as bone destruction, severe pain,
Immunomodulatory drugs (IMiDs) ­ Promising results are accumulating
and/or pressure on nerves or the spinal cord, local radiation can be dramati-
for the role of Revlimid in the maintenance setting. As reported at the 2010
cal y effective. The major disadvantage is that radiation therapy permanently
annual ASH meeting, Revlimid® maintenance therapy significantly prolongs
damages normal bone marrow stem cel s in the area of treatment. Wide-field
time to progression compared with placebo when given to patients with stable
radiation encompassing large amounts of normal bone marrow should be
disease or better after high-dose melphalan/ASCT (CALGB, McCarthy et al.),
avoided. A general strategy is to rely on systemic chemotherapy to achieve
and significantly prolongs progression-free survival when given to patients
overal disease control, limiting the use of local radiation therapy to areas with
after ASCT as consolidation therapy fol owed by a lower dose of Revlimid®
particular problems.
for maintenance therapy (Attal et al.). Fol ow-up data from the CALGB study
indicate that Revlimid maintenance post-ASCT not only doubles progression-
total Body Irradiation (tBI) ­ Total body or sequential radiation of half of
free survival as compared to placebo, but increases overal survival as wel .
the body has been used as part of an overal strategy for high-dose therapy with
Balanced against this favorable data is the low but increased risk of a second
transplant and/or in the management of relapsing refractory disease. Although
malignancy in the placebo arm of the trial. Further analysis is ongoing to
used in the past as a preparatory regimen for transplant, recent studies have
determine the nature of that risk.
shown no added benefit and, unfortunately, increased toxicity. Therefore, TBI
is no longer recommended as part of preparatory regimens. In patients with
VELCADE® ­ A HOVON/GMMG phase III study comparing VELCADE®,
refractory disease, sequential hemi-body radiation can be used to temporar-
Adriamycin®, and dexamethason (PAD) + VELCADE® maintenance, to
ily control the disease. This is rarely successful for very long, particularly in
vincrinstine, Adriamycin®, and dexamethasone (VAD) + thalidomide main-
patients with aggressive, active myeloma. There is also the disadvantage that
tenance, was presented at ASH 2010. Not only did VELCADE® result in
wide-field radiation destroys the normal bone marrow and makes it difficult if
improved PFS and overal survival, but its use as maintenance therapy admin-
not impossible to use other treatment options fol owing this approach.
istered on an every-other-week schedule was wel tolerated and resulted in
additional responses. Initial results also indicated benefit in patients with the
deletion 17p poor-risk FISH genetic feature.
31
32

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5. suPPortIVE CArE
Myeloma IX trial (Morgan et al.) showed that zoledronic acid was not only
superior to clodronate in preventing skeletal-related events (SRE), but also
Erythropoietin ­ Erythropoietin is a natural y occurring hormone now avail-
provided a survival benefit independent of SRE reduction, supporting anti-
able through genetic engineering techniques. Erythropoietin is administered
myeloma activity of zoledronic acid.
to improve the hemoglobin level in patients who have persistent anemia.
Erythropoietin injections (e.g., 40,000 units subq weekly) can show dramatic
Several concerns have emerged related to chronic bisphosphonate use. Two of
benefit in the level of hemoglobin and in performance status. It should be
these, kidney damage and a condition cal ed osteonecrosis of the jaw (ONJ)
strongly considered in patients who have persistent anemia. However, under
are addressed in detail in other IMF educational materials (Myeloma Minute©,
new strict guidelines, erythropoietin should only be used in the setting of
Myeloma Today©, and Understanding Bisphosphonate Therapy©). Both condi-
ongoing active treatment for myeloma. Erythropoietin should only be con-
tions are fortunately relatively uncommon, but awareness of these potential
tinued in patients showing clear benefit. Iron supplements may be required to
problems is the key to prevention. Kidney function must be serial y moni-
achieve maximum benefit. Under new FDA guidelines, it may become neces-
tored (especial y serum creatinine before each treatment dose), particularly
sary for patients to sign informed consents to take erythropoietin. As previ-
with Zometa® use. If the serum creatinine increases by 0.5 to 1.0 mg/dL, dose
ously noted, recombinant Epo (e.g., Epogen® or Procrit®) should be used with
and/or schedule adjustments for Aredia® or Zometa® may be required. For
caution in the light of recent reports of the association of Epo with increased
Zometa®, one of the simplest adjustments is to extend the infusion time from
tumor growth and reduced survival in patients with cancer, and the iden-
15 minutes to 30 to 45 minutes, which reduces the risk of renal impairment.
tification of Epo receptors on myeloma cel s, although this requires further
An American Academy of Oral Medicine position paper on the management
investigation.
of bisphosphonate-related ONJ (BONJ) was published in The Journal of the
FIGURE 5: HOW PAMIDRONATE WORKS
American Dental Association in December, 2005. The first recommendation
is prevention of BONJ through regular dental check-ups. If a problem is
found, referral to an expert (i.e., an oral surgeon) is strongly recommended.
Any major jaw surgery must be avoided until consultation has been sought.
Dental extractions should be avoided until ful consultation has been obtained
as wel . Infection may require antibiotic therapy. The Mayo Clinic published
the Mayo Consensus Statement for the Use of Bisphosphonates in Multiple
Myeloma in August, 2006, which includes the fol owing: "Pamidronate is
favored over zoledronic acid until more data are available on the risk of com-
plications (osteonecrosis of the jaw.)" Some modifications of these guidelines
were proposed by the IMF's International Myeloma Working Group and pub-
Bisphosphonates ­ Bisphosphonates are a class of chemicals that bind to
lished in the Mayo Clinic Proceedings in March, 2007. At the 2009 annual
the surface of damaged bones in patients with myeloma. This binding inhib-
meeting of the American Society of Hematology, key opinion leaders noted
its ongoing bone destruction and can improve the chances of bone healing
that the incidence of ONJ appears to have decreased dramatical y, probably
and recovery of bone density and strength. A randomized study utilizing the
due to improved dental hygiene.
bisphosphonate pamidronate (Aredia®) showed particular benefit in patients
responding to ongoing chemotherapy. It is currently recommended that
However, additional concerns have emerged with long-term used of bisphos-
bisphosphonate therapy be used as an adjunctive measure in myeloma patients
phonates. Atypical (subtrochanteric) fractures of the femur are rare, and there
who have bone problems (see Figure 5). Other bisphosphonates available
is data that establishes an association with five or more years of bisphospho-
include clodronate (Bonefos®), an oral formulation in use in Europe for the
nate treatment with their occurrence. In October, 2010, the FDA added sub-
treatment of myeloma bone disease, and zoledronic acid (Zometa®), approved
trochanteric fracture of the femur to the "Precautions and Warnings" section
in the U.S. and Europe as treatment of both hypercalcemia and bone disease.
of the package inserts for al bisphosphonates. Two recent publications dis-
Several new bisphosphonates are in clinical trials for myeloma. One, cal ed
cuss the possible association between oral bisphosphonates and cancer of the
ibandronate (Boniva®), is now used in Europe. In the US, it is currently FDA
esophagus. Using the same database, one group did not find an association
approved only for use in postmenopausal osteoporosis.
(Cardwel et al.), whereas the other group reported an increased risk (Green et
al.). These findings require further examination.
At the 2010 annual meeting of the American Society of Hematology, a ran-
domized comparison of zoledronic acid with clodronate as part of the MRC
33
34

---

The International Myeloma Working Group (IMWG) recommends discon-
If first relapse occurs after a remission of at least 6 months to 1 year, the first
tinuing bisphosphonates after one year of therapy for patients who achieve
strategy is to consider re-utilizing the therapy that produced the remission in
complete response and/or plateau phase. For patients who have active dis-
the first place. Approximately 50% of patients wil experience a second remis-
ease, who have not achieved a response, or who have threatening bone dis-
sion with the same therapy that produced the first. This is particularly true for
ease beyond two years, bisphosphonate therapy can decreased to every three
patients whose disease is in remission for over one year fol owing the initial
months. Current guidelines on the role of bisphosphonates in multiple
induction attempt. As an example, a patient who has received MP and whose
myeloma from the American Society of Clinical Oncology (ASCO) (Kyle et
myeloma has gone into remission for two years can again receive MP induc-
al., J Clin Oncology 2007) recommend treating for two years, then considering
tion. If remission has lasted less than six months, some alternative therapy wil
discontinuation of bisphosphonates for patients whose disease is responsive or
usual y be required. This is also the case if relapse has occurred fol owing a sec-
stable. Continued use of bisphosphonates should be at the discretion of the
ond or third use of the original induction therapy. The use of an Adriamycin®-
physician.
or Doxil®-containing regimen is an important consideration in this setting.
(See Figure 6, the multi-drug-resistant [MDR] myeloma cel .)
Antibiotics ­ Infections are a common and recurrent problem in patients with
myeloma. A careful strategy for infection management is required. Antibiotic
FIGURE 6: MDR MYELOMA CELL
therapy should be instituted immediately if active infection is suspected. Use
of preventative or prophylactic antibiotics with recurrent infection is contro-
versial. A recent comparative study (URCC/ECOG, Vesole et al.) presented at
ASH 2010 concluded that "the use of prophylactic antibiotics did not decrease
the incidence of serious infection (> grade 3 and/or hospitalization) nor of any
infection within the first 2 months of treatment." Based on this study, the
authors recommend that antibiotics should not be mandated in the first two
months of treatment, but should be considered on a case-by-case basis. The
continuation of prophylactic antibiotics can increase the chance of antibiotic
resistance, but it can also reduce the chance of recurrent infectious complica-
VELCADE® (bortezomib) for relapsing myeloma ­ The availability of
tions. The use of high-dose gamma globulin may be required in patients with
VELCADE® for relapse treatment has been a major step forward. After its
acute and severe recurrent infections. GM-CSF may be helpful to improve the
approval for patients with multiple myeloma who have received at least
white blood cel levels in an effort to overcome infectious complications. The
two prior therapies and have demonstrated disease progression on the last
use of G- or GM-CSF is helpful in the recovery phase fol owing bone marrow
therapy,VELCADE® was then evaluated in a multicenter phase III "APEX"
or stem cel transplantation. G-and GM-CSF are also used in harvesting stem
randomized trial comparing VELCADE® to high-dose dexamethasone in 669
cel s.
myeloma patients at 80 sites who had relapsed fol owing one to three prior
lines of therapy. The primary end point was time to progression. APEX also
Antivirals ­ An increased incidence of herpes zoster (shingles) has been
assessed the role of VELCADE® as maintenance therapy in responders. This
observed in some patient populations with myeloma (but not other malig-
study recruited international y and was the largest study ever completed in
nancies) who are treated with VELCADE®. Therefore, prophylactic antiviral
multiple myeloma. Overal , there was an approximately 30% improvement
therapy should be considered with VELCADE® therapy. This has led to the
in survival during the fist year with bortezomib (VELCADE®) as opposed
recommendation that patients on clinical trials of carfilzomib, a second-gen-
to dexamethasone. This was obviously very helpful information, and led to
eration proteasome inhibitor, receive antiviral prophylaxis. Myeloma patients
VELCADE®'s role as a platform on which to base combination therapies for
are cautioned not to get the shingles (Zostavax®) vaccine, as it is a live virus
relapse (Vel/Doxil®, VR, VRD, VCD, etc.).
that poses a significant risk to those who are immune compromised.
other options ­ It is important to keep in mind that a variety of single
6. MAnAGEMEnt oF rELAPsInG or rEFrACtory DIsEAsE
and combination chemotherapy protocols are available for the management
As il ustrated in the pathophysiology section, a frequent problem in myeloma
of relapsing and refractory disease. Depending upon the exact problem, a vari-
is the relapse that occurs fol owing a 1- to 3-year remission. Although main-
ety of interventions may be possible. For example, if relapse is associated with
tenance therapy may be useful in prolonging the initial remission period, the
the development of one or two bone lesions, radiation to the site(s) of bone
relapse, which supervenes inevitably, requires re-induction therapy. The fol-
involvement may be a satisfactory way to manage the relapse. If overal relapse
lowing is an overal strategy for the management of relapsing disease.
has occurred, dexamethasone as a single agent can be very useful in achieving
35
36

---

overal control of the disease. The use of dexamethasone is attractive because it
clinical trials, including proteasome inhibitors and immunomodulatory
can be given by mouth and does not cause significant side effects such as hair
agents, monoclonal antibodies, histone deacetylase (HDAC) inhibitors, heat
loss or reduction in peripheral blood count values.
shock protein (HSP) inhibitors, chemotherapeutic agents, and therapies
targeted to myeloma-specific pathways. Patients are encouraged to contact
Another important point is that relapse fol owing high-dose therapy with
the IMF via telephone (800-452-CURE [2873] in the U.S. and Canada,
transplant has, in many cases, a pattern similar to relapse fol owing more
+1-818-487-7455 elsewhere) or Internet (myeloma.org) and to check with
standard approaches. Second and sometimes third remissions can be achieved
their physicians regarding the availability of new clinical trials. The Myeloma
fol owing relapse after bone marrow transplantation. Whether a second high-
Matrix©, an IMF publication that lists al drugs currently in clinical trials for
dose therapy with transplant is the most appropriate strategy as opposed to
myeloma, is available with regular updates in print and with on-going updates
some other lower-dose chemotherapy approach is currently unclear, and must
on the IMF web site. Very good summaries of new therapies are presented
be based upon individual patient considerations.
in the IMF reports from ASH, ASCO, EHA, and IMWG (al available by
Given the continuing rapid rate of development of new therapies for
cal ing the IMF or on line at myeloma.org).
myeloma, including second-generation proteasome inhibitors, third-genera-
tion immunomodulatory drugs, monoclonal antibodies, and targeted thera-
pies, as wel as investigation of new combinations of existing and new agents,
REFERENCES
treatment in the context of clinical trials can be an option for patients with
NOTE: References rather than formal footnotes are provided as background source material
relapsed myeloma.
for each major section of the booklet. Within sections, articles are listed alphabetically by author.
A ful range of supportive care is crucial for the management of myeloma.
GENERAL
· Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med. 1997; 336: 1657-1664.
When first diagnosed, a number of emergency procedures may be required,
· Berenson James R. Biology and Management of Multiple Myeloma. Humana Press. 2004 ISBN 0-89603-706-1.
including dialysis, plasmapheresis, surgery, and radiation to reduce pressure on
· Gahrton G, Durie BGM, Samson DM. Multiple Myeloma and Related Disorders. Oxford University Press 2004 ISBN: 0-89603-
a nerve, spinal cord, or other crucial organ. The management of pain is essen-
706-1.
· Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111(6):2962-2972.
tial for the initial care of patients with myeloma. This can be difficult until
· Mehta J, Singhal S, eds. Myeloma, Dunitz M. Taylor and Francis Group, 2002: ISBN 1-901865-50-9.
initial disease control is achieved. There is no reason for patients with myeloma
· Palumbo A, Anderson L. Multiple myeloma. N Engl J Med. 2011; 364:1046-1060.
to have major ongoing pain with the range of new drugs and strategies avail-
HISTORY
able. There can be reluctance on the part of the patient and/or the physician to
· Kyle RA. History of multiple myeloma. In: Neoplastic Diseases of the Blood, 3rd edition. (Wiernik PH, Canellos GP, Kyle RA,
implement ful pain control procedures because of concerns about addiction.
Schiffer CA, eds). New York: Churchill Livingstone, 1996.
· Kyle RA. History of multiple myeloma. In: Neoplastic Diseases of the Blood, 2nd edition.(Wiernik PH, Canellos GP, Kyle RA,
Control of pain should always be the first priority. A brace or corset can help
Schiffer CA, eds). New York: Churchill Livingstone, 1991: 325-32.
stabilize the spine or other area, reducing movement and pain. Moderate exer-
EPIDEMIOLOGY
cise is also important in recovering bone strength and mobility and can help
· American Cancer Society. Cancer Facts & Figures 2010. Atlanta: American Cancer Society; 2010.
in overal pain reduction.
· Birmann BM, Giovannucci E, Rosner B, Anderson KC, Colditz GA. Body mass index, physical activity, and risk of multiple
myeloma. Cancer Epidemiol Biomarkers Prev 2007; 16(7):1474-1478.
7. nEW AnD EMErGInG trEAtMEnts
· Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma.
Blood. 2008; 111:2521-2526.
Most new treatments are available in the setting of clinical trials. Clinical
· Brown LM, Gridley G, Check D, Landgren O. Risk of multiple myeloma and monoclonal gammopathy of undetermined
significance among white and black make United States veterans with prior autoimmune, infectious, inflammatory, and allergic
trial phases are listed in Table 11. A whole range of agents is currently in
disorders. Blood 2008; 111(7):3388-3394.
· Herrington LJ, Weiss NS, Olshan AF. The epidemiology of myeloma. In: Myeloma Biology and Management (Malpas JS, Bergsagel
DE, Kyle RA eds.). Oxford, England, Oxford University Press: 1995: 127-168.
TABLE 12
· Infante PF. Benzene exposure and multiple diagnosis: A detailed meta-analysis of Benzene cohort studies. Ann NY Acad Sci.
Clinical Trial Phases
2006;1076:90-109.
I
Early testing to assess dosing, tolerance, and toxicity in patients
· Jemal A, Thomas A, Murray T, Thun M. Cancer statistics 2002. CA Cancer J Clin 2002; 52: 23-47.
II
Further testing to evaluate how effective treatment is at the dose and
· Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin. 2010; 60(5):277-300
schedule selected
· Kirkeleit J, Riise T, Bratveit M, Moen BE. Increased risk of acute myelogenous leukemia and multiple myeloma in a historical
cohort of upstream petroleum workers exposed to crude oil. Cancer Causes Control 2008;19:13-23.
III
Comparison of the new treatment with prior treatment(s) to determine
· Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood
if the new treatment is superior
2008; 111:2516-2520.
IV
Usually carried out after FDA approval to assess cost-effectiveness,
· LeMasters GK, Genaidy AM, Succop P, et al. Cancer risk among firefighters: A review and meta-analysis of 32 studies. J Occup
quality of life impact, and other comparative issues
Environ Med 2006;48(11):1189-1202.
37
38

---

· Lynch HT, Ferrara K, Barlogie B, et al. Familial Myeloma. N Engl J Med 2008; 259(2):152-157.
· Durie BGM, et al. Cytogenetic abnormalities in multiple myeloma. Epidemiology and Biology of Multiple Myeloma. New York:
· Schottenfeld D, Fraumeni JF Jr. (eds). Cancer Epidemiology and Prevention, 2nd edn. New York: Oxford University Press;
Springer-Verlag, 1991: 137-41.
1996:946-970.
· Fonseca R, Avet-Loiseau H, et al. International myeloma working group molecular classification of multiple myeloma: spotlight
· Schwartz GG. Multiple myeloma: clusters, clues, and dioxins. Cancer Epidemiol Biomarkers Prev. 1997; 6: 49-56.
review. Leukemia 2009; 23:2210-2222.
· Jaksic W, Trudel S, Chang H, et al. Clinical outcomes in t(4,14) multiple myeloma: a chemotherapy sensitive disease characterized
BONE DISEASE
by rapid relapse and alkylating agent resistance. J Clin Oncol 2005;23(28):7069-73.
· Bataille R, et al. Mechanism of bone destruction in multiple myeloma. The importance of an unbalanced process in determining
the severity of lytic bone disease.
· Konigsberg R, Zojer N, Ackermann J, et al. Predictive role of interphase cytogenetics for survival of patients with multiple
J Clin Oncol 1989; 7: 1909.
myeloma. J Clin Oncol. 2000; 18: 804-812.
· Berenson J, et al. Long-term pamidronate treatment of advanced multiple myeloma reduces skeletal events. J Clin Oncol 1998;
16: 593-602.
· Stewart AK: A risk-adapted approach to myeloma therapy. ASCO Educational Book. 2008:380-84 (ISSN:1548-8748).
· Berenson J, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med
MGUS AND ASYMPTOMATIC MYELOMA
1996; 334: 488-493.
· Kyle RA, Therneau TM, Rajkumar SV, Offord JR. A long-term study of prognosis in mono-clonal gammopathy of undetermined
· Bredella MA, Steinbach L, Caputo G, et al. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J
significance. N Engl J Med. 2002; 346: 564-569.
Roentgenol 2005;184:1199-1204.
· Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980; 302: 1347-49.
· Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group (IMWG) consensus statement and guidelines
· Weber DM, et al. Prognostic features of asymptomatic multiple myeloma. Br J Haematol. 1997; 97: 810-4.
regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia 2009;
23:1545-1559.
STAGING AND PROGNOSTIC FACTORS:
· Durie BGM, Salmon SE, Mundy GR. Relation to osteoclast activating factor production to extent of bone disease in multiple
· Bataille R, Boccadoro M, Klein B, et al. C-reactive protein and 2-microglobulin produce a simple and powerful myeloma staging
myeloma.
system. Blood 1992; 80: 733-7.
Br J Haematol 1981; 47: 21-26.
· Durie BGM, Waxman AD, D'Agnolo A, Williams CM. Whole-body (18) F-FDG PET identifies high-risk myeloma.
· Durie BGM, Stock-Novack D, Salmon SE, et al. Prognostic value of pre-treatment serum
J Nucl Med 2002;
2-microglobulin in myeloma: a
43:1457-1463.
Southwest Oncology Group study. Blood 1990; 75: 823-30.
· Jadvar H, Conti PS. Diagnostic utility of FDG PET in multiple myeloma.
· Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer 1975; 36: 842-54.
Skeletal Radiol 2002;31:690-694.
· Kato T, Tsukamoto E, Nishioka T, et al. Early detection of bone marrow involvement in extramedullary plasmacytoma by whole-
· Facon T, et al. Chromosome 13 abnormalities identified by FISH analysis and serum 2-microglobulin produce a powerful
body F-18 FDG positron emission tomography.
myeloma staging system for patients receiving high-dose therapy. Blood 2001; 97: 1566-71.
Clin Nucl Med 2000;25:870-873.
· Major P, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of
· Gahrton G, Durie BGM, Samson DM, editors. Multiple Myeloma and Related Disorders, The role of imaging in myeloma. A
two randomised, controlled clinical trials.
Hodder Arnold Publication, Oxford University Press, 2004; pp 155-63.
J Clin Oncol 2001; 19, 558-67.
· Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S et al. Collapsing focal segmental glomerulosclerosis following
· Greipp PR , Durie, BGM, et al. International Staging System for multiple myeloma. J Clin Oncol. 2005:23(15):3412-20.
treatment with high-dose pamidronate. J Am Soc Nephrol 2001; 12: 1164-1172.
· Greipp RR, San Miguel JF, Fonesca R, Avet-Loiseau H, Jacobson JL, Durie BGM. Development of an International Prognostic
· McCloskey EV, et al. A randomised trial of the effect of clodronate on skeletal morbidity in multiple myeloma.
Index (IPI) for myeloma: report of the International Myeloma Working Group. Haematol J 2003; 4 (suppl.1): p 7.1, S43-S44.
Br J Haematol
1998; 100: 317-25.
· Greipp PR, et al. Value of 2-microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly
· Moulopoulos LA, Dimopoulos MA, Weber D, et al. Magnetic resonance imaging in the staging of solitary plasmacytoma of bone.
diagnosed myeloma. Blood 1988; 72: 219-23.
J Clin Oncol 1993;11:1311-1315.
· Hungria VTM, Maiolino A, Martinez G, et al. Confirmation of the utility of the International Staging System and identification of a
· Mundy, GR, Yoneda T. Bisphosphonates as anticancer drugs.
unique pattern of disease in Brazilian patients with multiple myeloma. haematologica 2008; 93:791-792.
N Engl J Med 1998; 339: 398-400.
· Orchard K, Barrington S, Buscombe J, et al. Fluoro-deoxyglucose positron emission tomography imaging for the detection of
· Jacobson J, Hussein M, Barlogie B, Durie BGM, Crowley J. A new staging system for multiple myeloma patients based on the
occult disease in multiple myeloma.
Southwest Oncology Group (SWOG) experience. Br J Haematol 2003; 122: 441-450
Br J Hematol 2002;117:133-135.
· Roodman, GD. Bone building with bortezomib.
· Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood
J Clinic Invest 2008; 118(2):462-464.
2008; 111(5):2516-2520.
· Rosen LS, Gordon D, Antonio BS, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients
with breast cancer or osteolytic lesions of multiple myeloma: a phase II, double blind, comparative trial.
· Ludwig H, Durie BGM, Bolejack V, et al. Myeloma in patients younger than age 50 years presents with more favorable features and
Cancer J. 2001; 7:
377-387.
shows better survival: an analysis of 10549 patients from the International Myeloma Working Group. Blood 2008; 111(8):4039-
4047.
· Schirrmeister H, Bommer M, Buck AK, et al. Initial results in the assessment of multiple myeloma using 18F-FDG PET. Eur J Nucl
· Zojer N, et al. Deletion of 13q14 remains an independent prognostic variable in multiple myeloma despite its frequent detection
Med Mol Imaging 2002.29:361-366.
by interphase fluorescence in situ hybridization. Blood 2001; 95: 1925-30.
· Terpos E, Sezer O, Croucher P, Dimopoulos M-A. Myeloma bone disease and proteasome inhibition therapies. Blood 2007;
110(4):1098-1104.
RESPONSE CRITERIA :
· Walker R, Barologie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: Diagnostic and clinical implications.
· Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;
J Clin Oncol 2007; 25(9); 1121-1128.
20:1467-1473.
· Rajkumar SV, Durie BGM. Eliminating the complete response penalty from myeloma response criteria. Blood 2008; 111(12):5759.
ANEMIA
· Becker, PS, Miller CP, Wood BL, et al. Expression of erythropoietin receptors by plasma cells from patients with multiple
CHEMOTHERAPY & RADIATION TREATMENT :
myeloma: Potential relevance to pharmacological use of erythropoietin. J Clin Oncol 28:15s, 2010 (suppl; abstr 8124).
· Alexanian R, et al. Primary dexamethasone treatment of multiple myeloma. Blood 1992; 80: 887-90.
CLINICAL SYMPTOMS
· Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for myeloma. Am J Hematol 1990; 33: 86-9.
· Pruzanski W, Ogryzlo MA. Abnormal proteinuria in malignant diseases. Adv Clin Chem 1970;13:335-382.
· Alexanian R, et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA
1969; 208: 1680-5.
CHROMOSOMES
· Durie BGM, Jacobson J, Barlogie B, et al. Magnitude of Response with Myeloma Frontline Therapy Does Not Predict Outcome:
· Arzoumanian V, Hoering A, Sawyer J, et al. Suppression of abnormal karyotype predicts superior survival in multiple myeloma.
Importance of Time to Progression in Southwest Oncology Group Chemotherapy Trials. J Clin Oncol 2004; 22:1857-1863.
Leukemia 2008; 22:850-855.
· Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines, a consensus report from the Scientific Advisors of the
· Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14)
International Myeloma Foundation. The Hematology Journal 2003; 4:379-398.
myeloma but not outcome of patients with del(17p). J Clin Oncol 2010; 28(30):4630-4634.
· Kumar A, Loughran MA, Durie BGM, et al. Management of multiple myeloma: a systematic review and critical appraisal of
· Dewald GW, Therneau T, et al. Relationship of patient survival and chromosome anomalies detected in metaphase and/or
published studies. Lancet Oncology 2003; 4: 293-304.
interphase cells at diagnosis of myeloma. Blood. 2005;106(10):3553-8.
· MacLennan ICM, et al, for the MRC Working Party on Leukaemia in Adults. Combined chemotherapy with ABCM versus melphalan
· Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly diagnosed multiple myeloma based on Mayo stratification of
for treatment of myelomatosis. Lancet 1992; 339: 200-5.
myeloma and risk-adapted therapy (mSMART): Consensus statement. Mayo Clin Proc 2007; 82(3):323-341.
39
40

---

· Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple
· Mehta J, Powles RL. Autologous blood and marrow transplantation. In: Leukaemia and Associated Diseases. (Whittaker JA, Holmes
myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol 1998; 16: 3832-42.
JA, eds). Oxford: Blackwell Science, 1998; 455-81.
REFRACTORY DISEASE :
SYNGENEIC AND ALLOGENEIC TRANSPLANT :
· Alexanian R, Dimopoulus M. The treatment of multiple myeloma. N Engl J Med 1994; 330: 484-9.
· Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors
· Buzaid AC, Durie BGM. Management of refractory myeloma -a review. J Clin Oncol 1988; 6: 889-905.
on outcome. Blood 1996; 88: 2787-2793.
· Richardson P, Barlogie B, Berenson J, et al. A phase II multicenter study of the protease inhibitor bortezomib (VELCADE®
· Bensinger WI, Demirer, T, Buckner CD, et al. Syngeneic marrow transplantation in patients with multiple myeloma. Bone Marrow
formerly PS-341) in multiple myeloma patients (pts) with relapsed/refractory disease. N Engl J Med 2003; 348:2609-2617.
Transplant 1996; 18: 527-31.
· Durie BGM, Gale RP, Horowitz MM. Allogeneic and twin transplants for multiple myeloma: an IBMTR analysis. Multiple myeloma.
CYTOKINES AND SIGNAL TRANSDUCTION :
From biology to therapy. Current concepts. INSERM, Mulhouse, 24-26 October, 1994 (abstract).
· Bladé J, Estve J. Viewpoint on the impact of interferon in the treatment of multiple myeloma: benefit for a small proportion of
patients?
· Gahrton G, et al. Progress in allogeneic hematopoietic stem cell transplantation for multiple myeloma.
Med Oncology 2000; 77-84.
Bone Marrow Transplant
2000; 25 (suppl. 1): S54.
· Hideshima T, Bergsagel PL, Kuehl WM et al. Advances in biology of multiple myeloma: clinical applications. Blood 2004;
104:607-618.
· Gahrton G,. et al. Allogeneic bone marrow transplantation in multiple myeloma. Br J Haematol 1996; 92:251-254.
· Ludwig H, Fritz E, Kotzmann H, et al. Erythropoietin treatment of anemia associated with multiple myeloma.
· Maloney DG, Sahebi F, Stockerl-Goldstein KE, et al. Combining an allogeneic graft-vs.-myeloma effect with high-dose autologous
N Engl J Med 1990;
322: 1693-9.
stem cell rescue in the treatment of multiple myeloma [abstract]. Blood 2001; 98 (11. pt 1): 435a Abstract 2063.
· Mandelli F, et al. Maintenance treatment with alpha 2b recombinant interferon significantly improves response and survival
· Samson D. The current position of allogeneic and autologous BMT in multiple myeloma. Leukemia and Lymphoma 1992; 7:33.
duration in multiple myeloma patients responding to conventional induction chemotherapy. Results of an Italian randomized
MAINTENANCE:
study. N Engl J Med 1990; 322: 1430.
· Attal M, Cristini C, Marit G, et al. Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol 2010;28:15s (suppl;
· Musto P, et al. Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma:
abstr 8018).
role of cytokines and monitoring of erythropoiesis. Eur J Haematol 1997; 58: 314-19.
· McCarthy PL, Owzar K, Anderson KC, et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy
AUTOLOGOUS TRANSPLANT :
following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. J Clin Oncol 2010;28:15s
· Abdelkefi A, Ladeb S, Torjman L, et al. Single autologous stem-cell transplantation followed by maintenance therapy with
(suppl; abstr 8017).
thalidomide is superior to double autologous transplantation in multiple myeloma: Results of a multicenter randomized clinical
SUPPORTIVE CARE:
trial. Blood 2008; 111(4):1805-1810.
· Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-
· Attal M, Harousseau JL, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and
based national cohort study. J Bone Miner Res 2009;24:1095-1102.
chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91-97.
· Bertolotti P, Bilotti E, Colson K, et al. Management of side effects of novel therapies for multiple myeloma: Consensus statements
· Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl
developed by the International Myeloma Foundation's Nurse Leadership Board. Clin J Oncol Nursing 2008;S12(3):9-12.
J Med 2003;349:2495-2502.
· Cardwell CR, Abnet CC, Cantwell MM, et al. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 2010;
· Badros A, Barlogie B, Morris C, et al. High response rate in refractory and poor-risk multiple myeloma after allotransplantation
204:657-663.
using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 2001;97:2574-2579.
· Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the
· Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood
phase III APEX study. J Clin Oncol 2008;26:4784-4790.
1999; 93: 55-65.
· Chapel HM, Lee M, Hargreaves R, et al. Randomized trial of intravenous immunoglobulin as prophylaxis against infection in
· Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple
plateau-phase multiple myeloma. Lancet. 1994; 343: 1059-1063.
myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006;24:929-936.
· Faiman B, Bilotti E, Mangan PA, Rogers K, IMF NLB. Steroid-associated side effects in patients with multiple myeloma: Consensus
· Bensinger WI. The Role of Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Myeloma. J NCCN 2004;
statement of the IMF Nurse Leadership Board. Clin J Oncol Nursing 2008;S12(3):53-62.
2: 371-378.
· Green J, Czanner G, Reeves G, et al. Oral bisphosphonates and risk of cancer of the oesophagus, stomach, and colorectum: case-
· Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. M Engl J Med
control analysis within a UK primary care cohort. BMJ 2010; 341c4444 doi:10.1136/bmj/c4444.
2007;356:1110-1120.
· Hussein MA, Vrionis FD, Allison R, et al. The role of vertebral augmentation in multiple myeloma: International Myeloma Working
· Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (
Group Consensus Statement. Leukemia 2008; 22:1479-1484.
VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005;106:35-9.
· Johnson WJ, Kyle RA, Pineda AA, et al. Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis
· Cunningham D, et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma:
and chemotherapy. Arch Int Med. 1990; 150: 863-69.
long-term follow-up results. Br J Haematol 1998; 102: 495-502.
· Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995; 32:45-59.
· Desikan KR, Barlogie B, Sawyer J, et al. Results of high-dose therapy for 100 patients with multiple myeloma: durable complete
· Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role
remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 2000; 95: 4008-4010.
of bisphosphonates in multiple myeloma. J Clin Oncol 2007;25:2464-2472.
· Dispenzieri A, Kyle RA, Lacy MQ, et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood
· Ludwig H, Fritz E, Kotsmann H, et al. Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 1990;
stem cell transplantation: a case-control study. Blood 2004; 103: 3960-3963.
233:1693-1699.
· Fernand JP, Ravaud P, Chevert S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple
· Mateos MV. Management of treatment-related adverse events in patients with multiple myeloma. Cancer Treat Rev
myeloma: upfront or rescue treatment? Results of a multicenter sequential randomized clinical trail. Blood 1998; 92: 3131-3136.
2010;36:Suppl2:S24-32.
· Fernand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with
· Miceli T, Colson K, Gavino M, Lilleby K, IMF NLB. Myelosuppression associated with novel therapies in patients with multiple
conventional treatment in myeloma patients aged 55-65 years: long term results of a randomized control trial from the Group
myeloma: Consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nursing 2008;S12(3):13-19.
Myelome-Autogreffe. J Clin Oncol 2005;23:9277-9233.
· Morgan G, Davies F, Gregory W, et al. Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts)
· Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced
with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. J Clin Oncol 2010; 28:15s,
allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple
(suppl; abstr 8021).
myeloma. Blood 2006;107:3474-2480.
· Oken M, Pomeroy C, Weisdorf D, et al. Prophylactic antibiotics for the prevention of early infection in multiple myeloma. Am J
· Gore ME, Viner C, Meldrum M. Intensive treatment of multiple myeloma and criteria for complete remission. Lancet 1989;
Med. 1996; 100: 624-28.
14:879-882.
· Osterborg A, Boogaerts MA, Cimino R, et al. Recombinant human erythropoietin in trans-fusion-dependent anemic patients with
· Martinelli G, Terragna C, Zamagni E, et al. Molecular remission after allogeneic or autologous transplantation of hematopoietic
multiple myeloma and non-Hodgkin's lymphoma-a randomized multicenter study. Blood 1996; 87:2675-2682.
stem cells for multiple myeloma. J Clin Oncol 2000; 18: 2273-81.
· Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide and lenalidomide associated thrombosis in myeloma.
· McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 1983; 2: 822-824.
Leukemia 2008; 22:414-423.
41
42

---

· Rajkumar SV, Durie BGM. Eliminating the complete response penalty from myeloma response criteria. Blood 2008; 111(12):5759.
· Rajkumar SV, Rosinal L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide
· Rome S, Doss D, Miller K, Westphal J, IMF NLB. Thromboembolic events associated with novel therapies in patients with multiple
plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol
myeloma: Consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nursing 2008;S12(3):21-27.
2008;26(13):2171-2177.
· Smith LC, Bertolotti P, Curran K, Jenkins B, IMF NLB. Gastrointestinal side effects associated with novel therapies in patients
· Rajkumar SV, Hayman SR. Controversies surrounding the initial treatment of multiple myeloma. ASCO Educational Book
with multiple myeloma: Consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nursing 2008;S12(3):37-45.
2008;369-374.
· Tariman JD, Love G, McCullagh E, Sandifer S, IMF NLB. Peripheral neuropathy associated with novel therapies in patients with
· Rajkumar SV and Kyle R. Multiple Myeloma: Diagnosis and Treatment. Mayo Clinic Proc. 2005;80(10):1371-1382.
multiple myeloma: Consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nursing 2008;S12(3):29-35.
· Rajkumar SV, Jacobus S, Callender N, et al. A randomized phase III trial of lenalidomide plus high-dose dexamethasone versus
· Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma
lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern
patients receiving bortezomib therapy. Cancer 2009;115:229-232.
Cooperative Oncology Group. Blood 2006; 108: abstract #799.
· Rajkumar SV. Multiple myeloma: the death of VAD as initial therapy. Blood. 2005;106:2.
NEW THERAPIES :
· Arzoumanian V, Hoering A, Sawyer J, et al. Suppression of abnormal karyotype predicts superior survival in multiple myeloma.
· Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with CC-5013 (lenalidomide; Revlimid) plus dexamethasone (Rev/
Dex) for newly diagnosed myeloma (MM) [abstract].
Leukemia 2008; 22:850-855.
Blood. 2004;104:98a. Abstract 331.
· Barlogie B, Anaissie E, Bolejack V, et al. High CR and near-CR rates with bortezomib incorporated into up-front therapy of
· Richardson PG, Jagannath S, Avigen DE, et al. Lenalidomide plus bortezomib (Rev-VEl) in relapsed and/or refractory multiple
multiple myeloma with tandem transplants.
myeloma (MM): final results of a multicenter phase 1 trial.
J Clin Oncol 2006; 24: abstract #7519.
Blood 2006; 108: abstract #405.
· Barlogie B, Desikan KR, Eddelman P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent
· Richardson P, Schlossman RL, Hideshima F, et al. A Phase I study of oral CC5013, an immunomodulatory thalidomide (Thal)
thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.
derivative, in patients with relapsed and refractory multiple myeloma.
Blood 2001; 32: 45-59.
Blood 2001; 98: 775a.
· Barlogie B, Shaughnessy Jr. JD, Crowley J. Duration of survival in patients with myeloma treated with thalidomide.
· Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during
New Engl J
treatment of advanced multiple myeloma with bortezomib.
Med 2008; 359(2):210-212.
J Clin Oncol 2006;24:3113-3120.
· Berenson JR, Boccia R, Sigel D, et al. Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in
· Richardson PG, Chanan-Khan A, Schlossman R, et al. Single-agent bortezomib in previously untreated, symptomatic multiple
patients with relapsed or refractory multiple myeloma: a prospective, multicenter, phase II, single-arm study.
myeloma (MM): results of a phase 2 multicenter study.
Br J Haem 2006;
J Clin Oncol 2006; 24: abstract #7504.
135:174-183.
· Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. New
· Bruno B, Rotta M, Giaccone L, et al. New drugs for treatment of multiple myeloma Lancet Oncology 2004; 5( July) 1-16.
Engl J Med 2005;352:2487-2498.
· Dimopoulos MA, Kastritis E, Rajkumar SV. Treatment of plasma cell dyscrasias with lenalidomide.
· Richardson PG, Barlogie B, Berenson J, et al. Phase II study of the proteasome inhibitor PS341 in multiple myeloma patients with
Leukemia 2008; 22:1343-1353
relapsed/refractory disease. Proc Am Soc Clin Oncol 2002; 21: 11a.
· Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-
intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomized trial.
· San-Miguel J, Harousseau J-L, Joshua D, Anderson KC. Individualizing treatments of patients with myeloma in the era of novel
The
agents.
Lancet 2007; 370:1209-1218.
J Clin Oncol 2008; 26(16):2761-2766.
· Harousseau J-L, Marit G, Caillot D, et al. VELCADE/dexamethasone vs VAD as induction treatment prior to ASCT in newly
· Thomas D, Cortes J, O'Brian SM, et al. R115777, a farnesyl transferase inhibitor (FTI), has significant anti-leukaemia activity in
diagnosed multiple myeloma: A preliminary analysis of the IFM 2005-01 randomized multicenter phase 3 trial.
patients with chronic myeloid leukaemia (CML).
Blood 2006;
Blood 2001; 98: 727a.
108:abstract #56.
· Hussein MA, Mason J, Ravandi F, Rifkin R. A phase II clinical study of arsenic trioxide (ATO) in patients with relapsed or refractory
multiple myeloma; a preliminary report. Blood 2001; 98: 378a.
· Jagannath S, Durie BGM, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated
symptomatic multiple myeloma. Br J Haematol. 2005;129:776-83.
· Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination
therapy results in high complete- and overall-response rates in treatment-naïve symptomatic multiple myeloma. Blood
2008;111(3):1101-1109.
· Niesvizsky R, Jayabalan DS, Furst JR, et al. Clarithromycin, lenalidomide and dexamethasone combination therapy as primary
treatment of multiple myeloma. J Clin Oncol 2006; 24: abstract #7545.
· Oakervee HE, Popat R., et al. PAD combination therapy (PS341/bortezomib, doxorubicin and dexamethasone) for previously
untreated patients with multiple myeloma. Br J Haematol. 2005;129:755-62.
· Orlowski RZ, Peterson BL, Sanford B, et al. Bortezomib and pegylated liposomal doxorubicin as induction therapy for adult
patients with symptomatic multiple myeloma: Cancer and Leukemia Group B study 10301. Blood 2006; 108: abstract #797.
· Orlowski RZ, Zhuang SH, Parekh T, et al. The combination of pegylated liposomal doxorubicin and bortezomib significantly
improves time to progression of patients with relapsed/refractory multiple myeloma compared with bortezomib alone: results
from a planned interim analysis of a randomized phase III study. Blood 2006; 108: abstract #404.
· Palumbo A, Ambrosini MT, Benevolo G, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple
myeloma. Blood 2007; 109(7):2767-2772.
· Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2007; 111(8):
3968-3977.
· Palumbo A, Ambrosini MT, Benevolo G, et al. Combination of bortezomib, melphalan, prednisone and thalidomide ( VMPT) for
relapsed multiple myeloma: results of a phase I/II clinical trial. Blood 2006; 108: abstract #407.
· Palumbo A, Flaco P, Falcone A, et al. Oral Revlimid® plus melphalan and prednisone (R-MP) for newly diagnosed multiple
myeloma: results of a multicenter phase I/II study. Blood 2006; 108: abstract #800.
· Palumbo A, Bertola A, et al. A prospective randomized trial of oral melphalan, prednisone, thalidomide (MPT) vs. oral melphalan,
prednisone (MP): an interim analysis. [abstract] Blood. 2005;104(11):63a. Abstract 207.
· Pineda-Roman M, Zangari M, van Rhee F, et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly
effective in advanced and refractory multiple myeloma. Leukemia 2008; 22:1419-1427.
· Rajkumar SV, Hussein M, Catalano J, et al. A multicenter, randomized, double-blind, placebo-controlled study of thalidomide
plus dexamethasone versus dexamethasone alone as initial therapy for newly diagnosed multiple myeloma (MM 003). Blood
2006; 108: abstract #795.
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