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 and Canada): (800) 452 CURE (2873)
Cancer of the Bone Marrow
Tel: (818) 487-7455
Fax: (818) 487-7454
Email: TheIMF@myeloma.org
Website: www.myeloma.org
Dedicated to improving the quality of life
of myeloma patients while working
towards prevention and a cure.
International Myeloma Foundation
2006 Edition
Published by the International Myeloma Foundation
Prepared by Brian G.M. Durie, MD
© 2006, 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
8
BONE DISEASE
9
ANEMIA
10
KIDNEY DYSFUNCTION
10
OTHER ORGAN DYSFUNCTION
12
TYPES OF MYELOMA
13
CLINICAL SYMPTOMS
13
STAGING AND PROGNOSTIC FACTORS
14
DEFINITION OF CLINICAL RESPONSE
16
TREATMENT
17
CHEMOTHERAPY
18
TRANSPLANTATION
25
RADIATION
29
MAINTENANCE THERAPY
30
SUPPORTIVE CARE
31
MANAGEMENT OF RELAPSING
OR REFRACTORY DISEASE
32
NEW AND EMERGING TREATMENTS
35
REFERENCES
35

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INTRODUCTION
PRODUCTION OF MONOCLONAL PROTEIN
The IMF Concise Review of the Disease and Treatment Options is an
BY MYELOMA CELLS
overview of myeloma, with a discussion of the pathophysiology, clinical
features, and treatment options. It is hoped that the information will be
The characteristic property of myeloma cells is the production and
helpful to health professionals and patients alike.
release (or secretion) of monoclonal protein into the blood and/or urine.
The amount of monoclonal protein produced by myeloma cells varies
considerably from patient to patient. In assessing myeloma, it is very
WHAT IS MYELOMA?
important to know if a patient's myeloma cells are high producers or low
producers or even non-secretors with no protein released into the blood
Myeloma is a cancer of the plasma cells in the bone marrow. Myeloma
or urine. Once the relationship between the protein level and the amount
is synonymous with multiple myeloma and plasma cell myeloma. The
of myeloma in the bone marrow is known, it is possible to interpret and
malignant plasma cells (see Figure 1) or myeloma cells accumulate in the
understand the relationship between a particular protein level and the
bone marrow. The major features of myeloma result from the abnormal
myeloma tumor burden. Monoclonal protein is also called M-protein,
accumulation of myeloma cells within the bone marrow causing:
myeloma protein, para-protein, or the protein spike. The monoclonal
protein is called a spike because of the way it appears on protein elec-
· Disruption of normal bone marrow function reflected by anemia
trophoresis, a laboratory technique to separate and identify proteins (see
and/or low white counts or platelet counts
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 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 cell count is low.
Plasmacytomas are localized "tumors" composed of plasma cells, which
can grow inside bone (intramedullary) or outside bone (extramedullary
or soft tissue). When there are multiple plasmacytomas inside or outside
bone, this condition is also called multiple myeloma
myeloma cells producing M-protein
FIGURE 1: PLASMA (MYELOMA) CELLS
The monoclonal protein is an immunoglobulin or a component/frag-
ment of an immunoglobulin. Figure 3 illustrates the structure of a normal
immunoglobulin molecule. In myeloma cells, one or more mutations
have occurred in the genes responsible for immunoglobulin production.
Myeloma proteins therefore have an abnormal amino acid sequence and
protein structure. Typically, the normal antibody function of the immuno-
globulin is lost and the three-dimensional structure of the molecule may
be abnormal.
This abnormal immunoglobin structure and function has a number of
consequences:
· The excess M-protein accumulates in the blood stream and/or is excret-
ed in the urine as a monoclonal spike.
1
2

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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 can). In this case the
end result is either:
1. Amyloidosis ­ A disease entity in which the Bence Jones light
chains cross link in a highly symmetric ß-pleated fashion and
become deposited in tissue around the body, including, for exam-
ple, kidney, nerves, and heart-tissue; or
2. Light Chain Deposition Disease ­ The light chains are deposited
in a more haphazard fashion, but most especially in small blood
vessels of the eyes and kidneys.
Even in the absence of bodily dysfunction, routine blood testing may give
very strange results because of "stickiness" or hyperviscosity of myeloma
blood samples in automated chemical analyzers and/or interference with
chemical reactions necessary for routine testing.
· The abnormal monoclonal molecules can adhere to each other and/
or other tissues such as blood cells, blood vessel walls, and other
ANNOTATED HISTORY
blood components. This can reduce blood flow and circulation, caus-
ing hyperviscosity syndrome (discussed below).
Dr. Henry Bence Jones was the first to investigate a strange protein in the urine
· Approximately 30% of the time, more light chains are produced
of a myeloma patient. What caught Dr. Bence Jones' attention was a urine protein
than are needed to combine with the heavy chains to create a whole
that dissolved on boiling, but re-precipitated on cooling: what proved to be "Bence
immunoglobulin molecule. These excess light chains are Bence
Jones" light chains. It turned out that the patient also had a very strange bone
Jones proteins (see History section). Free Bence Jones proteins have
disease which we now call myeloma. The following is a brief annotated summary
a molecular weight of 22,000 daltons and are small enough to pass
of progress in research and treatment for multiple myeloma and related diseases
freely into the urine.
from that time forward
· The abnormal monoclonal proteins can also have a wide range of
other properties including:
1844 -1850 First case descriptions of myeloma referred to "mollities and
fragilitas ossium" (soft and fragile bones). The first patient,
· Binding to normal blood clotting factors, resulting in increased
Thomas Alexander McBean, was diagnosed in 1845 by Dr. William
bleeding tendency or enhanced blood clotting or phlebitis
Macintyre, a Harley Street consultant in London. The unusual
· Binding to circulating hormones or chemicals, resulting in a vari-
urine problem he discovered was fully investigated by Dr. Henry
ety of endocrine or metabolic dysfunctions.
Bence Jones, who published his findings in 1848. In 1846, Mr. John
Dalrymple, a surgeon, noted and published that the diseased
bones contained cells subsequently shown to be plasma cells. Dr.
FIGURE 4: DISEASE PHASES
Macintyre published the full details of this case of Bence Jones
myeloma in 1850. It has been noted that Dr. Samuel Solly pub-
lished 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 cell 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 cells.
1900
Wright discovered that multiple myeloma cells are plasma cells.
1903
Weber noted that myeloma bone disease (lytic lesions) shows up
on X-rays.
3
4

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1909
Weber suggested that plasma cells in the bone marrow actually
1984-1986
First reports of allogeneic transplants in multiple myeloma by vari-
produce the myeloma bone destruction.
ous investigators.
1930s
The routine diagnosis of myeloma remained difficult until the
1986-1996
Large numbers of studies evaluating high-dose therapy with
1930s, when bone marrow aspirates were first used on a larger
autologous bone marrow or stem cell rescue by various investi-
scale. The development of the ultracentrifuge and serum/urine
gators. Both single (McElwain) and double (Barlogie) transplant
protein electrophoresis improved both screening and diagnosis.
procedures introduced.
1953
Immunoelectrophoresis was introduced to allow exact identifica-
1996
· First randomized study indicating possible benefit of high-dose
tion of the monoclonal myeloma proteins. Immunofixation has
therapy with bone marrow transplant support versus standard
since been introduced as a more sensitive method.
chemotherapy (Attal).
1956
Korngold and Lipari noted that Bence Jones (BJ) proteins are relat-
· Randomized study of Aredia versus placebo indicates reduction
ed to normal serum gammaglobulin as well as abnormal serum
in bone problems ("skeletal related events").
proteins. In their honor, the two types of Bence Jones proteins are
1997
Evidence that viruses may be involved in triggering myeloma.
called Kappa (K), and Lambda (L).
Myeloma more common in patients with HIV and Hepatitis C.
1958
Discovery of sarcolysin in the USSR. From this, melpha-
Herpes virus (HHV-8) found in bone marrow dendritic cells. RNA
lan (Alkeran) was derived. For the first time, treatment was
found in blood with specificity for SV40 cancer-causing monkey
possible.
virus.
1961
Waldenström emphasized the importance of the differentiation
1998
· Continued research on the role of high-dose chemotherapy
between monoclonal and polyclonal gammopathies. He associ-
with autologous and allogeneic transplant. The magnitude of
ated IgM monoclonal proteins with macroglobulinemia, as distinct
benefit and patient population(s) likely to benefit remain uncer-
from myeloma.
tain. Transplant performed as part of initial (induction) therapy
is shown to produce results similar to transplant done at first
1962
First report of successful treatment of myeloma with melphalan
relapse.
(Alkeran) by Bergsagel.
· Chromosome 13 deletions shown to be poor prognostic factor for
1964
First report of successful treatment of myeloma with cyclophos-
transplantation as well as some other therapies.
phamide (Cytoxan) by Korst. Results with cyclophosphamide
proved to be similar to results with melphalan.
· New study reconfirms prednisone as a helpful maintenance
therapy with prolongation of remission. Alpha interferon also
1969
Melphalan combined with prednisone, by Alexanian, was shown
shown again to have some benefit in prolonging remission.
to give better results than melphalan alone.
1999
· Thalidomide shown to be an effective anti-myeloma therapy in
1975
Durie/Salmon staging system for myeloma introduced. Patients
patients with relapsing/refractory disease.
classified to assess benefits of chemotherapy at different disease
stages (I, II, III, A or B).
· "Mini allogeneic" transplant introduced as less toxic method to
achieve a "graft-vs-myeloma" effect.
1976-1992
Various combinations of chemotherapy agents tried, including the
M2 regimen (VBMCP), VMCP-VBAP, and ABCM, with some indi-
· Randomized French study shows no major benefit of double
cation of superiority versus MP. However, in 1992, a comparative
autologous transplant versus single transplant.
meta-analysis (Gregory) showed equivalent results for all combi-
· Longer-term follow-up shows that Aredia treatment continued
nations.
for 2 years is helpful.
1979-1980
Labeling index (growth fraction analysis) first introduced as a
2000
For the first time, there are several promising new approaches for
test in myeloma and related diseases. Stable remission or plateau
myeloma therapy. New clinical trials include thalidomide ana-
phase of myeloma identified. This is a period when the growth
logues (e.g. RevlimidTM and ActimidTM), long-acting Adriamycin
fraction (LI%) of residual bone marrow plasma cells is zero.
analogues (e.g. Doxil®), arsenic trioxide (Trisenox®), anti-angio-
1982
Twin transplants performed by Fefer and Osserman as treatment
genesis agents (e.g. VEGF tyrosine kinase inhibitor), agents to
for myeloma.
block cell adhesion, betathine, and proteasome inhibitors (e.g.
VELCADE®).
1983
First use of serum ß2 microglobulin as a prognostic test (Bataille,
Child, and Durie).
2001
· New classification system proposed for myeloma and related
diseases (see Table 1 below).
1984
Barlogie and Alexanian introduce VAD chemotherapy.
· New prognostic factor or staging systems proposed:
5
6

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2001 con't
· SWOG (Southwest Oncology Group) uses separation into 4
2005 con't
· International Staging System (ISS) developed by the International
groups based upon serum ß2 microglobulin and serum albu-
MyelomaWorkingGroupoftheInternationalMyelomaFoundation
min.
(IMF) is published (see page 15). New response criteria for assess-
· IFM (French Study Group) uses separation into 3 groups
ing treatment benefit is also developed and is scheduled for pub-
based upon serum ß2 microglobulin and presence/absence
lication in early 2006.
of abnormalities of chromosome 13 by FISH analysis.
· Numerous new agents in early development. Heat shock pro-
2002
· Evidence of efficacy of new agents in clinical trials including
tein-90 inhibitors enter Phase I ­ II trials.
VELCADE® (Phase III, Millennium) and RevlimidTM (Phase III,
· Addition of thalidomide to standard melphalan/prednisone
Celgene).
regimen shows remarkable added benefit. Several upfront trials
· Thalidomide combined with dexamethasone as frontline thera-
are ongoing.
py for myeloma produces response rate of approximately 70%.
· MRC in U.K. reports autotransplant results at ASH. Overall
benefit noted, especially for patients with high serum ß2 micro-
EPIDEMIOLOGY
globulin (> 7.5 mg/dl).
2003
· VELCADE
The average incidence of myeloma is 3-4/100,000 in the US, representing
® (bortezomib; formerly PS-341) approved by the
F.D.A. as treatment for actively relapsing myeloma following at
approximately 1% of all types of cancer. There are approximately 15,000
least 2 prior therapies.
new cases of myeloma in the US each year. Myeloma is more common in
African Americans than Caucasians. For example, in Los Angeles County
· MRC autotransplant results provided the second randomized
the incidence of myeloma in African American men is 9.8/100,000 versus
dataset indicating benefit of autotransplant versus standard-dose
4.3/100,000 for Caucasian men. The incidence varies from country to
chemotherapy.
country from a low of <1/100,000 in China to approximately 4/100,000
· Results of IFM study comparing single with double transplant
in most Western industrialized countries. The male/female ratio is 3:2.
published showing overall benefit with the double transplant.
The incidence rises with age. Better diagnostic techniques and the higher
However, no apparent added benefit for patients already in com-
average age of the general population may in part explain the rising
plete remission with the first transplant. Other questions about the
incidence over the last several decades. A trend toward more frequent
overall role of double transplant persist.
myeloma in patients under age 55 implies important environmental caus-
· Little Rock group (Shaugnessy/Barlogie) show that bone disease
ative factors in the past 60 years.
in myeloma is associated with production of a particular protein
called DKK-1.
PATHOPHYSIOLOGY
2004
· Results of ECOG randomized trial comparing thalidomide
plus dexamethasone versus dexamethasone alone for previously
The uncontrolled growth of myeloma cells has many consequences,
untreated myeloma were presented indicating a 59% response
including skeletal destruction, bone marrow failure, increased plasma
rate with the combination versus 41% with dexamethasone alone
volume and viscosity, suppression of normal immunoglobulin produc-
(ECOG Criteria).
tion, and renal insufficiency. Nonetheless, the disease can remain asymp-
· Results of multi-institutional randomized trial comparing
tomatic for many years, as noted in the discussion of MGUS. In the symp-
VELCADE® with dexamethasone were presented showing supe-
tomatic phase, the most common presenting complaint is bone pain.
riority for VELCADE® (details discussed in text).
The serum and/or urine M-protein is elevated and typically rising at the
· Early results with VELCADE® in the frontline setting presented
showing excellent results: 83% response rate for VELCADE
time of diagnosis. (Please note: M is used for Monoclonal, Myeloma,
®/
dexamethasone and 94% with VELCADE®/adriamycin/dexa-
Monoclonal immunoglobulin and M-component, which are not quite
methasone and the ability to harvest stem cells with successful
identical, but are used synonymously). The overall pattern of disease for
transplantation and engraftment. Further follow-up is required.
myeloma patients is illustrated in Figure 4. It is important to note that
there are frequently multiple periods of response and remission. The
· New myeloma staging system, the I.S.S. (International Staging
patho-physiology of myeloma is summarized in Table 2 in schematic
System), introduced. See page 15.
form
2005
· Two large Phase III trials showed that Revlimid® (lenalido-
mide) plus dexamethasone is superior to dexamethasone alone in
relapsed myeloma (time to progression > 15 months v. 5 months).
BONE DISEASE
FDA approval is anticipated in 2006.
7
8

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and repair. The mechanisms responsible for "un-coupling" in myeloma
TABLE 1
are under investigation. An important new observation is that the cho-
D M R M G
lesterol-low-ering drugs, statins (i.e. Lipitor®, Mevacor®, Baycol®, etc.),



can enhance osteoblast activity and promote bone healing. In addition,


the new agent VELCADE® (see relapse treatment) has been shown to
MGUS
MGUS
· Monoclonal protein present
promote bone healing, in addition to being a potent anti-myeloma agent.
(Monoclonal
(i.e., NO CHANGE)
· No underlying disease state
Studies to further investigate the benefit of such drugs in myeloma are
Gammopathy of
under way.
Undertermined
Significance)
ANEMIA
SMOLDERING
ASYMPTOMATIC
· Higher level of disease than
or INDOLENT
MYELOMA
MGUS, but still no symptoms or
Anemia is a characteristic feature of myeloma. Although simple physi-
MYELOMA
organ damage
cal displacement of marrow red cell precursors is undoubtedly a factor,
MYELOMA
SYMPTOMATIC
the specific inhibition of red cell production by micro-environmental
· Monoclonal protein present, and
MYELOMA
· One or more "CRAB" features of
cytokine and adhesion molecule effects is a more functional explanation.
organ damage present*
TNF- has been identified as one important inhibitor of erythropoiesis;
active myeloma, however, results in a complex interplay of factors that
*Organ damage classified as "CRAB"
can cause not just anemia, but neutropenia, and strangely, sometimes
C - calcium elevation (> 10 mg/l)
either increased or decreased platelet counts. Interleukin-6 is the factor
R - renal dysfunction (creatinine > 2 mg/dl)
most responsible for increased platelet counts levels. Increases in baso-
A - anemia (hemoglobin < 10 g/dl)
phils, eosinophils, and monocytes can also occur. Improvement in anemia
B - bone disease (lytic lesions or osteoporosis)
ONE OR MORE required for diagnosis of SYMPTOMATIC MYELOMA
occurs with successful treatment for the myeloma and can be enhanced
by use of recombinant erythropoietin (Epogen®, Procrit®, or Aranesp®
(darbapoietin).
Ever since the first recognition of myeloma in 1844, the presence of abnor-
mal protein has been linked with bone destruction. It has taken until quite
KIDNEY DYSFUNCTION
recently to determine the mechanisms involved. The first clue was that
both myeloma cells and increased numbers of osteoclasts are present at
Impairment of kidney function is a common complication in myeloma
sites of bone destruction. Understanding of the mechanisms has evolved
patients. However, this does not mean that every patient will have this
from the observation that myeloma cells produce osteoclast activating
problem. In some patients, myeloma proteins, especially Bence Jones
factors (OAFs) to the characterization of local cytokines such as IL-1ß, IL-
light chains, cause renal injury by a variety of mechanisms ranging from
6, and TNF- and -ß; chemokines such as MIP-1; and cell-cell adhesion
tubular damage from large accumulations of precipitated light chains, to
processes involving av ß3 integrin, all of which are involved in producing
effects of myeloma proteins deposited as amyloid, or selective tubular
increased numbers and activity of osteoclasts. Most recently a substance
damage resulting in the metabolic effects of an entity called Fanconi syn-
called RANK ligand (RANKL) has been identified as a critical mediator
drome. Fanconi syndrome is a type of selective kidney tubular damage
of osteoclast activation. Studies are already underway to evaluate the
with leakage of amino acids and phosphates into the urine, which can
clinical efficacy of specific inhibitors of RANKL, namely RANK.Fc and
cause metabolic bone disease.
osteoprotegerin (OPG), both of which have shown promise in laboratory
studies and preliminary clinical testing. A completely new finding is the
Other important factors related to kidney dysfunction in multiple myelo-
observation by the Little Rock group that lytic bone disease is associated
ma patients are increased levels of calcium and/or uric acid, infection,
with local production of a protein called DKK-1. This is yet another angle
and the effects of drugs such as nephrotoxic antibiotics, nonsteroidal
for new therapeutic strategies.
anti-inflammatory drugs, or contrast/dyes used for diagnostic studies.
Awareness of potential kidney damage and maintaining excellent fluid
Besides activation of osteoclasts, the other characteristic feature of
intake are especially important for myeloma patients to help avert the
myeloma bone disease is inhibition of osteoblasts, which are responsible
damaging effects of these various factors.
for new bone production and bone healing. "Coupling" between osteo-
clast and osteoblast function is responsible for normal bone remodeling
9
10

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TABLE 2
OTHER ORGAN DYSFUNCTION
S P
Myeloma cells can accumulate in bone marrow and/or in a variety of tis-
S F
sue sites and produce a broad range of potential complications.
· Solitary or multiple osteolytic lesions
· Neurologic Effects ­ Nerve tissue is often affected in myeloma
· Diffuse osteoporosis (osteopenia)
patients either by the direct antibody effects of myeloma proteins
A E O B D
against nerves (e.g. myelin sheaths) or deposition of amyloid fibrils
· Elevated serum calcium
on nerves, thus impairing function. These effects result in periph-
· Hypercalciuria (calcium increase in urine)
eral neuropathies that must be distinguished from other causes of
neuropathy such as diabetes mellitus. Because of the susceptibility
· Bone fractures
to infection, viral infections of nerve tissue are quite common, most
· Loss of height (vertebral collapse)
particularly varicella zoster (shingles) and Bell's palsy (partial facial
E S M (R)
paralysis).
· Soft tissue involvement, most commonly in head/neck area
· Plasmacytomas ­ Both in bone and soft tissue, plasmacytomas can
(e.g. nasopharynx); also in liver, kidney and other soft tissue
result in compression or displacement of nerves, the spinal cord, or
sites
even brain tissue. These pressure effects often represent a medical
emergency and require immediate treatment with high doses of cor-
P B
ticosteroids, radiation therapy, or neurosurgery.
· Anemia
·Infections ­ The predisposition to infections is perhaps the single
· Abnormal clotting
most characteristic feature of myeloma patients besides the strong
· Leukopenia
tendency for bone disease. The mechanisms responsible for infec-
· Thrombocytopenia
tion susceptibility are not fully understood. The presence of active
· Plasma cell leukemia
myeloma in the bone marrow results in impairment of normal
immune functions, including normal antibody production (reflected
· Circulating monoclonal B lymphocytes
by hypogammaglobulinemia), impaired T-lymphocyte function, and
(precursors of myeloma cells)
activated but aberrant monocyte/macrophage function. Some studies
P P C
indicate that a factor issuing from the activated macro phages both
· Hyperproteinemia (elevated protein)
enhances the activity of the myeloma, and inhibits normal immuno-
globulin production and T-lymphocyte functions.
· Hypervolemia (expanded volume)
· Monoclonal immunoglobulins
Myeloma patients are susceptible to both viral infections and infections
with "encapsulated" bacteria such as pneumococcus. However, in the
(IgG, IgD, IgA, IgM, IgE, light chains)
face of neutropenia and the effects of high-dose chemotherapy, and with
· Narrowed anion gap (low serum sodium)
the added local effects of implanted catheters (e.g. Hickman catheter), the
· Elevated serum ß2-microglobulin
whole range of bacterial, fungal, and opportunistic infections occurs in
· Decreased serum albumin
myeloma patients undergoing therapy.
· Elevated serum IL-6 and C-reactive protein (CRP)
K A
· Proteinuria, casts without leukocytes or erythrocytes
· Tubular dysfunction with acidosis
· Uremia (kidney failure)
· Amyloidosis
11
12

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Hypercalcemia, traditionally present in 30% of the patients at diagnosis,
TYPES OF MYELOMA
causes tiredness, thirst, and nausea. Precipitation of calcium salts can
result in deterioration of kidney function. Of note, in recent years the
The type of monoclonal protein produced varies from patient to patient.
incidence of hypercalcemia in newly diagnosed patients has dropped to
The most common is IgG and the rarest is IgE. Table 3 shows the percent-
10-15%, most likely because of earlier diagnosis. Hyperviscosity, due to
ages of different types of myeloma. Each type is associated with slightly
high myeloma protein levels, can cause problems such as bruising, nose
different patterns of disease. For example, IgA myeloma is more com-
bleeding, hazy vision, headaches, gastrointestinal bleeding, sleepiness,
monly associated with disease outside bone (extramedullary disease),
and a variety of ischaemic neurological symptoms caused by reduced
whereas IgD myeloma is more commonly associated with plasma cell
blood and oxygen supply to the nerve tissue. Hyperviscosity occurs in
leukemia and renal damage.
<10% of myeloma patients. Hyperviscosity affects about 50% of patients
with Waldenström's Macroglobulinemia (IgM paraprotein or M-compo-
CLINICAL SYMPTOMS
nent). Increased bleeding is often accentuated by thrombocytopenia, in
addition to the binding of monoclonal proteins to clotting factors and/or
About 70% of myeloma patients present with pain of varying intensity,
platelets.
often in the lower back or ribs. Sudden severe pain can be a sign of frac-
Neurologic involvement can result in specific problems depending on
ture or collapse of a vertebral body. General malaise and vague com-
location. Particularly common problems are spinal cord compression,
plaints are frequent. Significant weight loss is rare.
meningitis, and carpal tunnel syndrome. Although the first two are due
Both neutropenia and hypogammaglobulinemia increase the likelihood
to plasma cell tumor formation or infiltration, carpal tunnel syndrome is
of infections. Although pneumococcal pneumonia is the classic infection
usually due to amyloid deposition (deposition of Bence Jones proteins in
associated with myeloma at presentation, other bacteria, such as strepto-
a special ß-pleated form).
cocci and staphylococci, are now frequently isolated. Haemophilus infec-
tion and herpes zoster infections also occur.
STAGING AND PROGNOSTIC FACTORS
Prognosis in myeloma is determined by both the number and specific
properties of myeloma cells in a given patient. These specific properties
TABLE 3
include the growth rate of myeloma cells, the production rate of monoclo-
T M P (%)
nal proteins, and the production or nonproduction of various cytokines
1. Serum
%
Totals
and chemicals that damage or significantly impair other tissues, organs,
IgG
52
or bodily functions. In 1975, the Durie/Salmon staging system was devel-
IgA
21
75%
oped (see Table 4). This system brings together the major clinical param-
IgD
2
eters in correlation with measured myeloma cell mass (the total number
IgE
<0.01
of myeloma cells in the body).
2. Urine (Bence Jones or
The Durie/Salmon staging system continues to be used worldwide.
light chains only) types and
11%
However, numerous groups have proposed new systems to more accu-
rately and simply stage and/or classify myeloma patients into prognostic
3. Two or more monocloal
categories. Thus far, no new system has gained universal acceptance.
paraproteins
<1%
Heavy chains (G or A) only
<1%
2%
Just recently, however, a new staging system has been developed by the
No monoclonal paraprotein
1%
IMF-sponsored International Myeloma Working Group. Clinical and lab-
4. IgM (rarely myeloma
oratory data were gathered on 10, 750 previously untreated symptomatic
typically associated with
myeloma patients from 17 institutions, including sites in North America,
Waldenström's Macroglobulemia)
12%
Europe, and Asia. Potential prognostic factors were evaluated using a
variety of statistical techniques. Serum ß2 microglobulin (S ß2M), serum
TOTAL
100%
albumin, platelet count, serum creatinine, and age emerged as powerful
predictors of survival and were then further analyzed.
Source: Data on 1,827 MM patients collected and analyzed by Pruzanski and Ogryzlo, 1970.
13
14

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TABLE 4
TABLE 5
D S S S
I S S (ISS)
Criteria
Measured myeloma cell mass
STAGE
CRITERIA
(myeloma cells in billions/m2)*
1
Serum ß2 microglobulin <3.5 mg/dl
Serum albumin 3.5 g/dl
STAGE I ( )
600 *
All of the following:
2
Not 1 or 3*
· Hemoglobin value < 10 g/dl
· Serum calcium value normal or < 10.5 mg/dl
3
Serum ß2 microglobulin >5.5 mg/dl
· Bone X-ray, normal bone structure (scale 0)
*There are 2 possibilities for stage 2:
or solitary bone plasmacytoma only
· Serum ß2 microglobulin < 3.5 mg/dl, but serum albumin < 3.5 g/dl
· Low M-component production rates
or
IgG value < 5.0 g/dl
· Serum ß2 microglobulin 3.5 ­ 5.5 mg/dl irrespective of the serum albumin
IgA value < 3.0 g/dl
Urine light chain M-component on
electrophoresis < 4 g/24h
A combination of serum ß2 microglobulin and serum albumin provided
the simplest, most powerful and reproducible three-stage classification.
STAGE II ( )
600 1,200 B*
This new International Staging System (ISS) was fully validated and is
Fitting neither stage I nor stage III
shown in Table 5. The ISS was further validated by demonstrating effec-
tiveness in patients in North America, Europe, and Asia; patients < and >
65 years of age; with standard therapy or autotransplant; and in compari-
STAGE III ( )
> 1,200 B*
son with the Durie/Salmon system. The ISS is simple, based upon easy to
One or more of the following:
use variables (serum ß2M and serum albumin), and has been introduced
· Hemoglobin value < 8.5 g/dl
for widespread use.
· Serum calcium value normal or > 12 mg/dl
· Advanced lytic bone lesions (scale 3)
Other more sophisticated prognostic factors are still being further evalu-
· High M-component production rates
ated. For example, chromosome 13 abnormalities determined by cytoge-
IgG value >7.0 g/dl
netic and/or FISH (Fluorescent In Situ Hybridization) analysis, although
IgA value > 5.0 g/dl
known to impact prognosis, do not add to the predictive power of the ISS
Urine light chain M-component on
approach. Nonetheless, it is hoped that classification and staging at the
molecular level will emerge soon as a systematic basis for selection of new
electrophoresis > 12 g/24h
targeted treatment strategies.
SUBCLASSIFICATION ( A B)
· A: relatively normal renal function
DEFINITION OF CLINICAL RESPONSE
(serum creatinine value) < 2.0 mg/dl
· B: abnormal renal function
There are several methods to classify response to treatment (see Table
(serum creatinine value) > 2.0 mg/dl
7). Many variations of this classification are in use. Improvements in M-
component must be associated with evidence of clinical improvement
Examples: Stage IA (low cell mass with normal renal function)
(reduced bone pain, improved anemia, etc.). With the possible exception
Stage IIIB (high cell mass with abnormal renal function)
of complete response, it is important to keep in mind that a higher per-
cent regression does not necessarily confer a better survival. When there
*myeloma cells in the whole body
is residual disease, the characteristics of the remaining drug-resistant
myeloma cells determine the outcome. The fraction of resistant myeloma
cells is primarily dependent upon the pre-treatment tumor burden or
stage. Responding patients go from a high-risk to a lower-risk status until,
15
16

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ideally, no signs of MM are left, or they achieve a stable plateau phase,
1. STANDARD-DOSE CHEMOTHERAPY:
but with measurable residual disease. The time required to achieve the
plateau phase is variable, ranging from 3-6 months (rapid response), to
INTRODUCTION
12-18 months (slow response). Please refer to Figure 4 on page 3.
The first type of treatment for myeloma appeared when melphalan was
first introduced in 1962. Although the use of the simple oral combination
of melphalan plus prednisone is still a valid approach, several factors now
TREATMENT
influence the choice of this type of therapy.
· Melphalan can damage normal bone marrow stem cells and is there-
OVERVIEW
fore avoided in patients planning stem cell harvest.
Please see the History section for an overview of the evolution of current-
ly used treatments. Since melphalan was first introduced in 1962, various
· Since older age (>70 years) is not an absolute deterrent to stem cell
combination chemotherapy regimens have been utilized and attempts
harvest and transplant, the role of stem cell transplant must be
have been made to improve outcomes using high-dose chemotherapy
assessed for each patient on an individual basis.
regimens with bone marrow transplant (BMT) or peripheral stem cell
· There are oral alternatives to melphalan/prednisone such as thalido-
transplant (PSCT). In the standard type of BMT or PSCT, the "transplant"
mide and dexamethasone which do not damage stem cells. Also,
is a "rescue" with normal bone marrow stem cells when the stem cells
Cytoxan rather than melphalan is an option. Thus simple oral thera-
in the body have been destroyed by high-dose chemotherapy (usually
py can be used safely without a firm prospective decision about stem
melphalan). There is as yet no consensus as to the best way to manage
cell approaches.
myeloma. However, the following will provide some guidelines.
EXCLUDE MGUS OR ASYMPTOMATIC MYELOMA
The first and most important decision is to ascertain if therapy is required.
TABLE 6
Patients with MGUS and asymptomatic myeloma should be observed
closely rather than treated. There are currently no therapies that can
M T O
enhance the immune regulation of early myeloma or reduce the likeli-
1. Chemotherapy
hood of disease activation. However, research options such as anti-idio-
2. High dose-therapy with transplant
typic vaccines are available. Bisphosphonate therapy can be used for
3. Radiation
patients with early bone disease. Erythropoietin can be considered for
treatment of isolated anemia.
4. Maintenance therapy (e.g. alpha interferon, prednisone)
5. Supportive care:
Specific anti-myeloma treatment is recommended when symptomatic
· Erythropoietin
· Pain medication
myeloma has developed, as reflected by an increasing M-component and/
· Bisphosphonates
· Growth factors
or emerging or imminent clinical problems (Table 1). Problems sufficient
to require treatment include bone destruction (lytic lesions and/or osteo-
· Antibiotics
· Brace/corset
porosis), renal insufficiency, progressive reduction in blood counts (e.g.
· Exercise
anemia, neutropenia), elevated blood calcium, nerve damage, or other
· Emergency care (e.g. dialysis, plasmapheresis, surgery)
significant organ or tissue damage caused by myeloma or myeloma pro-
6. Management of drug-resistant or refractory disease
tein. The overall goals of treatment are to address specific problems and
to achieve general control of the disease. A summary of types of treat-
7. New and emerging treatments:
ments is provided in Table 6, and most commonly used chemotherapeutic
· Thalidomide and analogs Revlimid®/Actimid®
drugs appear in Table 8.
· VELCADE® (proteasome inhibitor)
· Doxil® (long-acting adriamycin) to substitute
for adriamycin infusion
· Trisenox® (arsenic trioxide) in clinical trials
· Mini-allo (non-myeloablative) transplant
· Heat shock protein -90 inhibitors
17
18

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CURRENT STANDARD-DOSE CHEMOTHERAPY RECOMMENDATIONS
row stem cells and can be considered in patients who want to remain
IF STEM CELL HARVEST IS NOT APLANNED OPTION
candidates for future stem cell transplantation. It has more immediate
side effects than melphalan, including such Gastro-intestinal toxicity as
This choice can relate to age, general medical condition, personal choice,
nausea.
or other factors.
More Complex Combination Schedules ­ Since the mid-1960s, many
Melphalan/Prednisone (MP) ­ The MP combination is still widely used
combinations and permutations of the most commonly used drugs have
for the treatment of elderly patients. However, even in this population,
been tried (see Tables 8 and 9). Combinations for which there is a sugges-
as discussed below "New Options", thalidomide plus dexamethasone is
tion of additional benefit versus MP or CP are identified. The M2 protocol
often used or thalidomide is added to the MP regimen to achieve greater
was developed at Memorial Sloan-Kettering Cancer Center in New York.
efficacy. With the MP regimen alone, 60% of patients have at least a
A few studies have suggested that there is a higher response rate and an
partial response, reflected by a 50% improvement in the M-protein level
overall better outcome using the M2 protocol versus MP. For example, in
plus improvement in blood count and other blood test results, along with
a recent analysis from the Eastern Cooperative Oncology Group (ECOG),
improvement in the various symptoms of the disease, such as bone pain
the overall survival of patients treated with M2 proved to be identical to
and fatigue. Cytoxan can be substituted for melphalan (CP) since it has
those receiving MP; the survival at five years, however, was superior in
similar anti-myeloma activity. Cytoxan is less toxic to normal bone mar-
the M2 protocol arm. The toxicity and the costs are significantly greater
with the M2 combination strategy. Similar information has been gathered
with the VMCP/VBAP and ABCM protocols. These have shown some
TABLE 7
indications of superiority versus MP, but they are more toxic and expen-
R C
sive. Proponents of these combination schedules, those who have used
TYPE
DEFINITION
them for many years, continue to recommend them because the outcome
C R
· M-Protein* no longer detectable in blood
is at least as good as with MP and there is a suggestion that it may even
(CR)
and/or urine
be slightly better. The current trend is to use MP or CP as a first choice
· Bone marrow shows no evidence
and reserve the more complex combinations as a back-up approach for
of myeloma
patients who fail to have a satisfactory response.
· Other tests confirm remission status
New Options ­ The most significant new option in this setting is the
N C R · M-Protein* is no longer measurable
combination of MP plus thalidomide as a first therapy. In essence, this
(CR)
but can still be found with sensitive testing
· Bone marrow shows evidence of residual
consists of adding thalidomide 100 mg by mouth daily. The group from
myeloma but < 5%
Torino, Italy has reported excellent results, including improvement in
the overall response rate to 94%, with about half of these being complete
P R
· M-Protein* reduced by > 50% but still a
responses. Some increased risk of infection, blood clotting problems
(PR)
measurable amount remains
(deep vein thrombosis), and peripheral neuropathy are concerns; but pre-
· Bone marrow plasma cells reduced by > 50%
ventative measures with antibiotics, anticoagulants, and anti-neuropathy
but still > 5% remain
strategies can help avert these problems. A trial has directly compared
M R
· M-Protein* reduced by > 25% but < 50%
MP with MP plus thalidomide, and shown added benefit for the three
(MR)
drug combination.
S D
· M-Protein* changes by > ±25%
IF STEM CELL HARVEST IS PLANNED
(SD)
VAD Chemotherapy ­ The VAD protocol, first introduced in 1984,
P D
· M-Protein* increases by > 25%
became a popular alternative to MP or CP induction. The major reason
(PD)
for this was that it can produce response without injuring the normal
* M-Protein is the level of the monoclonal protein measured by protein electrophonesis
bone marrow stem cells. However, significant disadvantages have
in serum (SPEP) or 24 hr. urine (UPEP).
emerged, including possible infection and blood clotting problems. In
** Changes in M-Protein must be supported with other evidence of treatment benefit to confirm response.
addition, high-dose dexamethasone, which is part of VAD, can be very
*** Some groups use a subcategory of "very good partial response" (VGPR) to indicate response
helpful in patients with initial aggressive disease and/or renal failure
close to complete response
who need rapid disease control to improve urgent medical problems.
A simple alternative when faced with these types of problems is to use
19
20

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dexamethasone alone. This can dramatically improve the clinical situa-
TABLE 8
tion without reducing blood count levels and without the need for inser-
M C U C D
tion of an intravenous catheter followed by a four-day infusion.



Thalidomide/dexamethasone (Thal/Dex) ­ Owing to the success of Thal/
Dex in the relapse setting, several groups have introduced thalidomide
Melphalan*
Alkeran®
Best single agent for treatment
in a frontline setting. A Mayo Clinic study combining pulse dexametha-
(M)**
(by mouth or IV)
sone with thalidomide produced a response rate of 64%. A subsequent
Cyclophosphamide* Cytoxan®
Similar efficacy to M but with more
randomized phase III trial of thalidomide plus dexamethasone versus
(C or CY )**
(by mouth or IV)
GI and GU toxicity and less bone
dexamethasone alone from ECOG produced a 68% response for Thal/
marrow stem cell injury
Dex versus 46% for dexamethasone alone. Since the 68% result is very
similar to that achievable with VAD, and because of the disadvantages
BCNU*
Bis-chloro-Nitrosurea® Similar to M and C but less effective
of VAD noted above, the thalidomide/dexamethasone combination has
(B)**
(IV only)
and more toxic especially bone
rapidly emerged as a leading frontline option. Many studies are ongo-
marrow and lung toxicity
ing. No large trial data sets are available. Several issues are unresolved,
including thalidomide dose, dexamethasone dose and schedule, and
Prednisone
Prednisolone®
Directly active, works well with
concomitant supportive care/treatment/medications, such as prophylactic
(P)**
(similar)
M, C, and B. Does not produce
(usually by mouth)
suppression of bone marrow
anticoagulation. Currently, 200 mg of thalidomide a day is recommended,
although lower doses such as 50-100 mg can be equally effective and less
Dexamethasone
Decadron®
Similar to prednisone but more
toxic. Thus thalidomide/ dexamethasone can be strongly considered as a
(D)**
(by mouth or IV)
potent. More severe side effects
frontline treatment option. Since the Mayo Clinic and ECOG studies both
incorporated stem cell harvesting and subsequent HDT, this is a reason-
Vincristine
Oncovin®
Modest activity, frequently used
able treatment setting for prior thalidomide/dexamethasone. Outside of
(V or O)**
(IV only)
as part of combination regimens
clinical trials, thalidomide is only available through the STEPS (Celgene)
(e.g. VAD)
program or a similar monitoring procedure depending on the country
and source(s) of drug (e.g. Pharmion: UK/Europe).
Doxorubicin
Adriamycin®
Modest activity, used in combinations
(A)**
(IV only)
(e.g. VAD, ABCM, VMCP-VBAP)
New Options ­ Several exciting new options have emerged. At the
American Society of Clinical Oncology meeting in June 2004, VELCADE®
Busulphan*
Myleran®
Similar activity to M and C, usually
(B or BU)**
(by mouth or IV)
part of high-dose therapy with
was evaluated as part of two phase II trials. Results with both bortezo-
transplant (e.g. BU/CY regimen)
mib (VELCADE®) alone (dexamethasone given after first 2 cycles) and
bortezomib combined with Adriamycin and dexamethasone (the "PAD"
VP - 16
Etoposide®
Modest activity, used alone
regimen [P=PS-341 or (VELCADE®]) were presented. Both of these early
or in combination
trials show remarkable benefit. Dr. Sundar Jagannath from St. Vincent's,
New York (Abstract #6551), representing the Salick Research Network,
Cisplatinum
Platinol®
Minimal activity alone, but used as
showed a 79% response rate (CR plus PR: i.e., all patients with >50%
(CP or P)**
(IV)
part of combinations (e.g. EDAP
reduction in myeloma protein level) with VELCADE® plus dexamthea-
and DT-PACE).
sone in the frontline setting. Dr. Jamie Cavanagh from St. Bartholomew's
Hospital, London (Abstract #6550), reported a remarkable 94% CR plus
* Alkylating agents
** Common abbreviations
PR rate with the three-drug PAD regimen after 4 cycles of therapy. Stem
cell harvesting and transplantation has been feasible in the usual fashion
in both of these trials, as was the case in the thalidomide/dexamethasone
studies above.
The preliminary VELCADE® results combined with the more mature
thalidomide data raises the expectation of very high response rates in the
upfront setting. Considering the possible combination or sequential ther-
apies and other strategies, the new goal becomes one of trying to achieve
response for all patients as a basis for stem cell harvesting and transplant.
21
22

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It is suddenly reasonable to think that this can be achieved soon.
2 or 3 cycles of therapy, most of the achievable response has occurred.
This abbreviates the up-front induction period versus VAD, for example.
With these high response rates, the issues and priorities become:
The major outstanding questions relate to response duration and survival
with and without stem cell consolidation. These questions are now the
· What are the side effects?
basis for several planned trials.
· Is stem cell transplant planned?
This is obviously very good news. The June 2004 ASCO meeting includ-
· How quickly is response achieved?
ed additional abstracts that further extend these notions. Firstly, two
· Is stem cell harvesting compromised?
abstracts focused on the role of Doxil® (Abstracts #6548 and 6509). In one
abstract (Abstract # 6458) presented by Mohammad Hussein from the
· Which approach gives the longest response duration (remission) and
Cleveland Clinic, the combination of Doxil® plus vincristine and dexa-
long-term survival?
methasone was shown to be equally effective versus traditional VAD and
We are just starting to form ideas about these and other questions.
much less expensive: about half the cost. In a related abstract (Abstract
Interestingly, DVT, which is a concern (16% likelihood) with thalidomide/
#6709), Dr. Antonio Vendette and colleagues evaluated the cost of 4 days
dexamethasone, has not occurred with the frontline VELCADE® trials
of pulse Adriamycin versus the traditional 4-day VAD infusion approach.
(0%). In the thalidomide/mephalan/prednisone study, the DVT percent-
The 4-day bolus approach was < 30% of the cost, with apparent equivalent
age was 19%. Neuropathy of different types is an issue with all these
efficacy. This may prove to have relevance related to the "PAD" protocol
new protocols. Of note, the neuropathy that occurred in the upfront
discussed above.
VELCADE® trials appears to be partially or completely reversible. Further
studies and follow-up are required. Stem cell transplant is feasible, except
In the second Doxil® abstract (Abstract #6509), Dr. Robert Rifkin, on
after thalidomide/melphalan/prednisone. Response is achievable rather
behalf of U.S. Oncology, again showed that the Doxil® combination was
quickly with both the thalidomide and VELCADE® combinations. Within
equivalent in efficacy to VAD, but had several clinical advantages, includ-
ing less neutropenia, alopecia, and hospital/clinic visits. In view of recent
observations that Doxil® is highly synergistic with VELCADE®, there is
TABLE 9
considerable interest in Doxil® as part of frontline strategies, in a fashion
comparable to PAD discussed above.
F U C
MP
Standard combination for initial therapy
Numerous presentations at ASH 2004, the International Myeloma Workshop
in Sydney, Australia in 2005 (see the IMF Sydney Guide, available thorough
CP
Alternative to MP
the IMF), ASCO 2005, as well as EHA 2005 in Stockholm, Sweden extended
the observations concerning the introduction of novel therapies in both the
VBMCP (M2)
Combination often used in eastern USA.
frontline and relapse settings. It is now important for patients to discuss the
Proponents suggest better response and
survival versus MP
latest information about the novel agents VELCADE®, REVLIMID®, and
thalidomide as they might apply to their own treatment situation. Several
VMCP/VBAP
Combination developed by SWOG and often used
trials in the frontline setting are ongoing.
in western USA. More toxic with minimal increased
benefit as is true for M2
Monitoring of Response ­ The most important aspect is to know if the
symptoms at presentation have improved. One must assess blood count
ABCM
Combination used in Europe, especially UK.
levels, chemistry results, and particularly levels of myeloma protein in the
Little extra benefit versus MP
serum and urine. Important markers of myeloma activity are the serum
2 microglobulin, the C-reactive protein, and the labeling index in the
VAD
Most commonly used alternative to MP, especially if:
peripheral blood and/or bone marrow. It is important to have a periodic
· Myeloma is aggressive
24-hour urine test to exclude the possibility of Bence Jones escape. This
· There is renal insufficiency
is a situation in which the urine protein may increase, even though the
· High dose therapy with transplant is planned
serum protein level has improved. Follow-up X-rays of the bones are
D or MD
D alone or combined with M or C can be used as
important to exclude possible new bone involvement. Additional scan-
or CD
alternative to VAD. Avoids need for four-day infusion.
ning, including MRI and CT, may be necessary to more closely evaluate
the status of the bones. DEXA scan can be used to quantify base-line and
follow-up bone density.
23
24

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Whole body FDG-PET scanning is also available as a new nuclear medi-
b. Stem cell purging is not recommended because of added expense
cine technology for whole body staging and disease assessment. This can
without additional clinical benefit.
be especially helpful in patients with myeloma which produces low levels
c. Peripheral blood stem cells are recommended over bone marrow
of M-protein or no protein (non-secretors). FDG is Flouro-Deoxy-Glucose,
both because of ease of collection and more rapid engraftment.
i.e., sugar which is labeled for nuclear medicine use. Scanning detects
d. The pre-transplant regimens including VAD, dexamethasone, tha-
areas in which active myeloma incorporates this sugar.
lidomide/dexamethasone, and Cytoxan are discussed above.
2. TRANSPLANTATION
Role of auto transplantation at time of first relapse
Part of the decision process for auto transplant involves knowledge of
H D T (HDT) A S C
the impact of waiting, with a view to transplant at relapse. Data from
T
· The role of autologous transplantation has been extensively
reviewed.
TABLE 10
· HDT with autologous stem cell transplantation has been shown to
T R T M T R
improve both response rates and survival in patients with myeloma.
However, this approach is not curative: unfortunately > 90% of
B T
· Routine blood counts
· Chemistry panel
patients relapse.
· Liver function tests
· Complete remission rates with HDT as a planned part of frontline
· Myeloma protein measurements
therapy range from 24-75%.
(serum protein electrophoresis plus
quantitative immunoglobulins)
· Partial remission rates (i.e. > PR) with HDT as frontline range from
· Serum ß2 microglobulin
75-90%.
· C-reactive protein
· Time to progression (first progression or relapse) is 18-24 months.
· Peripheral blood labeling index
· Serum erythropoietin level
· Median overall survival with HDT is in the 4- 5-year range. This is
reflected as being statistically superior in the randomized Attal study
U
· Routine urinalysis
(1996) and in the MRC study (2003), for example, as well as in the
· 24-hour urine for measurement of
historical case-controlled Nordic Myeloma Study (2000).
total protein, electrophoresis, and
immunoelectrophoresis
· Morbidity and Mortality -- With current growth factor, antibiotic,
· 24-hour urine for creatinine clearance
and other supportive care, the procedure-related mortality with HDT
if serum creatinine elevated
is very low: < 5%. The majority of centers use intravenous high-dose
melphalan alone at a dose of 200mg/m2 as the preparative regimen.
B E
· Skeletal survey by X-ray
Since the use of total body irradiation (TBI) adds toxicity without
· MRI/CT scan for special problems
clear survival benefit, few centers recommend TBI as part of the pre-
· Whole body FDG/PET scan if disease
para-tive regimen.
status unclear
· Bone density measurement (DEXA scan) as
· Both quality of life and cost-benefit analyses have been conducted
baseline and to assess benefit
for HDT compared to standard-dose chemotherapy. The Nordic
of bisphosphonates
Myeloma Study showed both improved quality and length (median
survival of 62 months versus 44) of survival at an estimated added
B M
· Aspiration and biopsy for diagnosis and
cost of $27,000/year.
periodic monitoring
· Special testing to assess prognosis (e.g.
Current Recommendations
look for chromosome 13 abnormalities,
HDT with autologous stem cell support should be strongly considered
immunotyping, LI%)
as part of the frontline therapy for newly diagnosed patients with symp-
tomatic myeloma.
O T
· Amyloidosis
( )
· Neuropathy
a. The standard conditioning regimen is melphalan 200mg/ m2.
· Renal or infectious complications
Total body irradiation is not recommended.
25
26

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two French randomized trials indicate no reduction in overall survival
from waiting to do the transplant at relapse. Quality of life becomes an
TABLE 11
important consideration. On the one hand, if transplant is not performed
H- T
as a planned primary strategy, then typically additional therapy, includ-
TYPE
ADVANTAGES
DISADVANTAGES
ing maintenance, is required, with corresponding toxicity and side effects.
Single Autologous · 50% excellent remissions
· Relapse pattern similar to standard
On the other hand, the major impact of the transplant is deferred, which
Transplant
· At least as good as standard
chemotherapy
for some patients is a better personal choice.
therapy regarding overall survival · More toxic and expensive
and probably better for patients
· Patients who decisively benefit from
Harvesting and storing stem cells for later use
with high Sß2M.
transplant not clearly identified
There is a strong reluctance in many centers to harvest stem cells without
· Basis for strategies to produce
· Maintenance therapy still required
true remission or long-term cure
(e.g. interferon, prednisone, vaccine)
a clear plan for use, typically immediate use. This reluctance arises from
· New preparative regimens may
protocol priorities, cost/utilization constraints for harvesting and storage,
produce true complete remission
as well as numerous other factors. Nonetheless, many patients request
and want their stem cells harvested, even though they may not be enthu-
Double Autologous · Advantages are the same as for
· As yet no clear benefit versus single
siastic about immediate high-dose therapy.
Transplant
single
transplant
· 2002 update of French data
· Much more toxic and expensive
Current Recommendations
indicates survival benefit for
versus single
a. Harvesting with storage for future use is recommended with review
subset of patients
on a case-by-case basis.
b. There is medical and scientific rationale for saving stem cells for
Traditional
· No risk of contamination of
· Even for HLA identical siblings,
later use.
Allogeneic
marrow/stem cells with myeloma
significant risk of early complications
Transplant
· Possible graft versus myeloma
and even death (25-30%)
c. Delayed transplant is a viable treatment option. A second transplant
effect to prolong remission
· Risk of complications unpredictable
in a patient is a viable option, especially if a first remission of > 2
· Restricted to age < 55
years has occurred. (See discussion below of "double" transplanta-
· More toxic and expensive versus
tion.)
autologous
T R D T T
· At present the added benefit of double or tandem transplantation
Mini-Allo
· Less toxic form of allo
· No anti-myeloma chemo-therapy
Transplant
· Preparative chemotherapy
given
versus a single autologous transplant is not known.
usually well tolerated
· Still produces graft-vs-host disease
· The results with planned primary tandem transplant (total therapy
· Results in anti-myeloma immune · Full benefits still unclear
I and II at the University of Arkansas) have been good. The median
graft
· Risk of initial mortality
approximately 17%
overall survival has been 68 months with some groups having even
longer survival.
Identical Twin
· No risk of myeloma
· No graft-vs-myeloma effect
· However, recent comparative studies, including the French random-
Transplant
contamination in transplanted
· Need identical twin < 55
ized studies, have shown benefit predominantly for a subgroup of
cells
patients (those who have not achieved CR). It is possible that longer
· Much less risky than allogeneic
follow-up will show added benefit.
transplant
Current Recommendations
a. At the present time, planned tandem transplant continues to be a
clinical trial option and should be carried out at centers specialized
in this approach.
b. A second transplant in a patient who has responded well with a first
transplant and relapsed after > 2 years is a helpful and viable option
(Sirohi [2001]).
c. Saving and storing enough stem cells for a second or additional
transplant, if appropriate, is strongly recommended.
27
28

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T R A T
chemotherapy to achieve overall disease control, limiting the use of local
· Details of results with allogeneic transplantation have been exten-
radiation therapy to areas with particular problems.
sively reviewed.
Total Body Irradiation (TBI) ­ Total body or sequential radiation of half of
· Despite medical improvements over the past 2 decades, allogeneic
the body can be used as part of an overall strategy for high-dose therapy
transplant, even with a perfectly matched family member donor,
with transplant and/or in the management of relapsing refractory disease.
is a high-risk procedure in the management of multiple myeloma.
Although used in the past as a preparatory regimen for transplant, recent
The initial treatment-related morbidity and mortality is high. Even
studies have shown no added benefit and, unfortunately, increased toxic-
at centers with the greatest experience, and in the best risk settings,
ity. Therefore, TBI is no longer recommended as part of preparatory regi-
initial mortality is at least 15-20%. In other centers, 20-30% or higher
mens. In patients with refractory disease, sequential hemi-body radiation
mortality is frequently reported. The pulmonary complications are
can be used to temporarily control the disease. This is rarely successful for
usually the most critical for myeloma patients.
very long, particularly in patients with aggressive, active myeloma. There
· The potential advantages of allogeneic transplantation are myeloma-
is also the disadvantage that wide field radiation destroys the normal
free stem cells and graft versus myeloma effect. But, despite these
bone marrow and makes it difficult if not impossible to use other treat-
factors, long-term cure is rare. Relapse continues at a rate of approxi-
ment options following this approach
mately 7% per year with long-term follow-up. Graft versus host dis-
ease can also be an ongoing problem, requiring therapy and reduc-
4. MAINTENANCE THERAPY
ing quality of life.
Alpha Interferon ­ For the past 15 years, many investigators have evalu-
· The graft versus myeloma effect can be enhanced by using donor
ated the efficacy of interferon, an agent shown to prolong remission
lymphocyte infusions and has been clinically beneficial in some
achievable with standard or high-dose therapy. Conflicting results have
series.
been obtained, but a small benefit in the prolongation of remission has
been observed. The benefit is only 10-15% in terms of prolongation of
· There is recent interest in non-myeloablative or "mini" allogeneic
remission and survival. Differences of 10-15% (e.g. 6-9 months) are hard
transplants in myeloma. The intent is primarily to achieve a graft
to prove in clinical studies. Ongoing studies include evaluation of inter-
versus myeloma effect with lesser toxicity than with a matched full
feron with initial chemotherapy, and the combination of alpha interferon
allogeneic transplant. However, although anti-myeloma effects have
with a variety of agents such as dexamethasone or IL-2 for maintenance.
been promising, with an 84% response rate in the first 32-patient
The use of alpha interferon has to be individualized, balancing potential
series, the risks remain high, with substantial acute (45%) and chron-
benefits with potential side effects, expense, and inconvenience. Most
ic (55%) graft versus host disease reported.
investigators think that alpha interferon has a definite (although small)
Current Recommendations
role in the management of myeloma.
a. Conventional full-match allogeneic transplantation is rarely recom-
mended as a primary strategy because the risks are too high.
Prednisone ­ It has been difficult to find therapy that can prolong remis-
b. "Mini" allogeneic transplantation is a promising new approach,
sions and survival in myeloma without compromising quality of life, as
which requires further evaluation as part of well-planned clinical tri-
is the case with alpha interferon. However, new studies have supported
als.
earlier observations from the 1980s that prednisone is an effective main-
tenance agent, and probably superior to alpha interferon. Prednisone
c. Identical twin, or syngeneic, transplantation is a rare option, which
administered three times per week (e.g. starting dose of 50mg) has accept-
is a safe procedure with good outcome and is recommended when
able toxicity and can prolong both remission and survival. A particular
an identical twin is available.
advantage is that patients can take prednisone for several years without
3. RADIATION:
developing resistance. However, caution is required because of longer-
term side effects, and dose reductions are usually necessary.
Radiation therapy is an important modality of treatment for myeloma.
Thalidomide ­ Data are just being gathered to fully assess the role of tha-
For patients with severe local problems such as bone destruction, severe
lidomide in the maintenance setting. Initial results are promising. It seems
pain, and/or pressure on nerves or the spinal cord, local radiation can be
that thalidomide alone or combined with steroids in some fashion will be
dramatically effective. The major disadvantage is that radiation therapy
helpful. Peripheral neuropathy is the major concern with long-term use
permanently damages normal bone marrow stem cells in the area of
of thalidomide.
treatment. Wide field radiation encompassing large amounts of normal
bone marrow should be avoided. A general strategy is to rely on systemic
29
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5. SUPPORTIVE CARE:
of renal impairment. As far as osteonecrosis is concerned, the first step
is regular dental check-ups. If a problem is found, referral to an expert
Erythropoietin ­ Erythropoietin (e.g. Procrit®) is a naturally occur-
(e.g. oral surgeon) is strongly recommended. Any major jaw surgery
ring hormone now available through genetic engineering techniques.
must be avoided until consultation has been sought. Regular, routine
Erythropoietin is administered to improve the hemoglobin level in
dental checkups are recommended. Dental extractions should be avoided
patients who have persistent anemia. Erythropoietin injections (e.g. 40,000
until full consultation has been obtained. Infection may require antibiotic
units SQ weekly) can show dramatic benefit in the level of hemoglobin
therapy.
and in performance status. It should be strongly considered in patients
who have persistent anemia. Erythropoietin should only be continued
Antibiotics ­ Infections are a common and recurrent problem in patients
in patients showing clear benefit. Iron supplements may be required to
with myeloma. A careful strategy for infection management is required.
achieve maximum benefit. The newer long-acting erythroprotein product
Antibiotic therapy should be instituted immediately if active infection is
Aranesp® (darbapoietin) is also available for use
suspected. Use of preventative or prophylactic antibiotics with recurrent
infection is controversial. The continuation of prophylactic antibiotics
FIGURE 5: HOW PAMIDRONATE WORKS
can increase the chance of antibiotic resistance, but it can also reduce
the chance of recurrent infective complications. A recent comparative
study showed benefit with prophylactic antibiotics used within the first 2
months of induction chemotherapy. The use of high-dose gammaglobulin
may be required in patients with acute and severe recurrent infections.
GM-CSF may be helpful to improve the white blood cell levels in an effort
to overcome infectious complications. The use of G- or GM-CSF is helpful
in the recovery phase following bone marrow or stem cell transplantation.
G-and GM-CSF are also used in harvesting stem cells.
6. MANAGEMENT OF RELAPSING OR REFRACTORY DISEASE:
Bisphosphonates ­ Bisphosphonates are a class of chemicals that bind
to the surface of damaged bones in patients with myeloma. This bind-
As illustrated in the pathophysiology section, a frequent problem in
ing inhibits the ongoing bone destruction and can improve the chances
myeloma is the relapse that occurs following a 1-to 3-year remission.
of bone healing and recovery of bone density and strength. A random-
Although alpha interferon, prednisone, or thalidomide maintenance may
ized study utilizing the bisphosphonate pamidronate (Aredia®) showed
be useful in prolonging the initial remission period, the relapse, which
particular benefit in patients responding to ongoing chemotherapy. It
supervenes inevitably, requires re-induction therapy. The following is an
is currently recommended that bisphosphonate therapy be used as an
overall strategy for the management of relapsing disease.
adjunctive measure in myeloma patients who have bone problems (see
If first relapse occurs after a remission of at least 6 months to 1 year, the
Figure 5). Other bisphosphonates are now available including clodronate,
first strategy is to consider re-utilizing the therapy that produced the
an oral formulation in use in Europe for the treatment of myeloma, and
remission in the first place. Approximately 50% of patients will achieve
zoledronic acid (Zometa®), approved in the U.S. and Europe as treatment
a second remission with the same therapy that produced the first. This is
of both hypercalcemia and bone disease. Several new bisphosphonates
particularly true for patients in remission for over one year following the
are in clinical trials. One, called ibandronate, is now available in Europe.
initial induction attempt. As an example, a patient who has received MP
Two new concerns have emerged related to chronic bisphosphonate use.
and has gone into remission for two years can again receive MP induction.
The first is kidney damage and the second is a condition called osteone-
FIGURE 6: MDR MYELOMA CELL
crosis of the jaw. These two issues have been addressed in detail in other
IMF educational materials (Myeloma Minute and Myeloma Today). Both
conditions are fortunately relatively uncommon, but awareness of these
potential problems is the key to prevention. Kidney function must be seri-
ally monitored (especially serum creatinine before each treatment dose),
particularly with Zometa use. If the serum creatinine increases by 0.5-1.0
mg/dl, dose and/or schedule adjustments for Aredia or Zometa may be
required. For Zometa, one of the simplest adjustments is to extend the
infusion time from 15 minutes to 30-45 minutes, which reduces the risk
31
32

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If remission has lasted less than six months, some alternative therapy will
responders. At the ASCO meeting in June, 2004, Dr. Paul Richardson pre-
usually be required. This is also the case if relapse has occurred following
sented the results of this randomized phase II trial for relapsed myeloma,
a second or third use of the original induction therapy. The use of VAD is
which compared bortezomib (VELCADE®) with dexamethasone. This
an important consideration in this setting.
study recruited internationally and was the largest study ever completed
in multiple myeloma. At the mandated early interim analysis, bortezo-
VELCADE® (bortezomib) for relapsing myeloma ­ The availability of
mib (VELCADE®) was significantly more effective than dexamethasone.
VELCADE® for relapse treatment is an important step forward. The FDA
There was a 58% improvement in the median time to progression for
approved VELCADE® for use in this setting in early 2003. Final results
the 327 patients receiving bortezomib versus the 330 patients receiving
of the 202-patient, multicenter, phase II "SUMMIT" trial of VELCADE®
high-dose dexamethasone (p<.0001 for difference). Overall, there was
in heavily pretreated (median 6 prior lines of therapy) patients with
an approximately 30% improvement in survival during the fist year
relapsed and refractory myeloma were presented at ASH in 2002. The
with bortezomib (VELCADE®). This is obviously very helpful informa-
response rates, according to the criteria defined by Bladé and confirmed
tion in establishing the role for VELCADE® and in future integration of
by an independent review committee, are summarized below:
VELCADE® into "standard of care" therapies.
RESPONSE TO VELCADE® ALONE IN THE SUMMIT TRIAL
Other Options - It is important to keep in mind that a variety of single and
combination chemotherapy protocols are available for the management
Response (Bladé criteria)
Percentage of patients
of relapsing and refractory disease. Depending upon the exact problem,
Complete response (IF neg)
4
a variety of interventions may be possible. For example, if relapse is
Complete response (IF pos)a
6
associated with the development of one or two bone lesions, radiation to
Partial Response
17
the site(s) of bone involvement may be a satisfactory way to manage the
Minimal response
8
relapse. If overall relapse has occurred, dexamethasone as a single agent
Stable disease
24
can be very useful in achieving overall control of the disease. The use of
Overall response
35%
dexamethasone is attractive because it can be given by mouth and does
aM-protein not measureable, but still detectable by immunofixation.
not cause significant side effects such as hair loss or reduction in periph-
eral blood count values.
The overall response rate (CR + PR + MR) was 35%. Of note, the median
response duration at that time was 12 months and median overall surviv-
Another important point is that relapse following high-dose therapy with
al was 16 months. Subsequent follow-up has revealed a median response
transplant has, in many cases, a pattern similar to relapse following more
duration in responding patients of 12.7 months. This compares very favor
standard approaches. Second and sometimes third remissions can be
ably to the much poorer outcome in refractory patients reported in the
achieved following relapse after bone marrow transplantation. Whether
literature. Results in earlier-stage disease in the "CREST" study were also
a second high-dose therapy with transplant is the most appropriate
presented at ASH. These patients had received a median of three prior
strategy as opposed to some other lower-dose chemotherapy approach
regimens, including stem cell transplant in 48%. In the CREST study,
is currently unclear. The group at the Royal Marsden Hospital in London
overall responses (CR, PR, MR) were 33% and 50% at doses of 1.0 and 1.3
has had excellent results using second and third rounds of high-dose
mg/m2. These studies were also evaluated using the response criteria of
melphalan for patients treated in the early to mid 1980s. It is important to
Bladé et al. In the Summit phase II study, responses were independent of
note that in this same patient population, the Royal Marsden group has
the number or type of prior therapies and were associated with improved
shown that maintenance alpha interferon following high-dose therapy
quality of life.
prolongs the quality and duration of the remission.
Based upon these promising results, VELCADE® was approved by the
A full range of supportive care aspects are crucial for the management
FDA for the treatment of patients with multiple myeloma who have
of MM. When first diagnosed, a number of emergency procedures may
received at least two prior therapies and have demonstrated disease pro-
be required, including dialysis, plasmapheresis, surgery, and radiation to
gression on the last therapy.
reduce pressure on a nerve, spinal cord, or other crucial organ. The man-
agement of pain is essential for the initial care of patients with MM. This
VELCADE® was then evaluated in a multicenter phase III "APEX" ran-
can be difficult until initial disease control is achieved. There is no reason
domized trial comparing VELCADE® to high-dose dexamethasone in 669
for patients with MM to have major ongoing pain with the range of new
myeloma patients at 80 sites who had relapsed following one to three
drugs and strategies available. There can be reluctance on the part of the
prior lines of therapy. The primary end point was time to progression.
patient and/or the physician to implement full pain control procedures
APEX also assessed the role of VELCADE® as maintenance therapy in
because of concerns about addiction. Control of pain should always be
33
34

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the first priority. A brace or corset can help stabilize the spine or other
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·JemalA,ThomasA,MurrayT,ThunM.Cancerstatistics2002. CACancerJClin2002;52:23-47.
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· Schottenfeld D, Fraumeni JF Jr. (eds). Cancer Epidemiology and Prevention, 2nd edn. New York:
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· Herrington LJ, Weiss NS, Olshan AF. The epidemiology of myeloma. In: Myeloma Biology and
C T P
Management (Malpas JS, Bergsagel DE, Kyle RA eds.). Oxford, England, Oxford University Press:
I
Early testing to assess tolerance and toxicity in patients.
1995:127-168.
II
Further testing to evaluate how effective treatment is at the dose
B D:
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· Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S et al. Col apsing focal seg-
mental glomerulosclerosis fol owing treatment with high-dose pamidronate. J AM Soc Nephrol 2001;
III
Comparison of the new treatment with prior treatment(s) to
12:1164-1172.
determine if the new treatment is superiort
· Rosen LS, Gordon D, Antonio BS, et al. Zoledronic acid versus pamidronate in the treatment of
V
Usually carried out after FDA approval to assess cost-effective-
skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase
ness, quality of life impact, and other comparative issues
II,doubleblind,comparativetrial. CancerJ2001;7:377-387.
· Major P, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia
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Oncology2001;19,558-67.
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· Berenson J, et al. Long-term pamidronate treatment of advanced multiple myeloma reduces skel-
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· McCloskey EV, et al.Arandomised trial of the effect of clodronate on skeletal morbidity in multiple
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· Mundy, GR, Yoneda T. Bisphosphonates as anticancer drugs. New England Journal of Medicine 1998;
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· Berenson J, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced
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contact the IMF via telephone or Internet (www.myeloma.org) and to check
· Batail e R, et al. Mechanism of bone destruction in multiple myeloma. The importance of an unbal-
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1909.
with regular updates and lists all drugs currently in clinical trials. The Mayo
· Durie BGM, Salmon SE, Mundy GR. Relation to osteoclast activating factor production to extent of
Clinic Proceedings (2005) article listed in the references is a very good sum-
bonediseaseinmultiplemyeloma.BrJHaematol1981;47:21-26.
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