INTERNATIONAL MYELOMA FOUNDATION
CONCISE REVIEW
OF THE DISEASE AND TREATMENT OPTIONS
MU LT I P L E MY E LOMA
Cancer of the B one Mar row
2001 EDITION
INCLUDES UPDATES FROM
VIIITH INTERNATIONAL MYELOMA WORKSHOP
PREPARED BY BRIAN G.M. DURIE, M.D.

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TABLE OF CONTENTS
INTRODUCTION
1
WHAT IS MYELOMA
1
PRODUCTION OF MONOCLONAL PROTEIN
2
ANNOTATED HISTORY
4
EPIDEMIOLOGY
7
PATHOPHYSIOLOGY
8
BONE DISEASE
9
ANEMIA
9
KIDNEY DYSFUNCTION
9
OTHER ORGAN DYSFUNCTION
11
TYPES OF MYELOMA
12
CLINICAL SYMPTOMS
12
STAGING AND PROGNOSTIC FACTORS
13
DEFINITION OF CLINICAL RESPONSE
16
TREATMENT
17
Chemotherapy
17
High Dose Therapy with Transplant
17
Radiation
23
Maintenance Therapy
23
Supportive Car e
25
Management of Drug Resistant or Refractory Disease
26
New and Emerging T reatments
27
REFERENCES
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INTRODUCTION
The I M F Concise Review of the Disease and Treatment Options i s
an overview of the history of myeloma, a discussion of pathophysiology, clinical
f e a t u res and treatment options. It is written primarily for health pro f e s s i o n a l s
who treat myeloma, but perhaps not on a routine basis. The focus is practical,
founded upon the most recent re s e a rch developments in the field. It is hoped
that the information will be helpful to physicians and patients alike.
WHAT IS MYELOMA?
Multiple myeloma (synonymous with myeloma and plasma cell myelo-
ma) is a malignancy of bone marrow plasma cells. It is therefore a hemotologi-
cal malignancy which most closely resembles leukemia. The malignant plasma
cells (see Figure 1), otherwise known as myeloma cells, accumulate in the bone
marrow and only rarely enter the blood stream as in a true leukemia. The major
features of myeloma result from this progressive accumulation of myeloma cells
within the marrow causing:
·
Disruption of normal bone marrow function most commonly reflected
by anemia.
·
Damage to surrounding bone.
·
Release of monoclonal protein (M-Protein) from the myeloma into
the blood stream.
·
Suppression of normal immune function, reflected by reduced levels
of normal immunoglobulins and increased susceptibility to infection.
Myeloma cells can also grow in the form of localized tumors or plasmacy-
tomas. Such plasmacytomas can be single or multiple and confined within bone mar-
row and bone (medullary) or develop outside of bone in soft tissue. Plasmacytoma
outside bone are called extramedullary plasmacytomas. When there are multiple
plasmacytomas inside or outside bone, this condition is also called multiple myeloma.
FIGURE 1: PLASMA (MYELOMA ) CELLS
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PRODUCTION OF MONOCLONAL PROTEIN
BY MYELOMA CELLS
The characteristic pro p e rty of myeloma cells is the production and re l e a s e
(or secreton) of monoclonal protein into the blood and/or urine. Monoclonal pro-
tein is also called M-protein, myeloma protein, para-protein or spike protein. The
monoclonal protein is called a spike because of the way it appears on protein elec-
t rophoneis, a laboratory technique to separate and identify protein (see Figure 2) .
FIGURE 2: MONOCLONAL " SPIKE "
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 immunoglobulin is lost and the
three-dimensional structure of the molecule is abnormal. This abnormal struc-
ture and function has a number of consequences:
·
Since the monoclonal immunoglobulin does not perf o rm its antibod y
function, more is produced because of this dysregulated synthesis
·
The abnormal monoclonal molecules can adhere to each other
and/or other tissues such as blood cells, blood vessel walls and other
blood components. This reduces blood flow and circulation causing
hyperviscosity syndrome discussed below.
·
Approximately 30% of the time, more light chains are produced than
a re needed to combine with the heavy chains to create a whole
immunoglobulin molecule. These excess light chains are Bence Jones
proteins (see History section). Free Bence Jones proteins have a
molecule weight of 22,000 daltons and are small enough to pass fre e l y
into the urine resulting in an increased 24-hour urine protein level in
the form of a Bence Jones monoclonal spike.
·
Free Bence Jones proteins can also adhere to each other and/or other
tissue (just as the whole immunoglobulin can). In this case the end
result is either:
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FIGURE 3: IMMUNOGLOBULIN MOLECULE STRUCTURE
1. Amylodosis ­ A disease entity in which the Bence Jones light
chains cross link in a highly symmetric ß-pleated fashion and becomes
deposited in tissue around the body including for example 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.
·
The abnormal monoclonal proteins can also have a wide range of
other properties including:
°
Binding to normal blood clotting factors resulting in incre a s e d
b l e e d i n g tendency or enhanced blood clotting or phlebitis.
°
Binding to circulating hormones or chemicals resulting in a
variety of endocrine or metabolic disfunctions.
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 chem-
ical reactions necessary for routine testing.
FIGURE 4: DISEASE PHASES
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ANNOTATED HISTORY
Since Dr. Henry Bence Jones was the first to discover the strange protein
(now named after him) in the urine of a patient with what proved to be myeloma, a
review of the history starting with his findings is appropriate. What was called to the
attention of Dr. Bence Jones was a urine sediment, which dissolved on boiling, but re-
precipitated on cooling. The following is a brief annotated summary of progress in
research and treatment for multiple myeloma and related diseases.
1844-1850
First case descriptions of myeloma called "mollities and fragilitas
ossium" (soft and fragile bones). The first patient, Thomas
Alexander McBean, was diagnosed in 1845 by Dr. Wi l l i a m
Macintyre, a Harley Street consultant in London. The unusual
urine problem he discovered was fully investigated by Dr. Henry
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.
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 case of myeloma (Sarah Newbury) in 1844.
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.
1909
Weber suggested that plasma cells in the bone marrow actually
produce the myeloma bone destruction.
1930s
The routine diagnosis of myeloma remained difficult until the
1930s when bone marrow aspirates were first used on a larger scale.
The development of the ultracentrifuge and serum/urine protein
electrophoresis improved both screening and diagnosis.
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1953
Immunoelectrophoresis was introduced to allow exact identifica-
tion of the monoclonal myeloma proteins. (Immunofixation has
since been introduced as a more sensitive method.)
1956
Korngold and Lipari noted that Bence Jones (BJ) proteins are
related to normal serum gammaglobulin as well as abnormal serum
proteins. In their honor, Bence Jones proteins are called Kappa
(), and Lambda ().
1958
D i s c o v e ry of sarcolysin in the USSR. From this melphalan
(Alkeran) was derived. For the first time, treatment was possible.
1961
Waldenstrom emphasized the importance of the differentiation
between monoclonal and polyclonal gammopathies. He associated
IgM monoclonal proteins with macroglobulinemia, as distinct
from myeloma.
1962
First report of successful treatment of myeloma with melphalan
(Alkeran) by Bergsagel.
1964
First report of successful treatment of myeloma with cyclophos-
phamide (Cytoxan) by Korst. Results with cyclophosphamide
proved to be similar to results with melphalan.
1969
Melphalan combined with prednisone, by Alexanian, was shown
to give better results than melphalan alone.
1975
Durie/Salmon staging system for myeloma introduced. Patients
classified to assess benefits of chemotherapy at different disease
stages (I, II, III, A or B).
1976-1992
Various combinations of chemotherapy agents tried, including the M2
regimen (VBMCP), VMCP-VBAP, and ABCM, with some indica-
tion of superiority versus MP. However, in 1992, a comparative meta-
analysis (Gre g o ry) showed equivalent results for all combinations.
1979-1980
Labeling index (growth fraction analysis) first introduced as a test
in myeloma and related diseases. Stable remission or plateau phase
of myeloma identified. This is a period when the growth fraction
(L1%) of residual bone marrow plasma cells is zero %.
1982
Twin transplants performed by Fefer and Osserman as treatment
for myeloma.
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1983
First use of serum B2 microglobulin as a prognostic test (Bataille
and Durie).
1984
Barlogie and Alexanian introduce VAD chemotherapy.
1984-1986 First reports of allogeneic transplants in multiple myeloma by var-
ious investigators.
1986-1996 Large numbers of studies evaluating high dose therapy with autol-
ogous bone marrow or stem cell rescue by various investigators.
Both single (McElwain) and double (Barlogie) transplant proce-
dures introduced.
1996
First, and thus far only, randomized study indicating possible ben-
efit of high dose therapy with bone marrow transplant support ver-
sus standard chemotherapy (Attal). As yet, no meta-analysis or
other larger comparative studies performed.
·
Randomized study of Aredia versus placebo indicates reduc-
tion in bone problems ("skeletal related events").
1997
Evidence that viruses may be involved in triggering myeloma.
Myeloma more common in patients with HIV and Hepatitis C.
Herpes virus (HHV-8) found in bone marrow dendritic cells.
RNA found in blood with specificity for SV40 cancer causing
monkey virus.
1998
Continued research on the role of high dose chemotherapy with
autologous and allogeneic transplant. The magnitude of benefit
and patient population(s) likely to benefit remain uncertain.
Transplant performed as part of initial (induction) therapy is
shown to produce similar results as transplant done at first relapse.
·
Chromosome 13 deletions shown to be poor prognostic factor
for transplantation as well as other therapies.
·
New study reconfirms prednisone as a helpful maintenance
with prolongation of remission. Alpha interferon also shown again
to have some benefit in prolonging remission.
1999
Thalidomide shown to be an effective anti-myeloma therapy in
patients with relapsing/refractory disease.
·
"Mini allogeneic" transplant introduced as less toxic method
to achieve a "graft-vs-myeloma" effect.
·
Randomized French study shows no added benefit of double
autologous transplant versus single transplant.
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· Longer term follow up shows that Aredia treatment out to 2
years is helpful.
· Holmium introduced as a form of "targeted skeletal radiation"
in an eff o rt to improve complete remissions with autologous transplant.
2000
For the first time, there are several promising new approaches for
myeloma therapy. New therapies for myeloma entering clinical trials
include thalidomide analogues (e.g. IMiD 501), long acting adri-
amycin analogues (e.g. Doxil), arsenic trioxide (ATO), anti-angio-
genesis agents (e.g. VEGF tyrosine kinase inhibitor), agents to block
cell adhesion, betathine and proteasome inhibitors (e.g. PS 341).
2001
·
New classification system proposed for myeloma and related
diseases (see Table 1).
·
New prognostic factor or staging systems pro p o s e d :
°
SWOG (Southwest Oncology Group) uses separation
into 3 groups based upon serum ß2 m i c ro globulin and
serum albumin,
°
IFM (French Study Group) uses separation into 3 gro u p s
based upon serum ß2 m i c ro globulin and pre s e n c e / a b s e n c e
a b n o rmalities of chromosome 13 by FISH analysis.
·
Evidence of efficacy of new agents in clinical trials including
PS 341 (Phase II, Millenium) and ImiD 501 (Phase I, Celgene).
·
Thalidomide combined with dexamethasone as frontline
therapy for myeloma with response rate of approximately 70%.
2003
Result of large US interg roup transplant study comparing conven-
tional chemotherapy with transplant is expected.
EPIDEMIOLOGY
The incidence of myeloma is 3-4/100,000 in the US, representing
approximately 1% of all types of cancer. There are approximately 13,500 new
cases of myeloma in the US each year. Myeloma is more common in African
Americans than Caucasians (e.g. in Los Angeles County, African American
men 9.8/100,000 versus Caucasian men 4.3/100,000). The incidence varies from
country to country from a low of <1/100,000 in China to approximately
4/100,000 in most Western industrialized countries. The male/female ratio is
3:2. The incidence rises with age. Better diagnostic techniques and the higher
average age of the general population may in part explain the rising incidence
over the last several decades. A trend toward more frequent myeloma in patients
under age 55 implies important environmental causative factors in the past 60
years.
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TABLE 1
DEFINITIONS OF MYELOMA AND RELATED MONOCLONAL GAMMOPATHIES
STANDARD NAME
PROPOSED NEW NAME *
DEFINITION
MGUS
PMG: LOW RISK
· monoclonal protein
(Monoclonal
(Primar y
present
Gammopathy of
Monoclonal
· no underlying disease
Undetermined
Gammopathy)
state associated
Significance)
SMOLDERING
PMG: HIGH RISK
MGUS, but evidence of
or
(evidence of change)
i n c r easing M-component
INDOLENT
level and/or early bone
MYELOMA
disease
MYELOMA
ACTIVE MYELOMA
· monoclonal protein
present, and
· end organ damage **
*
Presented at the VIIIth International Myeloma Workshop by Dr. Philip
Greipp on behalf of the Prognostic Factor Study Group.
**
Anemia (dropping hemoglobin level); new bone disease evident on X-ray
and/or scan; renal insufficiency (increasing serum creatinine); major
myeloma complications (i.e. problem directly due to myeloma progression
which requires medical intervention).
PATHOPHYSIOLOGY
The uncontrolled growth of myeloma cells has many consequences
including skeleton destruction, bone marrow failure, increased plasma volume
and viscosity, suppression of normal immunoglobulin production, and renal
insufficiency. Nonetheless, the disease can remain asymptomatic for many years,
as noted in the discussion of MGUS. In the symptomatic phase, the most com-
mon presenting complaint is bone pain.
The serum and/or urine M-protein is elevated and typically rising at the
time of diagnosis. Please note: M is used for Monoclonal, Myeloma, Monoclonal
immunoglobulin, M-component (all are not quite identical but are used some-
what synonymously). Treatment improves the clinical situation in about 75% of
patients. It is important to emphasize that multiple periods of remission and
relapse can occur. The overall disease course is as illustrated in Figure 4. The
pathophysiology of myeloma is summarized in Table 2 in schematic form.
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BONE DISEASE
Ever since the first recognition of myeloma in 1844, the presence of
abnormal protein has been linked with bone destruction. It has taken until quite
recently to determine the mechanisms involved. The first clue was that both
myeloma cells and increased numbers of osteoclasts are present at sites of bone
destruction. Understanding of the mechanisms has evolved from the observa-
tions that myeloma cells produce osteoclast activating factors (OAFs) to the
characterization of both local cytokines such as IL-1ß, IL-6 and TNF and ß,
chemokines such as MIP-1 and cell-cell adhesion processes involving v ß3
integrin, all of which, are involved in producing increased numbers and activi-
ty of osteoclasts. Most recently a substance called RANK ligand (RANK L) has
been identified as a critical mediator of osteoclast activation. Studies are already
underway to evaluate the clinical efficacy of specific inhibitors of RANK L,
namely RANK.Fc and osteoprotegrin (OPG), both of which have shown prom-
ise in laboratory studies and preliminary clinical testing.
Besides activation of osteoclasts, the other characteristic feature of
myeloma bone disease is inhibition of osteoblasts. Normal "coupling" between
osteoclast and osteoblast function is responsible for normal bone remodeling
and repair. The mechanisms responsible for "un-coupling" in myeloma are under
investigation. An important new observation is that the cholesterol lowering
drugs, statins (i.e. Lipitor®, Mevacor®, Baycol®, etc.) can enhance osteoblast
activity and promote bone healing. Studies to investigate the benefit of such
drugs in myeloma are underway.
ANEMIA
Anemia is a characteristic feature of myeloma. Although simple phys-
ical displacement of marrow red cell precursors is undoubtedly a factor, the spe-
cific inhibition of erythropoiesis by micro-environmental cytokine and adhesion
molecule effects is a more functional explanation. TNF- has been identified as
one important inhibitor of erythropoiesis, however active myeloma results in a
complex interplay of factors that can cause not just anemia, but neutropenia and
frequently increased platelet counts related to high levels of IL-6 in the marrow.
Increases in basophils, eosinophils and monocytes can also occur. Improvement
in anemia occurs with successful treatment for the myeloma and can be
enhanced by use of recombinant erythropoietin (Epogen® or Procrit®).
KIDNEY DYSFUNCTION
Impairment of kidney function is a common complication in myeloma
patients. As noted above, myeloma proteins cause renal injury by a variety of
mechanisms ranging from tubular damage from large accumulations of abnormal
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TABLE 2
SCHEMA OF P ATHOPHYSIOLOGY
SKELETAL
· Solitary or multiple osteolytic lesions
FINDINGS
· Diffuse osteoporosis (osteopenia)
ASSOCIATED
· Elevated serum calcium
EFFECTS OF BONE · Hypercalciuria (calcium increase in urine)
DESTRUCTION
· Bone fractures
· Loss of height (vertebral collapse)
EXTRA
· Soft tissue involvement, most commonly
SKELETAL
in head/neck area (e.g. nasopharynx);
MYELOMA
also liver, kidney and other soft tissue sites
PERIPHERAL
· Anemia
BLOOD
· Abnormal clotting
· Leukopenia
· Thrombocytopenia
· Plasma cell leukemia
· Circulating monoclonal B lymphocytes
(precursors of myeloma cells)
PLASMA
· Hyperproteinemia (elevated protein)
PROTEIN
· Hypervolemia (expanded volume)
CHANGES
· Monoclonal immunoglobulins
(IgG, IgD, IgA, IgM, IgD, light chains)
· Nar rowed anion gap (low serum sodium)
· Elevated serum B 2-microglobulin
· Decreased serum albumin
· Elevated serum IL6 and C-reactive
protein (CRP)
KIDNEY
· Proteinuria, casts without leukocytes or
ABNORMALITIES
erythrocytes
· Tubular dysfunction with acidosis
· Uremia (kidney failure)
· Amyloidosis
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protein, to effects of myeloma proteins deposited as amyloid or selective tubular
damage resulting in the metabolic effects in Fanconi Syndrome. Fanconi syn-
drome is a selective kidney tubular defect with leakage of amino acids and phos-
phates in the urine which can cause metabolic bone disease. Increased levels of
calcium and/or uric acid, infection and toxic effects of drugs such as nephrotox-
ic antibiotics, non steroidal anti-inflammatory drugs or contrast/dyes used for
diagnostic studies can further compromise kidney function. Maintaining excel-
lent fluid intake is especially important for myeloma patients to help avert the
potential damaging effects of these various factors.
OTHER ORGAN DYSFUNCTION
Myeloma cells can accumulate in bone marrow and/or in a variety of
tissue sites and produce a broad range of potential complications.
·
Neurologic Effects ­ n e rve tissue is often affected in myeloma patients
either by the direct antibody effects of myeloma proteins against nerves
(e.g. myelin sheaths) or deposition of amyloid fibrils on nerves impairing
function. These effects result in peripheral neuropathies that must be
distinguished from other causes of neuropathy such as diabetes mellitus.
Because of the susceptibility to infection, viral infections of nerve tissue are
quite common most particularly varicella zoster (shingles) and Bell's palsy.
·
Plasmacytomas ­ both in bone and soft tissue, can result in compre s s i o n
or displacement of nerves, the spinal cord or even brain tissue. These
p re s s u re effects often re p resent a medical emergency and re q u i re immediate
t reatment with high doses of coriosteroids and/or radiation therapy.
·
Infections ­ the predisposition to infections is perhaps the single most
characteristic feature of myeloma patients besides the predilection for
bone disease. The mechanisms are not fully understood. The presence
of active myeloma in the bone marrow results in inhibition of normal
immune functions including normal antibody production (reflected
by hypo gamma globulinemia) impaired T-lymphocyte function and
activated but, aberrant monocyte/macrophage function. Some studies
indicate that a factor coming from the activated macrophages both
enhances the activity of the myeloma, but conversely inhibits normal
immunoglobulin production and T-lymphocyte functions.
Myeloma patients are particularly susceptible to viral infections and
infections with "encapsulated" bacteria such as pnemococcus. However, in the
face of neutropenia and the effects of high dose chemotherapy plus the local
e ffects of implanted catheters (e.g., Hickman catheter) the whole range of bacte-
rial, fungal and opportunistic infections occur in myeloma patients underg o i n g
t h e r a p y.
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TYPES OF MYELOMA
The types of monoclonal protein produced varies from patient to
patient. The most common is IgG and the rarest is IgE. Table 3 shows the per-
centages of different types of myeloma. Each type is associated with slightly dif-
ferent patterns of disease. For example, IgA myeloma is more commonly associ-
ated with disease outside bone (extraskeletal disease) whereas, IgD myeloma is
more commonly associated with plasma cell leukemia and renal damage.
TABLE 3
TYPES OF MONOCLONAL PROTEIN (%)
1. S ERUM
%
T OTALS
IgG
52
IgA
21
75%
IgD
2
IgE
<0.01
2. Urine (Bence Jones, or light
chains only) types
and
11%
3. Two or more monoclonal paraproteins
<1
Heavy chains (G or A) only
<1
2%
No monoclonal paraprotein
1
4. IgM (rarely myeloma, typically
associated with Waldenstrom' s
Macroglobulinemia)
12%
Total
100%
Source: Data on 1,827 MM patients collected and analyzed by Pruzanski and Ogryzlo, 1970.
CLINICAL SYMPTOMS
About 70% of myeloma patients present with pain of varying intensi-
ty, often in the lower back or ribs. Sudden severe pain can be a sign of fracture
or collapse of a vertebral body. General malaise and vague complaints are fre-
quent. Significant weight loss is rare.
Both neutropenia and hypogammaglobulinemia increase the likelihood
of infections. Although pneumococcal pneumonia is the classical infection
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associated with myeloma at presentation, other bacteria, such as streptococci
and staphylococci, are now frequently isolated. Haemophilus infection and her-
pes zoster infections also occur.
Hypercalcemia, present in 30% of the patients at diagnosis, causes
t i redness, thirst and nausea. Precipitation of calcium salts can result in deteriora-
tion of kidney function. Hyperv i s c o s i t y, due to high myeloma protein levels, can
cause problems such as bruising, nose bleeding, hazy vision, headaches, gastro i n-
testinal bleeding, sleepiness, and a variety of ischaemic neurological symptoms
caused by reduced blood and oxygen supply to the nerve tissue. Hyperv i s c o s i t y
occurs in <10% of myeloma patients. Hyperviscosity affects about 50% of
patients with Wa l d e n s t ro m 's Macroglobulinemia (IgM paraprotein or M-compo-
nent). Increased bleeding is often accentuated by thrombocytopenia, in addition
to the binding of monoclonal proteins to clotting factors and/or platelets.
N e u rologic involvement can result in specific problems depending on
location. Particularly common problems are spinal cord compression, meningitis
and carpal tunnel syndrome. Although the first two are due to plasma cell tumor
f o rmation or unfiltration, carpal tunnel syndrome is usually due to amyloid dep-
osition (deposition of Bence Jones proteins in a special ß-pleated form ) .
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 include
growth rate (fraction), production rate of monoclonal proteins and production
or non production of various cytokines and chemicals which damage or signifi-
cantly impair other tissue, organ or bodily functions. In 1975, the Durie/Salmon
staging system was developed (see Table 4). This system brings together the
major clinical parameters in correlation with measured myeloma cell mass (the
total number of myeloma cells in the body).
The Durie/Salmon staging system continues to be used worldwide.
However, numerous groups have proposed new systems to more accurately and
simply stage and/or classify myeloma patients into prognostic categories. Thus far,
no new system has gained universal acceptance. In the last year, two new systems
have been put forw a rd which are under active discussion and consideration.
F i r s t l y, the IFM group in France has proposed a system based upon serum ß2 micro
globulin and chromosome analysis using the FISH technique.
P re - t reatment serum ß2 m i c roglobulin (Sß2M) is the most powerful sin-
gle prognostic factor for the prediction of length of survival for myeloma patients.
Using a cutoff value of 2.5mg/L the IFM group re c o n f i rmed the utility of Sß2M
level. They then searched for another factor that can improve discrimination and
establish 3 groups ranging from favorable to unfavorable. Deletion or abnorm a l i t y
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TABLE 4
DURIE AND SALMON ST AGING SYSTEM
Criteria
Measured myeloma cell mass
(cells x 10 12/m2)
STAGE I (low cell mass)
<0.6
All of the following:
· Hemoglobin value > 100g/l
· Serum calcium value normal
or <2.60 mmol/l
· Bone X-ray, normal bone structur e
(scale 0) or solitary bone plasmacytoma only
· Low M-component production rates
IgG value <50g/l
IgA value <30g/l
Urine light chain M-component on
electrophoresis <4g/24h
STAGE II (intermediate cell mass)
0.6 - 1.2
Fitting neither stage I nor stage III.
STAGE III (high cell mass)
>1.2
One or more of the following:
· Hemoglobin value <85g/l
· Serum calcium value >3.00mmol/l
· Advanced lytic bone lesions (scale 3)
· High M-component production rates
IgG value >70g/l
IgA value >50g/l
Urine light chain M-component on
electrophoresis >12g/24h
SUBCLASSIFICATION (either A or B)
· A: relatively normal renal function
(serum creatinine value <170umol/l)
· B: abnormal renal function
(serum creatinine value =170umol/l)
Examples:
Stage IA (low cell mass with normal renal function)
Stage IIIB (high cell mass with abnormal renal function)
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TABLE 5
MYELOMA TREA TMENT OPTIONS
1. Chemotherapy
2. High dose therapy with transplant
3. Radiation
4. Maintenance therapy (e.g. alpha interferon, prednisone)
5. Supportive care:
· Erythropoietin
· Pain medication
· Bisphosphonates
· Growth factors
· Antibiotics
· Brace/corset
· Diet
· Exercise
· Emergency care (e.g. dialysis, plasmapheresis, surgery)
6. Management of drug resistant or refractory disease
7. New and emerging treatments:
· Anti-angiogenesis strategies (e.g. Thalidomide)
· Reversal of multi-drug resistance (e.g. PSC-833)
· New cytokines (e.g. IL-6, 2, 12)
· New vaccines (e.g. anti-idiotype)
· New chemotherapy drugs (e.g. Navelbine)
of chromosome 13 on fluorescent chromosome analysis (FISH) proved to be the
most useful additional factor (13). They there f o re proposed use of these two fac-
tors for routine prognostic screening. However, they recognized that some back-
up was re q u i red in the absence of 13 testing or data. It turns out that by using
the routinely available age, sex and myeloma protein subtype information; very
similar discrimination can be achieved when combined with Sß2M. Obviously
this is simpler and less expensive. The question then becomes why patients with
13 do more poorly? This is under investigation by several groups.
The additional question addressed by the Southwest Oncology Group
(SWOG) is whether or not any other single factor can powerfully add to Sß2M
as a predictive factor. Their data, confirm data from the mid-1980s that serum
albumin is a very powerful predictive factor and can be combined with Sß2M to
create a very simple, reliable, prognostic system. It is very important that the
large SWOG database, with long-term survival follow-up data, confirms prior
observations. Therefore, there are two simple systems currently available for
prognostic classification as a basis for review of potential treatment options and
to give guidance to individual myeloma patients.
15

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DEFINITION OF CLINICAL RESPONSE
T h e re are several methods to classify response to treatment (s e e Table 6).
Many variations of this classification are in use. The improvements in M-com-
ponent must also be associated with evidence of clinical improvement (reduced
bone pain, improved anemia, etc.). With the possible exception of True
Complete Response, it is important to keep in mind that a higher percent regres-
sion does not necessarily confer a better survival. When there 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, ideally, no signs of MM are left or they achieved
a stable plateau phase, but with measurable residual disease. The time required
to achieve the plateau phase is variable, ranging from 3-6 months (rapid
response), to 12-18 months (slow response). Please refer to Figure 4 on page 3.
TABLE 6
RESPONSE TO TREA TMENT
COMPLETE RESPONSE (CR)
Standard Definition: *
=75% reduction in serum
myeloma protein level
(>90% in urine).
TRUE COMPLETE RESPONSE
More Stringent Definition:
Elimination of M-component
from serum and urine plus
no evidence of myeloma in
the bone mar row.
PARTIAL RESPONSE (PR)
>50% <75% regression
OBJECTIVE RESPONSE (OR)
Stable Disease
>25% <50% regression
NO RESPONSE (NR)
Progressive Disease
<25% regression
* A long standing definition used by SWOG (South Western Oncology Group)
16

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TREATMENT
Please see History section for an overview of the evolution of currently
used treatments. Since melphalan was first introduced in 1962, various combi-
nation chemotherapy regimens have been utilized and attempts made to
improve outcomes using high dose chemotherapy regimens with bone marrow
transplant (BMT) or peripheral stem cell transplant (PSCT). In the standard
type of BMT or PSCT, the "transplant" is a "rescue" with normal bone marrow
stem cells when the stem cells in the body have been destroyed by high dose
chemo. There is as yet no consensus as to the best way to manage myeloma.
However, the following will provide some guidelines.
Since myeloma is not curable, the first and most important decision is to
a s c e rtain if therapy is re q u i red. Patients with MGUS and smoldering myeloma
should be observed closely rather than treated. There are currently no therapies
that can enhance the immune regulation of early myeloma or reduce the likelihood
of disease activation. However, re s e a rch options are available, (e.g. anti-idiotypic
vaccines). Treatment is recommended when the M-component is incre a s i n g
and/or clinical problems have emerged or are imminent. Problems sufficient to
re q u i re treatment include bone destruction (lytic lesions and/or osteoporosis), re n a l
i n s u ff i c i e n c y, reduced blood counts (e.g. anemia, neutropenia), elevated blood cal-
cium, nerve damage or other significant organ or tissue damage caused by myeloma
or myeloma protein. The overall goals of treatment are to address specific pro b l e m s
and to achieve general control of the disease. A summary of types of treatments is
p rovided in Table 5.
1. CHEMOTHERAPY : The treatment options include induction chemother-
apy, higher dose chemotherapy and supportive care therapy. The most com-
monly used drugs are listed in Table 7. Since first introduced in 1962, melphalan
has remained the best single agent for the management of MM. The majority of
patients respond to treatment with this agent particularly when combined with
prednisone.
·
Melphalan/Prednisone (MP), Cytoxan/Prednisone (CP) ­ The MP
combination is the most frequently used. Sixty percent of patients have an
objective response reflected by a 50% improvement in the M-protein
level plus improvement in blood count and other blood test results,
along with improvement in the various symptoms of the disease, such as
bone pain and fatigue. Cytoxan can be substituted for melphalan since it
has a similar anti-myeloma activity. Cytoxan is less toxic to normal
bone marrow stem cells and can be considered in patients who may be
candidates for future stem cell transplantation. It has more immediate
side effects than melphalan including GI toxicity, such as nausea.
17

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TABLE 7
MOST COMMONLY USED CHEMOTHERAPY DRUGS
DRUG NAME
OTHER TREATMENT NAME COMMENTS
Melphalan*
Alkeran ®
Best single agent for
(M)**
(by mouth or IV)
treatment.
Cyclophosphamide * Cytoxan®
Similar efficacy to M
(C or CY) **
(by mouth or IV)
but with more GI and
GU toxicity and less bone
marrow stem cell injur y.
BCNU *
Bis-chloro-Nitrosurea ®
Similar to M and C but less
(B)**
(IV only)
effective and more toxic,
especially bone mar row and
lung toxicity.
Prednisone
Prednisolone ® (similar)
Directly active, works well
(P)**
(usually by mouth)
with M, C and B. Does not
produce suppression of bone
marrow.
Dexamethasone
Decadron ®
Similar to prednisone but
(D)**
(by mouth or IV)
more potent. More sever e
side effects.
Vincristine
Oncovin®
Modest activity, frequently
(V or O) **
(IV only)
used as part of combination
regimens (e.g. VAD).
Doxorubicin
Adriamycin ®
Modest activity, used in
(A)**
(IV only)
combinations (e.g. VAD,
ABCM, VMCP-VBAP).
Busulphan *
Myleran ®
Similar activity to M and C,
(B or BU) **
(by mouth or IV)
usually part of high dose
therapy with transplant
(e.g. BU/CY regimen).
VP - 16
Etoposide ® (IV)
Modest activity, used alone or
(E)**
in combination.
Cis-platinum
Platinol®
Minimal activity,
(CP)**
(IV)
occasionally used.
* Alkylating agents ** Common abbreviations
18

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·
More Complex Combination Schedules ­ Since the mid-1960s,
many combinations and permutations of the most commonly used
d rugs have been tried. Combinations for which there is a suggestion of
additional benefit versus MP or CP are listed in Table 8. The M2
p rotocol was developed at Memorial Sloan-Kettering Cancer Center
in New York. A few studies have suggested that there is a higher
response rate and an overall better outcome using the M2 p rotocol
versus MP. For example, in a recent analysis from the Eastern
Cooperative Oncology Group (ECOG), the overall survival of patients
t reated with M2 p roved to be identical to those receiving MP.
H o w e v e r, the survival at five years was superior in the M2 p rotocol
a rm. 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
indications of superiority versus MP, however they are more toxic and
expensive. Proponents of these combination schedules, those who have
used them for many years, continue to recommend them because the
outcome is at least as good as with MP and there is a suggestion that it
may even be slightly better. The current trend is to use MP or CP as a
first choice and re s e rve the more complex combinations as a back
up approach for patients who fail to have a satisfactory re s p o n s e .
A confusing aspect of myeloma treatment has been the discovery that
more dramatic reductions in the amount of myeloma, as reflected by the level of
myeloma protein in the serum and/or urine, does not necessarily translate into
longer remissions or longer overall survival. The major factor which determines
outcome is the intrinsic drug sensitivity or resistance of the myeloma. Since no
current therapy eradicates all the myeloma cells, the characteristics of the cells
left following initial chemotherapy are of particular importance. A few aggres-
sive residual myeloma cells can potentially cause more trouble than a larger
number of inactive cells.
·
VAD Chemotherapy ­ The VAD protocol, first introduced in 1984,
has become a popular alternative to MP or CP induction. The major
reason for this is not that it produces better overall outcome, but that
it can produce response without injuring the normal bone marrow
stem cells. It is a particular advantage in patients who are scheduled
to have high dose therapy with transplantation. In addition, the high
dose dexamethasone, which is part of the VAD, can be very helpful in
patients with initial aggressive disease and/or renal failure who need
rapid disease control to improve urgent medical problems. A simple
alternative is dexamethasone alone. This can dramatically improve
the clinical situation without reducing blood count levels and without
the need for insertion of an intravenous catheter followed by a four
day infusion.
19

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TABLE 8
FREQ UENTL Y USED COMBINA TIONS
MP
Standard combination for initial therapy .
CP
Alternative to MP .
VBMCP (M 2)
Combination often used in eastern USA.
Proponents suggest better response and
survival versus MP .
VMCP/VBAP
Combination developed by SWOG and often
used in western USA. More toxic with
minimal increased benefit as is true for M 2.
ABCM
Combination used in Europe, especially UK.
Little extra benefit versus MP .
VAD
Most commonly used alternative to MP ,
especially if:
· Myeloma is aggressive
· There is renal insufficiency
· High dose therapy with transplant
is planned
D or MD or CD
D alone or combined with M or C can be
used as alternative to VAD. Avoids need
for four day infusion.
·
Monitoring of Response ­ The most important aspect is to know if
the symptoms at presentation have improved. One must assess blood
count levels, chemistry results, and particularly levels of myeloma
p rotein in the serum and urine. Important markers of myeloma activity
a re the serum B2 m i c roglobulin, the C-reactive protein plus the labeling
index in the peripheral blood and/or bone marrow. It is important to
have a periodic 24-hour urine test to exclude the possibility of Bence
Jones escape. This is a situation in which the urine protein may
increase, even though the serum protein level has improved. Follow
up X-rays of the bones are important to exclude possible new bone
involvement. Additional scanning, including MRI and CT, may be
necessary to more closely evaluate the status of the bones. DEXA
scan can be used to quantitate base line and follow up bone density.
20

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2. HIGH DOSE THERAPY WITH TRANSPLANT
: For the past 15 years,
a major approach has been the application of high dose therapy, using alkylat-
ing agents such as melphalan, cytoxan or busulphan, either alone or in combi-
nation. Following high doses of these alkylating agents, rescue is required in the
form of either growth factors for intermediate doses, or stem cell rescue for high
doses. Rescue can be in the form of an autologous transplant (the patient's own
normal stem cells are utilized) or in the form of an allogeneic/syngeneic trans-
plant (HLA identical or twin donor stem cells are utilized). The possible advan-
tages and disadvantages of these three types of transplants are summarized in
Table 10. The benefit of all strategies is that, with the administration of high
dose chemotherapy, a more dramatic myeloma cell kill and remission can be
achieved in a majority of patients. Currently 50% of patients can achieve com-
plete response with high dose therapy, see Table 10. The most immediate features
of myeloma are reversed and the patient is without symptoms of the disease.
Excellent clinical remission is the major advantage. A crucial disadvantage is
that the disease is still not cured. Relapse occurs, with a similar time pattern to
that observed after standard chemotherapy. Relapse can be delayed by the use of
interferon as a maintenance after the high dose approach. The benefit is great-
est for patients who achieve a complete remission with the high dose strategy.
As far as the overall benefit with high dose therapy versus MP, there is only one
randomized study that compared high dose treatment with conventional thera-
py. In this study, there is a significant advantage in terms of achieving remission,
as well as a trend towards improved survival, with the high dose approach. This
study was predominantly restricted to patients with advanced aggressive disease
under the age of 60. The major concern about high dose therapy is that only a
fraction of patients may need and benefit from the high dose approach. We don't
yet know which patient population needs this approach. A recent analysis from
Italy suggests that the major sub-population needing and benefiting from high
dose therapy is the group of patients under the age of 60, with Stage III disease,
who have very aggressive disease as reflected by a high pre-treatment bone mar-
row labeling index. The immediate question is whether patients with Stage I, II
or III, with less aggressive features, need or benefit from high dose strategies.
·
Allogeneic and Twin Transplants ­ The relative advantages and
disadvantages of allogeneic or twin transplants are listed in Table X.
Such transplants are limited to patients who either have a twin or an
HLA identical brother or sister. The patient also should be under age
55. With allogeneic transplant, the risks are quite daunting in that at
least 25-30% of patients are at risk from early death because of com-
plications related to the transplant. For some reason, in patients with
myeloma, risks of complications remain high despite intensive support i v e
care at even the most experienced treatment centers. The risks with
twin transplants are much less, which can usually be recommended
for young patients with an identical twin. None of these procedures is
curative. In all but a rare few patients, relapse supervenes.
21

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TABLE 9
TESTS REQ U IRED TO MONITOR THERAPY RESPONSE
BLOOD TESTS
· Routine blood counts
· Chemistry panel
· Liver function tests
· Myeloma protein measurements
(serum protein electrophoresis plus
quantitative immunoglobulins)
· Serum B2 microglobulin
· C-reactive protein
· Peripheral blood labeling index
· Serum erythropoietin level
URINE
· Routine urinalysis
· 24-hour urine for measurement of
total protein, electrophoresis and
immunoelectrophoresis
· 24-hour urine for creatinine clearance
if serum creatinine elevated
BONE EVALUATION
· Skeletal survey by X-ray
· MRI/CT scan for special problems
· Whole body FDG/PET scan if
disease status unclear
· Bone density measurement
(DEXA scan) as baseline and to
assess benefit of bisphosphonates
BONE MARROW
· Aspiration and biopsy for
diagnosis and periodic monitoring
· Special testing to assess prognosis
(e.g. look for chromosome 13 ab-
normalities, immunotyping, LI%)
OTHER TESTING
· Amyloidosis
(special circumstances)
· Neuropathy
· Renal or infectious complications
22

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3. RADIATION:
Radiation therapy is an important modality of treatment for
myeloma. For patients with severe local problems such as bone destruction, severe
pain and/or pre s s u re on nerves or the spinal cord, local radiation can be dramati-
cally effective. The major disadvantage is that radiation therapy permanently dam-
ages normal bone marrow stem cells in the area of treatment. Wide field radiation
encompassing large amounts of normal bone marrow should be avoided. A gener-
al strategy is to rely on systemic chemotherapy to achieve overall disease contro l ,
limiting the use of local radiation therapy to areas with particular problems.
·
Total Body Radiation (TBI) ­
Total body or sequential radiation of
half of the body can be used as part of an overall strategy for high
dose therapy with transplant and/or in the management of relapsing
re f r a c t o ry disease. Although used in the past as a pre p a r a t o ry re g i m e n t
for transplant, recent studies have shown no added benefit and,
unfortunately, increased toxicity. Therefore, TBI is no longer
recommended as part of preparatory regiments. In patients with
refractory disease, sequential hemi-body radiation can be used to
temporarily control the disease. This is rarely successful for very long,
particularly in patients with aggressive, active myeloma. There is also
the disadvantage that wide field radiation destroys the normal bone
marrow and makes it difficult if not impossible to use other treatment
options following this approach.
4. MAINTENANCE THERAPY :
·
Alpha Interferon ­ For the past 15 years, many investigators have
evaluated the efficacy of interf e ron, an agent shown to prolong re m i s s i o n
achievable with standard or high dose therapy. Conflicting results have
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
remission and survival. Diff e rences of 10-15% (e.g. 6-9 months) are hard
to prove in clinical studies. Ongoing studies include evaluation of
i n t e rf e ron with initial chemotherapy and the combination of alpha
i n t e rf e ron with a variety of agents such as dexamethasone or IL-2 for
maintenance. The use of alpha interf e ron has to be individualized,
balancing potential benefits with potential side effects, expense and
inconvenience. Most investigators think that alpha interf e ron has a
definite (although small) role in the management of myeloma.
·
Prednisone as Maintenance ­ It has been difficult to find therapy
which can prolong remissions and survival in myeloma without
compromising quality of life as was the case with alpha interferon.
However, new studies have supported earlier observations from the
1980s that prednisone is an effective maintenance agent, and pro b a b l y
superior to alpha interferon. Prednisone administered three times per
23

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TABLE 10
HIGH DOSE THERAPY
TYPE
ADVANTAGES
DISADVANTAGES
Single
· 50% excellent remissions
· Relapse pattern similar to
Autologous
· At least as good as
standard chemotherapy
Transplant
standard therapy
· More toxic and expensive
regarding overall survival
· Patients who benefit from
and probably better
transplant not clearly
for some patients
identified
· Basis for strategies to
· Maintenance therapy still
produce true remission
required (e.g. interferon,
or long term cur e
prednisone, vaccine)
· New preparative regimens
may produce true complete
remission
Double
· Same as single
· As yet no clear benefit
Autologous
versus single transplant
Transplant
· Much more toxic and
expensive versus single
Traditional
· No risk of contamination
· Even for HLA identical
Allogeneic
of mar row/stem cells
siblings significant risk of
Transplant
with myeloma
early complications and
· Possible graft versus
even death (25-30%)
myeloma effect to
· Risk of complications
prolong remission
unpredictable
· Restricted to age 55
· More toxic and expensive
versus autologous
Mini-Allo
· Less toxic form of allo
· No anti-myeloma chemo-
Transplant
· Preparative chemotherapy
therapy given
usually well-tolerated
· Still produces graft -vs-host
· Results in anti-myeloma
disease
immune graft
· Full benefits still unclear
· Risk of initial mortality
is low (1-3%)
Twin
· No risk of myeloma
· No graft -vs-myeloma effect
Transplant
contamination in
· Need identical twin 55 age
transplanted cells
· Much less risky than allogeneic transplant.
24

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week (e.g. starting dose of 50mg) has acceptable toxicity and can
prolong both remission and survival. A particular advantage is that
patients can take prednisone for several years without developing
resistance. However, caution is required because of longer term side
effects and dose reductions are usually necessary.
5. SUPPORTIVE CARE:
·
Erythropoietin ­ E ry t h ropoietin (e.g. Procrit) is a naturally occurr i n g
hormone now available through genetic engineering techniques.
Erythropoietin is administered to improve the hemoglobin level in
patients who have persistent anemia. Erythropoietin injections (e.g.
40,000 units SQ weekly) can show dramatic benefit in the level of
hemoglobin and in perf o rmance status. It should be strongly considere d
in patients who have persistent anemia. Erythropoietin should only
be continued in patients showing clear benefit. Iron supplements may
be required to achieve maximum benefit.
·
Bisphosphonates ­ Bisphosphonates are a class of chemicals which
bind to the surface of damaged bones in patients with myeloma. This
binding inhibits the ongoing bone destruction and can improve the
chances of bone healing and recovery of bone density and strength. A
randomized study utilizing the bisphosphonate pamidronate (Aredia)
showed particular benefit in patients responding to ongoing chemo-
therapy. It is currently recommended that pamidronate be used as an
adjunctive measure in myeloma patients who have bone problems.
Please see Figure 5. Other bisphosphonates are available including
Clodronate, an oral formulation in use in Europe for the treatment of
myeloma. Several new bisphosphonates are in clinical trial, including
zoledronate (Zometa) and Ibandronate.
FIGURE 5: HOW PAMIDRONATE WORKS
25

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·
Antibiotics ­ Infections are a common and re c u rrent problem in
patients with myeloma. A careful strategy for infection management is
re q u i red. Antibiotic therapy should be instituted immediately if active
infection is suspected. Use of preventative or prophylactic antibiotics
with re c u rrent infection is controversial. The continuation of pro p h y -
lactic antibiotics can increase the chance of antibiotic resistance, but it
can also reduce the chance of re c u rrent 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 re q u i red in patients with acute and
s e v e re re c u rrent infections. GM-CSF may be helpful to improve the
white blood cell levels in an eff o rt to overcome infectious complications.
The use of G or GM-CSF is helpful in the re c o v e ry phase following bone
m a rrow or stem cell transplantation. G and GM-CSF are also used in
h a rvesting stem cells.
6. MANAGEMENT OF DRUG RESISTANT OR REFRACTORY DISEASE:
As illustrated in the pathophysiology section, a frequent problem in myeloma is
the relapse which occurs following a 1 to 3 year remission. Although alpha inter-
f e ron or prednisone maintenance may be useful in prolonging the initial re m i s s i o n
p e r i od, the relapse, which supervenes inevitably, re q u i res re-induction chemother-
a p y. The following is an overall strategy for the management of relapsing disease.
If relapse occurs after a remission of at least 6 months to 1 year, the first
strategy is to re-utilize the therapy which produced the remission in the first
place. Approximately 50% of patients will achieve a second remission with the
same therapy that produced the first. This is particularly true for patients in
remission for over one year following the initial induction attempt. As an exam-
ple, a patient who has received MP and has gone into remission for two years can
again receive MP induction. If remission has lasted less than six months, some
a l t e rnative therapy will usually be re q u i red. This is also the case if relapse has
o c c u rred following a second or third use of the original induction therapy. The
use of VAD is an important consideration in this setting. If VAD is not immedi
FIGURE 6: MDR
MYELOMA CELL
26

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ately successful, VAD combined with some new agent, such as PSC 833 (to over-
come MDR) or Doxil (long acting adriamycin) may be appropriate. See F i g u re 6.
It is important to keep in mind that a variety of single and combination
chemotherapy protocols are available for the management of relapsing and
refractory disease. Depending upon the exact problem, a variety of interventions
may be possible. For example, if relapse is associated with the development of
one or two bone lesions, radiation to the site(s) of bone involvement may be a
satisfactory way to manage the relapse. If overall relapse has occurred, the use of
dexamethasone as a single agent can be very useful in achieving overall control
of the disease. The use of dexamethasone is attractive because it can be given by
mouth and does not cause significant side effects such as hair loss or reduction
in peripheral blood count values.
Another important point is that relapse following high dose therapy
with transplant has, in many cases, a pattern similar to relapse following more
standard approaches. Second and sometimes third remissions can be achieved
following relapse after bone marrow transplantation. Whether a second high
dose therapy with transplant is the most appropriate strategy as opposed to some
other lower dose chemotherapy approach is currently unclear. The group at the
Royal Marsden Hospital in London has had excellent results using second and
third rounds of high dose melphalan for patients treated in the early to mid
1980s. It is important to note that in this same patient population, the Royal
Marsden group has shown that maintenance alpha interferon following high
dose therapy prolongs the quality and duration of the remission.
A full range of supportive care aspects are crucial for the management
of MM. When first diagnosed, a number of emergency pro c e d u res may be
re q u i red, including dialysis, plasmapheresis, surg e ry, and radiation to reduce pre s-
s u re on a nerve, spinal cord, or other crucial organ. The management of pain is
essential for the initial care of patients with MM. This can be difficult until ini-
tial disease control is achieved. There is no reason for patients with MM to have
major ongoing pain with the range of new drugs and strategies available. There
can be a reluctance on the part of the patient and/or the physician to implement
full pain control pro c e d u res because of concerns about addiction. Control of pain
should always be the first priority. A brace or corset can help stabilize the spine
or other area, reducing movement and pain. Moderate exercise is also import a n t
in recovering bone strength and mobility and can help in overall pain reduction.
7. NEW AND EMERGING TREATMENTS:
Most new treatments are
available in the setting of clinical trials. Clinical trial phases are listed in Table 11.
A whole range of agents are entering clinical trials, covering a spectrum from
conventional chemotherapy products (e.g. Doxil) to cytokines (e.g. IL-12), bio-
logic agents (e.g. Betathine), novel agents (e.g. arsenic trioxide [ATO]), as well
as gene therapy and vaccine strategies. Patients are encouraged to contact the
27

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IMF via telephone or Internet (www.myeloma.org) and to check with their
physicians re g a rding the availability of new clinical trials in their region of the US.
·
Thalidomide and analogs ­ In 1999, it became clear that thalidomide
is an active anti-myeloma agent. Initial studies at the Arkansas Cancer
R e s e a rch Center in Little Rock showed a 25% response rate (>5 0 %
re g ression) in patients with re l a p s i n g / re f r a c t o ry myeloma mostly post
double transplant. The problem was the substantial toxicity with the
rapid dose escalation protocol used, going from 200mg/day to 800mg/day
or higher over 6 weeks. Several other groups confirmed efficacy in
relapsing patients. Durie et al at Cedars-Sinai Comprehensive Cancer
Center in Los Angeles showed that dosages of 50mg-400mg (median
200mg) were equally effective with greatly reduced toxicity. New studies
a re now under way to evaluate use in combination (e.g. plus dexamethasone
and/or Biaxin) both frontline and for maintenance. New analogs
(IMiDS) as well as specific anti-angiogenic agents (e.g. VEGF t y rosine
kinase inhibitors) are entering clinical trials. It will take time to assess
the role of thalidomide and related compounds. For summary of basic
results, please contact the IMF for a copy of The Comprehensive Guide
to Banff: Understanding the VIIIt h I n t e rnational Myeloma Wo r k s h o p .
·
New Treatments for Bone Disease ­ Since bone damage is the m a j o r
cause of disability for myeloma patients it is especially encouraging
that new drugs are on the horizon. The current bisphosphonates work
well but powerful new bisphosphonates are now available for myeloma
patients. Obviously, the hope is that they will not only improve bone
healing, but further contribute to the slowing of myeloma growth in
the bone marrow (i.e. have a significant anti-myeloma effect). A new
technology called vert e b roplasty is also being introduced which may be
beneficial for myeloma patients. This pro c e d u re involves the injection
of plastic cement into a collapsed vertebra in the spine in an eff o rt to
recover normal strength and stru c t u re for patients disabled by loss of
height and spine curv a t u re. Initial results have been encouraging.
Trials are underway to assess if statins (cholesterol drugs) can imrove
bone healing.
·
New Chemotherapy Drugs ­ Several new chemotherapy agents
have been introduced for the treatment of myeloma. In a recent study
from Spain, Vinorelbine (Navelbine®, Glaxo Wellcome) combined
with dexamethasone showed considerable promise for patients seeking
to achieve remission after failing standard and/or high dose chemotherapy.
Likewise, Taxol® and Taxotere® (two "Taxoids" originally derived from
the yew tree), as well as Topotecan, a drug which blocks metabolism
in drug resistant cells, have shown some activity in relapsing or re f r a c t o ry
myeloma. Several trials continue with PSC 833, a drug which helps
reverse resistance with the VAD or VAMP protocols. Responses have
28

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o c c u rred in patients resistant to VAD and VAMP although the overall
impact of such therapy remains to be explored. Doxil, a liposomal
preparation of adriamycin, is also being tested in this setting.
·
Biologic Agents ­ Promising biologic agents entering clinical trial are
Betathine and interleukins 2 and 12, all of which have shown benefit
in pre-clinical and early patient testing.
·
Transplantation ­ Numerous studies are under way to improve the
outcome with high dose therapy and bone marrow/peripheral stem cell
rescue. Strategies include new drugs, diff e rent drug dosages and immune
cell boosting with infusions of lymphocytes.
·
Vaccines ­ Much interest has focused on the potential for boosting
natural immunity against myeloma using vaccines. One type, using a
patient's own cells (dendritic cells) primes the immune system against
the exact ("idiotypic") specificity of the myeloma. Another type under
development, uses DNA combined with an immune stimulator to
specifically boost the immune response against myeloma. Time will
tell if these can help delay myeloma re-growth.
·
Other ­ A completely new approach is to consider strategies directed
against potential causes of myeloma (possible treatment or pre v e n t i o n ) .
Although the cause or causes of myeloma are still not clearly delineated,
possible factors include viruses, toxic exposure and stress. "Anti-virus"
treatment could prove useful in reducing myeloma triggering, as could
e ff o rts to reduce stress. Reduction and/or elimination of potential toxic
e x p o s u res (e.g. pesticides) is obviously a longer term prevention strategy.
TABLE 11
CLINICAL TRIAL PHASES
I
Early testing to assess tolerance and toxicity in patients.
II
Further testing to evaluate how effective treatment is at
the dose and schedule selected.
III
Comparison of the new treatment with prior treatment(s)
to determine if the new treatment is superior .
IV
Usually carried out after FDA approval to assess cost-
effectiveness, quality of life impact and other comparative
issues.
29

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· MGUS AND SMOLDERING /INDOLENT MYELOMA :
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