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Emerging
Therapies
for Multiple
Myeloma
A Guide for
Health Care Professionals
NeoRx Corporation
300 Elliott Avenue West, Suite 500
Seattle, Washington 98119-4119
www.neorx.com
© 2004 NeoRx Corporation
All rights reserved.
NRX-101-2500
October 2004
Printed in USA

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Multiple Myeloma
Multiple myeloma is a treatable, but incurable
disease. Myeloma comprises about 1% of all
cancers. At present, there are approximately
50,000 people in the United States living with
multiple myeloma with approximately 15,300 new
cases diagnosed each year. The median age at
diagnosis is 65 years with incidence increasing
with age. Myeloma is more common in African
Americans than in Caucasians and affects men
more commonly than women. Risk factors
include family history, chemical exposure known to
occur in farmers and petroleum workers, and
radiation exposure such as that seen in survivors
of the atomic bomb explosions in Japan and in
radiologists or workers in nuclear plants. The
majority of patients, however, have no clear risk
factors.
Although multiple myeloma affects the bone,
it is a hematologic or blood-borne disease that
originates in the bone marrow. Bone disease in
myeloma is very different from primary bone
cancers like osteosarcoma or Ewing's sarcoma
which begin in the hard outer part of the bone, or
tumors originating in one area of the body, such
as breast, prostate, or lung cancer, that metastasize
to the bone.
In multiple myeloma, the body produces an
excessive number of abnormal or malignant plasma
cells called myeloma cells. Myeloma cells collect
in the bone marrow and in the area of hard bone
that supports the bone marrow, causing holes
and even fractures to develop in any area of the
skeleton, forming multiple sites of disease.
Myeloma cells may also secrete excessive
amounts of immunoglobulins (monoclonal protein
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or M protein) which can be measured in the
The diagnosis and treatment of myeloma is a
blood and urine. This type of disease is referred
complex process. No single test result determines
to as secretory multiple myeloma. Another less
the treatment or prognosis of this disease.
common form of myeloma is a plasmacytoma
Management of myeloma is tailored to the
which forms when myeloma cells collect in only
individual patient based on many factors including:
one bone and create a single tumor. Patients
with a plasmacytoma may go on to develop
· Results of a physical exam
secretory myeloma.
· Results of laboratory tests
· The stage or classification of disease
The excessive number of myeloma cells and the
· Age and general health
amount of abnormal immunoglobulins that they
· Co-morbid conditions (such as diabetes,
produce (M protein) can cause serious medical
renal disease, and cardiac disease including
problems. Myeloma cells produce or stimulate
hypertension)
the production of cytokines that damage and
weaken bones increasing the likelihood of bone
· Symptoms
fractures or skeletal events, often causing severe
· Presence of complications of the disease
bone pain. When bones are damaged, calcium is
(such as baseline renal dysfunction due to
released into the blood. Hypercalcemia can lead
myeloma and current or impending skeletal
to loss of appetite, nausea, thirst, weakness,
events)
restlessness and confusion. Myeloma cells in the
· Previous treatment for the disease and
bone marrow may also prevent the development
resultant responses
of normal plasma cells and other important blood
cells. Patients with myeloma are, therefore, more
Response to therapy may fall into one of several
susceptible to infection, anemia, and bleeding
categories. The amount of M protein in the urine
because of lowered platelet counts. Myeloma
and blood are used as markers of response to
patients may also experience renal problems
treatment. Response to treatment and survival
because excessive calcium and M protein prevent
are often better in patients < 60 years of age.
the kidneys from properly filtering and cleaning the
blood.
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Response Category
Description
Response Criteria1
Complete
Absence of the original M protein in serum and urine
Responsive Disease
Decrease in M protein of at
Response (CR)
by immunofixation, maintained for a minimum of
least 50%
6 weeks; < 5% plasma cells in a bone marrow
aspirate and also on trephine bone biopsy, if biopsy
is performed; no increase in the size or number of
Plateau
Response that has reached
lytic bone lesions, and disappearance of soft tissue
a certain point and does
plasmacytomas. Development of a compression
fracture does not exclude response.
not change
Very Good Partial
>90% reduction in the level of M protein, maintained
Stable Disease
Decrease in M protein that
Response (VGPR)
for a minimum of 6 weeks; urine M protein absent
by immunofixation, maintained for a minimum of 6
has not reached 50%, but
weeks; <5% plasma cells in a bone marrow aspirate
remains stable during
and also on trephine blue biopsy, if biopsy is
performed; no increase in the size or number of lytic
therapy or after therapy is
bone lesions, and disappearance of soft tissue
plasmacytomas. Development of a compression
stopped
fracture does not exclude response.
Progressive Disease
Myeloma continues to
Partial Response
>50% reduction in the level of serum M protein,
(PR)
maintained for a minimum of 6 weeks; reduction in
worsen despite therapy
24h urinary light chain excretion by either >90% or
to <200 mg, maintained for a minimum of 6 weeks;
Relapsed Disease
Myeloma initially responded
>50% reduction in the size of soft tissue
plasmacytomas; and no increase in size or number
to treatment, but has begun
of lytic bone lesions.
to progress again
Minimal Response 25-49% reduction in the level of serum M protein
(MR)
maintained for a minimum of 6 weeks; 50-89%
Refractory Disease
Myeloma that has not
reduction in 24h urinary excretion (if still greater
responded to therapy or
than 200 mg/24h), maintained for a minimum of
6 weeks; for subjects with non-secretory myeloma
relapsed disease that does
only, 25-49% reduction in plasma cells in a
bone-marrow aspirate and on trephine biopsy, if
not respond to subsequent
biopsy is performed, maintained for a minimum of 6
treatment
weeks; 25-49% reduction in the size of soft tissue
plasmacytomas; and no increase in size or number of
Primary Refractory
Myeloma that does not
lytic bone lesions.
Disease
respond to initial or
No change
Not meeting the criteria of either minimal or greater
subsequent therapy
response or progressive disease.
Plateau
Stable values (within 25% above or below value at
the time response is assessed) maintained for at
least 3 months
Relapse from CR
At least one of the following: confirmed reappearance
Cures have not been documented in patients with
of serum or urinary M protein on immunofixation or
routine electrophoresis; >5% plasma cells on a bone
myeloma. The best outcomes achieved have
marrow aspirate or on trephine bone biopsy;
development of new lytic bone lesions or soft tissue
been molecular complete responses (MCR), i.e.,
plasmacytomas or definite increase in the size of
no evidence of myeloma cells in the bone marrow
residual bone lesions; or development of hypercalcemia
(corrected serum calcium >11.5 mg/dL or 2.8 mmol/L)
using the most sensitive laboratory molecular
not attributable to any other cause.
testing techniques available. The definition of an
Progressive
One or more of the following compared to best
Disease
response: confirmed > 25% increase in the level of
MCR is constantly evolving as technology
serum M protein (must also be an absolute increase
of at least 5 g/L); confirmed >25% increase in the
improves and more sensitive techniques are
24h urinary light chain excretion (must also be an
absolute increase of at least 200 mg/24h); >25%
developed.
increase in plasma cells in a bone marrow aspirate
or on trephine biopsy (must also be an absolute
increase of at least 10%); definite increase in the
size of existing bone lesions or soft tissue
plasmacytomas; development of new bone lesions or
soft tissue plasmacytomas; or development of
hypercalcemia (corrected serum calcium >11.5 mg/dL
or 2.8 mmol/L not attributable to any other cause.
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Patients with primary refractory multiple myeloma
together and administered intravenously as a single
have few satisfactory treatment options.
agent. The first component, DOTMP, attaches to
Response rates to conventional chemotherapy are
bone while the second, 166Ho, is radioactive
traditionally very low, ranging from 0 to 43%, with
holmium. The high energy and long-path length of
complete responses (CRs) rarely observed.2-10
holmium-166 beta particles provide deep penetration
Although there are no large, randomized clinical
and uniform irradiation of disease sites in the
studies directly comparing conventional dose
bone, thereby effectively killing tumor cells while
salvage chemotherapy to stem cell transplantation
potentially reducing the exposure of normal
regimens in primary refractory myeloma, published
organs and tissues to damaging radiation.
clinical data suggest that autologous stem cell
transplantation results in higher response rates
than conventional dose chemotherapy
(8%-10% versus 2%-3%).11-21 This finding
was noted in myeloma patients who had primary
refractory disease.
Emerging Therapies for Myeloma
Despite recent advances, there is no cure for
myeloma. Treatment options for patients with
refractory myeloma include participation in a
clinical trial of new agents which may involve stem
cell transplantation. According to the
Multiple Myeloma Research Foundation
(www.multiplemyeloma.org) and the International
Myeloma Foundation (www.myeloma.org), a
number of new agents and therapies are available
or are in the later stages of clinical development
for the treatment of myeloma.
Skeletal Targeted Radiotherapy
Skeletal Targeted Radiotherapy (also know as STRTM,
166Ho-DOTMP; NeoRx® Corporation) is a bone-seeking
radioactive drug that is under development for
Anterior and posterior gamma camera images of
use with high-dose chemotherapy and peripheral
a multiple myeloma patient 4 hours after injection of
30 mCi tracer dose of 166Ho-DOTMP. Note specific
blood stem cell transplantation (PBSCT) for the
localization of radioactivity to the skeleton.
treatment of secretory multiple myeloma. STRTM
The bladder is also visible, as drug that does not
consists of two components which are bound
localize to the skeleton is excreted in the urine.
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Administered intravenously in the out-patient
Results from a Phase I/II study of 166Ho-DOTMP
setting as a single, short course of therapy, STRTM
showed a CR rate of 23% and a partial response
is designed to be used in combination with
(PR) rate of 45% in patients with primary refractory
high-dose chemotherapy. This regimen produces
disease.22 Median event-free survival in that study
a direct therapeutic effect on tumor sites in the
was 22 months. Analysis of these and other data
bone plus a marrow ablative effect aimed at
indicated that an STRTM dose of 750 mCi/m2
destroying myeloma cells in the bone marrow.
provided optimal patient safety and tumor response.
Because STRTM causes marrow ablation, it can
Among the 10 evaluable patients who received
be used as a preparative regimen for PBSCT.
this dose, not all of whom had primary refractory
166Ho-DOTMP that is not localized in the bone is
disease, disease control (i.e., disease stabilization
rapidly excreted from the kidneys and bladder.
or better) was achieved in 8 patients, complete
response was reported in 4 patients, and the
3-year survival rate was 90%.
In early STRTM clinical trials many patients
experienced bladder problems and a few also
experienced renal problems. Bladder problems
are preventable using a technique called
continuous bladder irrigation (CBI). Renal problems
predominantly occurred in patients who received
the highest doses of STRTM which are no longer
used. A smal number of these patients died of
renal failure. In all current and future STRTM trials
patients will undergo CBI and receive aggressive
intravenous hydration to assist in clearing radiation
from the kidneys and bladder.
Skeletal Targeted Radiotherapy (STRTM, 166Ho-DOTMP)
STRTM is followed by high-dose chemotherapy
with the drug melphalan. Most of the potential
side effects of transplantation are the result of
high-dose chemotherapy. The more common
side effects include nausea, vomiting, fatigue,
diarrhea, mouth sores, skin rash, and hair loss.
Because high-dose chemotherapy destroys
normal blood-producing cells in the bone marrow,
patients are susceptible to infection, anemia, and
bleeding until engraftment of the new stem cells
has occurred. Stem cell transplantation is not
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appropriate for all patients due to the toxicities
Other New Agents
and risks involved. Patients over the age of 65-70
Two new myeloma therapeutic agents, thalidomidea
years, or those with a poor performance status or
and bortezomibb, target unique biochemical pathways.
even minimally impaired kidney function may not be
Thalidomide is an oral immunomodulatory agent
eligible for this type of therapy within a clinical trial.
currently approved by the U.S. Food and Drug
Administration (FDA) for the treatment of leprosy
STRTM is being evaluated in an ongoing, phase III,
(Hansen's disease). It is being studied alone and
multicenter study of 240 patients with primary
in combination with other drugs for the treatment
refractory myeloma. Patients age >18 and <70
of myeloma. Thalidomide may inhibit the growth and
years who are <18 months from the beginning of
survival of myeloma cells by multiple mechanisms.
It may 1) inhibit the growth of new blood vessels
induction therapy to enrollment on study with
(angiogenesis), 2) alter the adhesion of cells to the
adequate pulmonary, cardiac, liver, and renal
bone marrow supporting cells, and 3) stimulate
function as defined in the trial protocol are eligible.
the immune system to attack tumor cells. Common
All patients will receive a tracer dose (30 mCi of
166
side effects of thalidomide include drowsiness/
Ho-DOTMP) to determine skeletal uptake and
somnolence, peripheral neuropathy, dizziness/
determine favorable biodistribution. If uptake is
orthostatic hypotension, and neutropenia. Two other
adequate, patients are randomized to receive
immunomodulatory drugs similar to thalidomide,
either 166Ho-DOTMP (750 mCi/m2) plus
RevlimidTM (formerly RevimidTM, lenalidomide,
200 mg/m2 melphalan followed by PBSCT, or
CC-5013) and ActimidTM (also known as CC-4047)
200 mg/m2 melphalan alone followed by PBSCT.
are also under development for the treatment of
myeloma. Bortezomib is the first of a new class
STRTM as a treatment for cancers involving the
of medicines called proteasome inhibitors. It is
bone is being tested in other forms of cancer
approved by the FDA for the treatment of myeloma
where stem cell transplantation is used as support
patients who have received at least two prior
of high-dose radiation followed by high-dose
therapies and have demonstrated disease
chemotherapy. Such disease may include
progression during the last therapy. Common
leukemias, metastatic bone disease due to breast,
side effects of bortezomib include nausea, fatigue,
prostate, or lung cancers, and primary bone
decreased blood counts, and peripheral
cancers such as Ewing's sarcoma.
neuropathy. Administered intravenously, bortezomib
reversibly blocks proteasome (a key enzyme complex
present in all cells that helps regulate cel growth).
By inhibiting proteasome, bortezomib further
promotes apoptosis (programmed cell death).
Bortezomib is also currently being studied alone
and in combination with other drugs for the
treatment of refractory myeloma as wel as in
previously untreated myeloma.
aThalomid®; Celgene Corporation
bVelcade®; Millennium Pharmaceuticals, Inc.
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Glossary
Allogeneic stem cell transplant: Transplant in which
bone marrow or peripheral blood is taken from a donor
While myeloma remains a serious disease with an
and infused ("donated") to a patient who has received
unmet therapeutic need, the outlook for improved
high-dose chemotherapy or radiation therapy
treatment with increased rates of response, prolonged
Anemia: Decrease in the number of oxygen-carrying red
survival and improved quality of life is encouraging.
blood cells in the blood; associated with tiredness and
weakness
New therapies under development target the bone
Antibody: Protein produced by plasma cells that is
and biochemical abnormalities unique to myeloma
generated in response to a foreign body (antigen); an
cells. As many new treatment regimens remain
antibody is also known as an immunoglobulin
investigational, physicians need to strongly consider
Apoptosis: Natural cell death which occurs in
the life cycle of nearly all cells; in cancerous cells the
clinical trials as viable treatment options for their
signals for cell death are blocked or altered and natural
patients. In counsel with their physicians, patients
cell death does not occur resulting in overgrowth and
longer life of the malignant cell
and their families should also be highly encouraged
to consider participation in clinical trials.
Autologous stem cell transplant: Transplant in which
bone marrow is taken from the patient, stored and
frozen to be infused following high-dose chemotherapy
References
and/or radiation therapy
1. Blade J, et al. Br J Haematol.
12. Rajkumar SV, et al. Bone Mar
Bone marrow: Soft, spongy tissue found in the center
1998; 102:1115-1123.
Trans. 1999;23:1267-1272.
of many bones; area where red blood cells, white blood
cells and platelets are produced; plasma cells arise from
2. Barlogie B, et al. N Engl J Med. 13. Harousseau JL, et al. Blood.
the bone marrow
1984;310:1353-1356.
1995;85:3077-3085.
B-lymphocyte: A specific type of white blood cell that
3. Alexanian R, et al.
14. Vesole DH, et al. Blood.
is found in the blood and lymph nodes that participates
Ann Intern Med. 1986;105:8-11.
1994;84:950-956.
in the body's immune response
4. Browman GP, et al. Br J
15. Vesole DH, et al. J Clin Oncol.
Complete response: Multiple myeloma treatment
Haematol. 1992;82:555-559.
1999;17:2173-2179.
outcome where there is no detectable M protein in the
serum and urine (using an immunofixation assay) and a
5. Giles FJ, et al. Am J
16. Alexanian R, et al. Blood.
normal percentage of plasma cells in the bone marrow
Hematol. 2000;63:125-130.
1994;83:512-516.
or absence of myeloma cells in the bone marrow by
6. Leoni F, et al. Br J Haematol.
17. Alexanian R, et al. Blood.
standard staining techniques
1991;77:180-184.
1994;84:4278-4282.
Continuous bladder irrigation (CBI): A procedure
7. Ganjoo RK, et al. Canc Chemo
18. Jagganath S, et al. Blood.
where a catheter is inserted into the bladder allowing for
Pharmacol. 1995;35:343-344.
1990;76:1860-1866.
continuous flushing of the bladder with fluid; CBI allows
for rapid clearance of toxins that may build up in the
8. Colombi M, et al. Leuk
19. Alegre A, et al. Bone Mar Trans.
bladder following certain types of radiation therapy or
Lymphoma. 2000;40:87-94.
1998;21:133-140.
chemotherapy
9. Ohrling M, et al. Eur J
20. Shimoni A, et al. Bone Mar
Cytokine: Soluble chemical produced by cells that has
Haematol. 1993;51:45-49.
Trans. 2001;27:821-828.
an effect on other cells
10. Leoni F, et al. Leuk
21. Giralt S, et al. Blood.
Hematologic: Pertaining to the blood
Lymphoma. 1992;7:481-487.
2003;102:2684-2691.
High-dose chemotherapy: Administration of higher,
11. Dimopoulos MA, et al. Blood.
22. Bensinger W, et al. Blood. 2003;
more effective doses of chemotherapy; because
1993;82:2324-2328.
102(11). Abstract 3664.
high-dose chemotherapy destroys the bone marrow,
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a stem cell transplant is required to replenish blood-
Myeloma cell: A plasma cell that has become
forming bone marrow cells
cancerous or malignant; the abnormal cell responsible
for multiple myeloma; excessive numbers of identical
Hypercalcemia: Condition characterized by elevated
myeloma cells producing an overabundance of
levels of calcium in the blood due to increased bone
immunoglobulins (M protein) are responsible for
destruction
symptoms characteristic of multiple myeloma
Immune Response: A bodily defense reaction to
Peripheral neuropathy: Abnormal or decreased
invasion by a foreign body or pathogen such as a virus,
sensation or burning/tingling in the hands and feet;
bacteria or tumor cell; the immune system produces
peripheral neuropathy may or may not resolve following
antibodies in an attempt to destroy or fight the foreign
the end of chemotherapy for myeloma
invader
Plasma cell: Antibody-secreting immune cell that
Immunoglobulins: Produced by plasma cells, antibodies
develops from a B-cell
generate a response to a foreign protein (antigen), thus
producing an immunity against that protein;
Plasmacytoma: Single tumor comprised of malignant
immunoglobulins are made up of 2 heavy chains and
plasma cells that occurs in bone or soft tissue; some
2 light chains that form a "Y"-like structure and can be
patients may also develop secretory myeloma
of the IgA, IgD, IgE, IgG, or IgM class
Proteasome: A complex of enzymes found within cel s
Lymphatic system: A system of soft tissues and
that play a key role in the regulation of cell function and
vessels similar to blood vessels located throughout the
growth; proteasomes break down and clear out proteins
body which contain and circulate lymphocytes, a
after they have done their job and are no longer needed;
specific type of white blood cell that defends the body
some cancer cells appear to be particularly dependent
against toxins and pathogens such as bacteria or
on proteasomes to grow, survive and undergo
viruses
programmed cell death (apoptosis); if proteasome
activity is blocked, tumor cells may undergo apoptosis
Melphalan: (also known as Alkeran®) Type of
as a mechanism of the drug's action
chemotherapy often used in the treatment of myeloma;
belongs to a class of drugs cal ed alkylating agents; at
Proteasome inhibitor: A new class of medicines that
standard doses does not require stem cell
reversibly blocks proteasome and promotes apoptosis
transplantation; melphalan is typically given as an oral
in cancer cells
drug; in the transplantation setting, melphalan is
Primary refractory myeloma: Myeloma that does not
administered intravenously
respond to initial or subsequent therapy
Metastasis: Process by which tumor cells travel from
Refractory myeloma: Myeloma that has not responded
the initial or primary site (e.g., breast, prostate, lung) to
to initial therapy, as well as relapsed myeloma that does
other parts of the body (e.g., bone, liver, lung, brain)
not respond to subsequent treatment
and develop into tumors; metastases can also occur
when tumor cells spread from the initial site to nearby,
Secretory myeloma: The more common form of
adjacent tissues
multiple myeloma that typically involves desease in the
bone and bone marrow, circulation of myeloma cells in
Molecular complete response: No evidence of
the body, and the presence of M protein in the urine
myeloma cells in the bone marrow using sensitive
molecular techniques in laboratory testing
Stem cells: Parent cells that grow and divide to
produce red blood cells, white blood cells, and
Monoclonal (M) protein: Identical immunoglobulin
platelets; found primarily in the bone marrow but also
(antibody) protein produced by myeloma cells;
found in the peripheral blood or venous system
M protein is found in the blood or urine and is used as a
marker for the amount of myeloma disease present in
Skeletal Targeted Radiotherapy: (also known as
the body
STRTM, or 166Ho-DOTMP) An investigational bone-
seeking radioactive drug under development with
Multiple myeloma: An uncommon blood-borne cancer
high-dose chemotherapy and stem cell transplantation
which originates in the bone marrow and is associated
for the treatment of myeloma; STRTM consists of two
with the excessive production of abnormal or malignant
components: DOTMP which targets and attaches to
plasma cells (myeloma cells)
bone and radioactive holmium, 166Ho, which can
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destroy cancer cells; the goal of STRTM is to target
radiation to the bone and bone marrow; by attempting
to target therapeutic radiation to the bone, STRTM may
reduce radiation exposure to other normal organs and
tissues
TTP/HUS: Thrombocytopenic thrombotic purpura/
hemolytic uremia syndrome is a rare syndrome
associated with radiation damage to the kidneys; findings
include abnormal blood clotting in small vessels, low
platelet counts leading to bleeding, and kidney failure
which may require dialysis and can result in death
Venous system: Part of the circulatory system which
carries blood throughout the body; the venous system
consist of veins which carry blood away from muscles
and organs and back to the heart and lungs
Resources for Myeloma
1. American Cancer Society®
www.cancer.org
All About Multiple Myeloma
2. International Myeloma Foundation
www.myeloma.org
3. Multiple Myeloma Research Foundation
www.multiplemyeloma.org
4. National Cancer Institute®
www.cancer.gov
Cancer Information Service 1-800-4-CANCER
What You Need to Know AboutTM Multiple Myeloma
Taking Part in Clinical Trials: What Cancer
Patients Need to Know
5. The Leukemia and Lymphoma Society®
www.leukemia-lymphoma.org
Patient Services: Multiple Myeloma
#1, #4, #5 are registered trademarks of their
respective organizations.
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