Multiple Myeloma

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Multiple Myeloma

• Cynthia Lan, MD
• Feb. 14, 2006

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Introduction

• Multiple myeloma is a disease of neoplastic B
  lymphocytes that mature into plasma cells which
  make abnormal amounts of immunoglobulin (Ig).
• Clinical manifestations are heterogeneous and
  include tumor formation, monoclonal Ig
  production, decreased Ig secretion by normal
  plasma cells leading to hypogammaglobulinemia,
  impaired hematopoiesis, osteolytic bone disease,
  hypercalcemia, and renal dysfunction.
• Symptoms are caused by tumor mass effects, by
  cytokines released directly by tumor cells or
  indirectly by marrow stroma and bone cells in
  response to adhesion or tumor cells and by the
  myeloma protein.
• The median length of survival after diagnosis is
  about three years.

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History

• The earliest evidence of myeloma had been found
  in the Egyptian mummies, but the first published
  clinical description was reported in 1850 in
  England.
• Thomas Alexander McBean (the patient) presented
  to Dr. William Macintyre of London in 1845 with
  episodes of fatigue, diffuse bone pain and
  urinary frequency.
• In 1843, Mr. McBean, 44 years of age and a
  highly respectable grocer of temperate habits
  and exemplary conduct experienced easy fatigue
  and was noted to stoop when walking.
• He complained of frequent calls to make water
  and noted that his body linen was stiffened by
  his urine although there was no urethral
  discharge.
• He took a vacation in the country in Sept 1844 to
  regain his strength, but while vaulting out of an
  underground cavern, he suddenly felt as if
  something had snapped or given way within the
  chest. Dr Macintyre subsequently applied a
  strengthening plaster to the chest because
  movement of the arms produced chest pain.

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• In the spring of 1845, Mr McBean saw Dr Watson
  for wasting, loss of colour, and puffiness of
  the face and ankles, who prescribed a course of
  steel and quinine. He improved rapidly and by
  mid-summer traveled to Scotland.
• In October 1845, he developed severe lumbar
  sciatic pain.
• Warm baths, Dovers powder, acetate of ammonia,
  camphor julap and compound tincture of camphor
  were prescribed, but did not help. (Dovers
  powder A powdered drug containing ipecac and
  opium, used to relieve pain and induce
  perspiration)
• Dr. Macintyre saw him on Oct 30 1845 and
  examined his urine. The urinalysis test results
  detected a urinary protein with the heat
  properties often observed for urinary light
  chains, and Macintyre called the disorder
  mollities and fragilitas ossium based on the
  patients bony symptoms.
• Later that year, Dr. Henry Bence Jones also
  tested urine specimens provided by Macintyre and
  corroborated the heat properties of urinary light
  chains. Bence Jones thought the protein was the
  hydrated deuteroxide of albumin (now called
  Bence Jones proteins) and published his findings
  several years before Macintyre published his case
  report.

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• When the patient died in 1846, autopsy revealed
  that the ribs crumbled under the heel of the
  scalpel. They were so soft and so brittle that
  they could be easily cut by the knife, and
  readily broken. The interior of the ribs was
  filled with a soft gelatiniform substance of a
  blood-red colour and unctuous feel.
• A surgeon, Dr. John Dalrymple, examined several
  bones and made gross and microscopic
  observations. His drawings are consistent with
  the morphology of myeloma cells.

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• The term multiple myeloma was coined by J.von
  Rustiz in 1873 after his independent observation
  in a similar patient with multiple bone lesions.
• Professor Otto Kahler in 1889 published a review
  on this condition, and the disease became known,
  especially in Europe, as Kahlers disease.
• Ellinger, in 1899, described the increased serum
  proteins and sedimentation rate in myeloma.
• In 1900, Wright described the involvement of
  plasma cells, countering the original belief that
  MM originated from the red marrow. For the first
  time, he described the x-ray abnormality in
  myeloma, which to date remains one of the
  diagnostic tests.
• The development of BM aspiration (1929),
  electrophoresis to separate proteins (1937), and
  a later report of a specific spike in the gamma
  globulin region enhanced the diagnosis and
  understanding of myeloma.

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• No effective systemic therapy existed before
  1947, when urethan was reported to show an effect
  in a few patients. But a subsequent randomized
  trial showed that the survival of patients
  receiving urethan was inferior to that observed
  with placebo.
• The first successful chemotherapy for MM was
  reported in 1958 with the use of D and
  L-phenylalanine mustards. The L-isomer of
  phenylalanine mustard was later found to have the
  antimyeloma activity, and it was called melphalan.

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Etiology and epidemiology

• The cause of MM is not known. There is
  speculation that radiation may play a role in
  some patients an increased risk of MM has been
  reported in atomic bomb survivors exposed to more
  than 50 Gy, as well as in radiologists exposed to
  relatively large doses of long-term radiation.
• Increased risk has been reported in farmers,
  especially in those who use herbicides and
  insecticides, woodworkers and furniture
  manufacturers (presumably from exposure to
  chemical resins), paper producers, and in people
  exposed to certain organic solvents. However, the
  number of cases is small with each of these risk
  factors, and the data for chemical exposure is
  not convincing
• MM has also been reported in familial clusters of
  two or more first degree relatives and in
  identical twins, suggesting a genetic factor.

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• Multiple myeloma accounts for approximately 1
  percent of all malignant disease and about 10
  percent of hematologic malignancies in the United
  States.
• It is the second most common hematologic cancer
  after non-Hodgkin's lymphoma and more than 50,000
  patients in the United States alone have the
  disease.
• The annual incidence of multiple myeloma is
  approximately 4 per 100,000.
• MM occurs in all races and all geographic areas,
  although rates are lower in Asian populations.
• The incidence among African Americans is twice
  that of white Americans, is higher in Pacific
  islanders, and is slightly more frequent in men
  than in women.
• The median age at diagnosis is 60 years, and
  while in the past only 18 and 3 of patients
  were younger than 50 and 40 years, respectively,
  the percentages among younger patients appear to
  be increasing.
• The median length of survival after diagnosis is
  approximately 3 years.

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Pathophysiology

• The first pathogenetic step in the development of
  myeloma is the emergence of a limited number of
  clonal plasma cells, clinically known as
  monoclonal gammopathy of unknown significance
  (MGUS).
• Pts with MGUS do not have symptoms or evidence of
  end-organ damage, but they do have an annual risk
  of 1 of progression to myeloma or a related
  malignant disease.
• About 50 of pts have translocations that involve
  the immunoglobulin heavy-chain locus on
  chromosome 14q32 and one of 5 partner
  chromosomes, 11q13 being the most common.
• Complex genetic events occur in the neoplastic
  plasma cell causing MGUS to progress to MM.
• Changes also occur in the bone marrow, including
  the induction of angiogenesis, the suppression of
  cell-mediated immunity and the development of
  paracrine signaling loops involving cytokines
  such as interluekin-6 and vascular endothelial
  growth factor.
• The development of bone lesions in MM is thought
  to be related to an increase in the expression by
  osteoblasts of the receptor activator of nuclear
  factor kappa B ligand and a reduction in the
  level of its decoy receptor, osteoprotegerin.

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Mechanisms of Disease Progression in the
Monoclonal Gammopathies
Kyle, R. A. et al. N Engl J Med 20043511860-1873
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Clinical Manifestations

• The most common symptoms on presentation are
  fatigue, bone pain, and recurrent infections.
• Bone pain, especially in the back or chest, and
  less often in the extremities, is present at the
  time of diagnosis in about 65 percent of
  patients. The pain is usually induced by movement
  and does not occur at night except with change of
  position. The patient's height may be reduced by
  several inches because of vertebral collapse.
• Weakness and fatigue are common (50 percent) and
  often associated with anemia (65).
• Weight loss is present in 24 percent of patients,
  half of whom have a weight loss of more than 9 kg
  (20 lbs). Patients may have symptoms related to
  complications of myeloma, such as hypercalcemia,
  renal insufficiency, or amyloidosis.

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• Anemia affects more than 2/3 of patients with
  myeloma.
• Thrombocytopenia is not usually present.
• Hyperviscosity occurs in less than 10 of
  patients. Symptoms of hyperviscosity result from
  circulatory problems leading to cerebral,
  pulmonary, renal and other organ dysfunction.
  (e.g headache, visual blurring, mental status
  changes, ataxia, vertigo, stroke). Hyperviscosity
  often is associated with bleeding.
• Bleeding has been reported in 15 of patients
  with IgG myeloma and in more than 30 of pts with
  IgA myeloma.

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Physical Exam

• Pallor is the most frequent physical finding. The
  liver is enlarged in about 15 of patients, but
  splenomegaly is rare. Extramedullary
  plasmacytomas are uncommon and are usually
  observed late in the course of the disease as
  large, purplish, subcutaneous masses, but they
  may occur in other tissues, including the lung
  and gastrointestinal tract.

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Neurologic disease

• Radiculopathy, usually in the thoracic or
  lumbosacral area, is the most common neurologic
  complication of multiple myeloma. It can result
  from compression of the nerve by a paravertebral
  plasmacytoma or rarely by the collapsed bone
  itself.
• Cord compression Spinal cord compression from an
  extramedullary plasmacytoma or a bone fragment
  due to fracture of a vertebral body occurs in 5
  percent of patients it should be suspected in
  patients presenting with severe back pain along
  with weakness or paresthesias of the lower
  extremities, or bladder or bowel dysfunction or
  incontinence. This is a medical emergency MRI or
  CT myelography of the entire spine must be done
  immediately, with appropriate follow-up treatment
  by chemotherapy, radiotherapy, or neurosurgery to
  avoid permanent paraplegia.
• Peripheral neuropathy Peripheral neuropathy is
  uncommon in multiple myeloma and, when present,
  is usually due to amyloidosis.

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Other systemic complications

• Infections are increased in MM Streptococcus
  pneumoniae and gram-negative organisms are the
  most frequent pathogens. Pts with MM are more
  prone to infections due to impairment of antibody
  response, reduction of normal immunoglobulins,
  neutropenia, and treatment with glucocorticoids,
  particularly when high doses of dexamethasone are
  used.
• There is an increased tendency for thrombosis,
  which may lead to deep vein thrombosis and
  pulmonary embolism in about 5 of patients, and
  treatment of MM, including steroids and
  thalidomide, can increase this risk to between
  10 to 15.
• Plasmacytomas of the ribs have been reported in
  12 of cases and may present either as expanding
  costal lesions or as soft tissue masses.

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Diagnosis

• The diagnosis of even symptomatic MM often is
  delayed by months.
• Pts may have complaints of persistent back pain
  following minor trauma or of recurrent
  infections. Such c/o in the setting of
  unexplained hyperproteinemia or proteinuria,
  anemia, renal insufficiency, hypoalbuminemia,
  dysproteinemia or marked elevation of ESR should
  prompt laboratory evaluation for plasma cell
  myeloma.
• The initial evaluation includes a CBC, chemistry
  (creatinine, calcium, albumin, uric acid, LDH),
  B2-microglobulin, CRP, complete skeletal x-ray
  survey, serum and urine protein electrophoresis
  and immunofixation, quantitative Ig G levels,
  urinary protein excretion in 24 hours, and bone
  marrow aspiration and biopsy.

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Serum protein electrophoresis Monoclonal pattern
of serum protein from densitometer tracing after
electrophoresis of serum on cellulose acetate
(anode on left) tall, narrow-based peak of ?
mobility dense, localized band representing
monoclonal protein in ? area. B, Polyclonal
pattern of serum protein from densitometer
tracing after electrophoresis on cellulose
acetate (anode on left) broad-based peak of ?
mobility ? band is broad.

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Distribution of serum monoclonal protein,
according to immunoglobulin type, in 984 patients
with multiple myeloma at the Mayo Clinic,
19821994.
23
Plasma cells in bone marrow of patient with
multiple myeloma. (From Kyle RA Multiple
myeloma, macroglobulinemia, and the monoclonal
gammopathies. In Bone R ed Current Practice of
Medicine, Vol 3. Philadelphia, Current Medicine,
1996, p. 19.1.)
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Imaging studies

• X-rays of the long bones, skull and ribs can
  reveal osteolytic lesions.
• Detectable osteolytic lesions require at least
  30 loss of bone mass and thus represent an end
  state of bone destruction.
• MRI of axial marrow including head, spine,
  pelvis, shoulders and sternum detects
  intramedullary focal disease in 60-70 of
  patients at diagnosis, long before the onset of
  bone destruction.
• Fluorodeoxyglucose (FDG)-PET whole body scanning
  can be helpful when performed in the context of
  CT scanning. Its usefulness is being investigated
  for predicting response and survival by early
  therapy-induced FDG suppression.
• Bone scan (DEXA) should be done annually and can
  assess for the need for bisphosphonate use.

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Punched out lesions in the bones
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This lateral view of the lumbar spine shows
deformity of the L4 vertebral body resulting from
a plasmacytoma.
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Criteria for diagnosis of Multiple Myeloma (from
the International Myeloma Working Group)

• Major Criteria
• Plasmacytomas on tissue biopsy
• Marrow plasmacytosis with gt30 plasma cells
• Monoclonal globulin spike on serum
  electrophoresis gt3.5 g/dl for IgG or gt2.0 g/dl
  for IgA 1.0 g/24 h of kappa or lambda light
  chain excretion on urine electrophoresis in the
  absence of amyloidosis
• Minor Criteria
• Marrow plasmacytosis 10-30
• Monoclonal globulin spike present but less than
  the levels defined above
• Lytic bone lesions
• Normal IgM lt0.05 g/dl, IgA lt0.1 g/dl, or IgGlt0.6
  g/dl
• M-protein in serum and/or urine
• Marrow (clonal) plasma cells or plasmacytoma
• Related Organ or Tissue Impairment
• The diagnosis of MM is cofirmed when at least one
  major and one minor criterion or at least three
  minor criteria are documented in symptomatic
  patients with progressive disease.

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Differential diagnosis

• Differential diagnosis includes MGUS, smoldering
  MM, primary amyloidosis and metastatic carcinoma.
• MGUS is characterized by
• M-protein lt 3g/dL
• lt10 plasma cells in the bone marrow
• Lack of symptoms
• Normal blood counts and renal function
• Absence of lytic lesions and evidence of
  end-organ involvement
• About 1 of patients per year will experience
  progression to typical multiple myeloma.

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• Smoldering MM is characterized by
• M-protein gt 3g/dL and/or greater than 10 plasma
  cells in the bone marrow.
• Lack of symptoms
• Absence of lytic lesions and evidence of
  end-organ involvement.
• About 3 of patients/year will progress to
  typical multiple myeloma.
• Factors predicting progression include gt10
  plasma cells in the bone marrow, detectable
  Bence-Jones proteinuria, and IgA subtype.

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• Primary Amyloidosis is a clonal expansion of
  plasma cells resulting in the overproduction of
  monoclonal light chains.
• The diagnosis of AL amyloid often can be made by
  fine needle aspiration of subcutaneous fat or by
  biopsy of the rectal mucosa, although it is
  recommended to biopsy the clinically involved
  tissue.
• Staining the tissue with Congo red may reveal
  perivascular amyloid with its classic apple-green
  birefringence when viewed under polarized light.
• AL amyloid can also be detected on marrow biopsy.
• Should be suspected in pts with macroglossia or
  racoons eyes (from periorbital subcutaneous
  hemorrhages b/c of vascular fragility), carpal
  tunnel syndrome, nephrosis, or cardiomegaly
  associated with arrhythmias or low-voltage and
  conduction defects on electrocardiogram.
• Endomyocardial biopsy may establish the
  diagnosis.

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• Metastatic Carcinoma
• Many malignant processes can produce lytic
  lesions and plasmacytosis.
• In the absence of significant M-protein in the
  blood or urine, the diagnosis of metastatic
  carcinoma must be excluded before the diagnosis
  of MM is made.

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Staging The Durie-Salmon staging system has been
in use for the past 30 years. (Cell mass is
estimated by studies measuring in vitro Ig
production by myeloma cells).
36

• However, the system does not correlate well with
  prognosis because the majority of patients are
  stage III at diagnosis. Other prognostic factors
  have shown better predictive value, including
  beta-2 microglobulin (small protein noncovalently
  linked with class I human leukocyte antigen
  molecules), LDH, and the presence or absence of
  chromosome 13 abnormalities.
• Currently there is an International Staging
  System (ISS) based on serum beta 2 microglobulin
  (B2M, mg/L) and serum albumin (g/dL)
• Stage 1 B2M lt 3.5 Alb gt or 3.5
• Stage 2 B2M lt 3.5 Alb lt3.5 or B2M
  3.5-5.5
• Stage 3 B2M gt5.5

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Treatment

• For 50 years, the oral alkylating agent melphalan
  (L-phenylalanine mustard Alkeran), ionizing
  radiation, and corticosteroids were the
  cornerstones of treatment for myeloma.
• Their use can relieve symptoms and cause
  regression of the disease but has not produced
  improved survival beyond the median of three
  years.
• Melphalan and radiation are toxic to bone marrow
  and increase the risk of leukemia because they
  can trigger genetic damage in stem cells.

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Treatment

• Not all patients who fulfill the minimal criteria
  for the diagnosis of MM should be treated.
• SMM or asymptomatic stage I MM often remains
  stable over many years, and has not been shown to
  prolong survival or to prevent progression in
  presymptomatic disease therapy.
• Options include conventional chemo, high dose
  corticosteroids, dose intensive chemotherapy with
  autologous hematopoietic cell rescue, allogeneic
  stem cell transplantation, as well as newer
  therapies such as thalidomide or its analogs or
  the proteosome inhibitor bortezomib.
• Bisphosphonate treatments can prevent or slow
  bone destruction.
• No modality with the possible exception of
  allogeneic stem cell transplantation is curative
  in multiple myeloma.
• However, event-free survival and overall
  survival is improved by approx one year after
  autologous hematopoietic stem cell
  transplantation compared to conventional chemo.

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• All patients younger than 60 years should be
  considered for high-dose chemo with autologous
  stem cell transplantation.
• The most convincing data regarding survival
  advantage for transplantation is in patients
  younger than 55-60, with somewhat conflicting
  evidence in the 60-70 year age group.
• In symptomatic patients older than 70 and in
  younger patients who are not candidates for
  transplantation, alkylating agents such as oral
  melphalan remains the standard.

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Induction therapy in patients eligible for
autologous stem-cell transplantation

• Pts eligible for autologous stem-cell
  transplantation are first treated with a regimen
  that is not toxic to hematopoietic stem cells.
  (Use of alkylating agents is best avoided.)
• Vincristine, doxorubicin and dexamethasone for
  3-4 months is often used as induction therapy an
  alternative is oral thalidomide plus oral
  dexamethasone. However, DVT was an unexpected
  adverse event in 12 of pts in a trial with oral
  thalidomide dexamethasone.
• In a separate trial of oral thalidomide
  dexamethasone, use of prophylactic
  anticoagulation with warfarin or LMWH
  (therapeutic doses) prevented DVTs. (Weber, et
  al. J Clin Oncol 20032116-9)

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Induction therapy in pts not eligible for
transplantation

• Pts who are not eligible for transplantation
  because of age, poor physical condition, or
  coexisting conditions receive standard therapy
  with alkylating agents.
• The oral regimen of melphalan prednisone is
  preferable to minimize side effects, unless there
  is a need for a rapid response, such as in pts
  with large, painful lytic lesions or with
  worsening renal function. Other regimens which
  can be used include vincristine, doxorubicin
  dexamethasone, dexamethasone alone, or
  thalidomide dexamethasone.

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Autologous stem-cell transplantation

• Although not curative, autologous stem-cell
  transplantation improves the likelihood of a
  complete response, and prolongs disease-free
  survival and overall survival.
• Mortality rate is 1-2, and about 50 of pts can
  be treated entirely as outpatients.
• Whether or not a complete response is achieved is
  an important predictor of the eventual outcome.
• Melphalan is the most widely used preparative
  regimen.
• Data are limited on the effectiveness of
  autologous stem-cell transplantation in pts gt65
  years and those with end-state renal disease.

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Tandem Transplantation

• In tandem (double) autologous stem-cell
  transplantation, pts undergo a second planned
  autologous stem-cell transplantation after they
  have recovered from the first.
• In a recent randomized trial in France,
  event-free survival and overall survival were
  significantly better among recipients of tandem
  transplantation than among those who underwent a
  single autologous stem-cell transplantation.

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Single vs double autologous stem-cell
transplantation for multiple myeloma (Attal, et
al. NEJM 34926. Dec 25, 2003)

• Randomized trial of the treatment of MM with
  high-dose chemo followed by either one or two
  successive autologous stem-cell transplants.
• 399 previously untreated patients under the age
  of 60 years were randomly assigned to receive a
  single or double transplant.
• Exclusion criteria were prior treatment for
  myeloma, another cancer, abnormal cardiac
  function, chronic respiratory disease, abnormal
  liver function, and psychiatric disease.
• Patients randomized to the single transplant
  group received melphalan (140 mg/m2) and
  total-body irradiation (8 Gy delivered in four
  fractions over a period of 4 days). Patients in
  the double transplant group received the first
  transplant after melphalan alone (140 mg/m2)
  melphalan and the same dose of total body
  irradiation that the single-transplant group
  received were given before the second
  transplantation.
• Results a complete or a very good partial
  response was achieved by 42 of pts in the single
  transplant group and 50 of pts in the double
  transplant group (p0.10). The probability of
  surviving event-free for 7 years after the
  diagnosis was 10 in the single-transplant group
  and 20 in the double transplant group (p0.03).

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• The estimated overall 7 year survival rate was 21
  in the single-transplant group and 42 in the
  double-transplant group (p0.01).
• Among pts who did not have a very good partial
  response within 3 months after one
  transplantation, the probability of surviving 7
  years was 11 in the single-transplant group and
  43 in the double-transplant group.
• Four factors were significantly related to
  survival base-line serum levels of beta 2
  microglobulin, LDH, age, and treatment group.
• Conclusions as compared with a single autologous
  stem-cell transplantation after high-dose chemo,
  double transplantation improves overall survival
  among patients with myeloma, especially in those
  who do not have a very good partial response
  after undergoing one transplantation.

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Tandem transplantation (cont)

• However, preliminary data from 3 other randomized
  trials showed no convincing improvement in
  overall survival among pts receiving tandem
  transplantation, although the follow-up was too
  short for definitive conclusions to be drawn.
• Thus, on the basis of the results of the French
  trial, it is reasonable to consider tandem
  transplantation for pts who do not have at least
  a very good partial response (defined as a
  reduction of 90 or more in monoclonal protein
  levels) with the first transplantation.

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Allogeneic transplantation

• The advantage of allogeneic transplantation is a
  graft that is not contaminated with tumor cells.
• But only 5-10 of pts are candidates for
  allogeneic transplantation when age, availability
  of an HLA-matched sibling donor, and adequate
  organ function are considered.
• Also the high rate of treatment-related death has
  made conventional allogeneic transplantation
  unacceptable for most pts with MM.
• Several recent trials have used nonmyeloablative
  (reduced intensity) conditioning regimens (also
  known as mini allogeneic transplantation).
• The greatest benefit has been reported in pts
  with newly diagnosed disease who have first
  undergone autologous stem-cell transplantation to
  reduce the tumor burden and afterward undergone
  mini-allogeneic (nonmyeloablative)
  transplantation of stem cells from an
  HLA-identical sibling donor.
• The rate of treatment-related deaths was 15-20
  with this strategy.

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Allogenic transplantation (cont)

• There is also a high risk of both acute and
  chronic graft-vs-host disease.
• Preliminary results from a French trial indicated
  that in pts with high-risk myeloma (those with a
  deletion of chromosome 13 plus high levels of
  beta-2 microglobulin), the overall survival with
  this approach may not be superior to that with
  tandem autologous stem-cell transplantation.
• Currently, the use of autologous stem-cell
  transplantation followed by mini-allogeneic
  transplantation remains investigational and is
  best performed as part of a clinical trial.

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Therapy for relapsed and refractory multiple
myeloma

• Almost all pts with MM have a risk of eventual
  relapse.
• If relapse happens more than 6 months after
  conventional therapy is stopped, the initial
  chemotherapy regimen should be reinstituted.
• The highest response rates in relapsed MM have
  been with the use of iv vincristine, doxorubicin,
  and dexamethasone. Dexamethasone alone is also
  effective.
• In the past 5 years, major advances have been
  made with the use of thalidomide and the arrival
  of novel approaches such as bortezomib.

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Thalidomide

• Thalidomide was used as a sedative in the 1950s
  and was withdrawn from the market after initial
  reports of teratogenicity in 1961.
• Subsequently, the efficacy of thalidomide in
  erythema nodosum leprosum, Behcets syndrome, the
  wasting and oral ulcers associated with HIV
  syndrome and graft-versus-host disease permitted
  it use in clinical trails and for compassionate
  use.
• Thalidomides efficacy in advanced and refractory
  myeloma was first reported in 1999 in a trial at
  the University of Arkansas.
• Since then, several studies have confirmed the
  activity of thalidomide in relapsed myeloma, with
  response rates from 25-35.
• Currently, thalidomide alone or in combination
  with corticosteroids is considered standard
  therapy for relapsed and refractory MM.
• However, peripheral neuropathy is a major side
  effect that affects 50-80 of pts and often
  necessitates the discontinuation of the therapy
  or a dose reduction.
• Other side effects include sedation, fatigue,
  constipation, or rash, but are usually responsive
  to dose reduction.

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Bortezomib

• Bortezomib (Velcade), a proteasome inhibitor
  which represents a new class of agents.
• Was granted accelerate approval by the FDA for
  the treatment of advanced MM in May 2003.
• A recent phase 3 trial involving 670 pts and
  comparing bortezomib with pulsed dexamethasone
  therapy was closed early b/c of a longer time to
  disease progression in pts receiving bortezomib.
• Most common adverse effects of bortezomib are GI
  symptoms, cytopenia, fatigue, and peripheral
  neuropathy.

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Bortezomid or High-Dose Dexamethasone for
Relapsed MM (Richardson, et al. NEJM
352242487-98, June 16, 2005)

• Bortezomib (Velcade) is a proteasome inhibitor
  that induces apoptosis, reverses drug resistance
  of multiple myeloma cells, and affects their
  microenvironment by blocking cytokine circuits,
  cell adhesion and angiogenesis in vivo.
• APEX trial (Assessment of proteasome inhibition
  for extending remissions)
• Eligible patients had measurable progressive
  disease after 1-3 previous treatments. Patients
  were excluded if they had previously received
  bortezomib or had disease that was refractory to
  high dose dexamethasone, had at least grade 2
  peripheral neuropathy (paresthesias and/or loss
  of reflexes interfering with function, but not
  with activities of daily living), or had any
  clinically significant coexisting illness
  unrelated to myeloma.
• Randomized (11), open-label, phase 3 study.
• 669 pts were randomized to iv bolus of bortezomib
  for eight 3-week cycles, followed by three 5-week
  cycles, or high dose dexamethasone (40 mg) for
  four 5-week cycles. Pts assigned to the
  dexamethasone group were permitted to cross over
  to receive bortezomib in a companion study after
  disease progression.

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• Results pts treated with bortezomib had higher
  response rates, a longer time to progression, and
  a longer survival than patients treated with
  dexamethasone.
• Combined complete and partial response rates were
  38 for bortezomib and 18 for dexamethasone
  (P0.001), and the complete response rates were
  6 (bortezomib) and less than 1 (dexamethasone)
  (P0.001). (Complete responseabsence of
  monoclonal immunoglobulin M protein in serum and
  urine, and partial responsereduction of M
  protein in serum of at least 50 and reduction in
  urine of 90.)
• Median times to progression were 6.22 months in
  the bortezomib and 3.49 months in the
  dexamethasone group (Plt0.001).
• The one year survival rate was 80 among patients
  taking bortezomib and 66 among patients taking
  dexamethasone (P0.003).
• Grade 3 or 4 events were reported in 75 of
  patients treated with bortezomib and in 60 of
  those treated with dexamethasone. The most common
  grade 3 or 4 adverse events were
  thrombocytopenia, anemia and neutropenia in pts
  receiving bortezomib and anemia in pts receiving
  dexamethasone.
• Conclusion bortezomib is superior to high-dose
  dexamethasone for the treatment of patients with
  MM who have had a relapse after one to three
  previous therapies.

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CC-5013 (Revlimid)

• CC-5013 is an immunomodulatory agent that is an
  aminosubstituted variant of thalidomide.
• It induces apoptosis and decreases the binding of
  myeloma cells to stromal cells in bone marrow.
• It also inhibits angiogenesis and promotes
  cytotoxicity mediated by natural killer cells.
• It exhibits almost no sedative effects and only
  occasionally exhibits neurotoxic side effects.
• Responses have been reported in one third of
  patients with advanced or refractory MM in phase
  2 trials.
• Trials conducted for approval by the FDA are
  currently underway.

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Treatment of complications of MM

• Myeloma bone disease do bisphosphonates have a
  role in the treatment of MM?
• Systematic review and meta-analysis which
  included data from 11 trials with 2183 pts on the
  role of bisphosphonates in MM. (Kumar A. et al.
  Management of multiple myeloma a systematic
  review and critical appraisal of published
  studies. The Lancet Oncology Vol 4 May 2003)
• Their conclusion was that bisphosphonates have no
  effect on survival but do decrease the
  probability of vertebral fractures and improve
  bone pain. Most data involve pamidronate and
  clodronate.

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Treatment of Complications in Multiple Myeloma
Kyle, R. A. et al. N Engl J Med 20043511860-1873
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References

• www.uptodate.com
• Abeloff Clinical Oncology, 3rd ed. Pp 2956-2970.
  
• Bethesda Handbook of Clinical Hematology, pp
  221-231.
• DeVita, Vincent Cancer Principles and Practice
  of Oncology, 7th ed. Pp 2155-2187.
• Kyle RA, et al. Drug therapy Multiple Myeloma.
  NEJM 2004 351 1860-73.
• Kyle RA. Historical Review, Multiple myeloma An
  Odyssey of Discovery. British Journal of
  Hematology 2000, 111, 1035-1044.
• Lichtman, Marshall. Williams Hematology, 7th ed.
  Pp 1501-1524.

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