Antitumor Activity of Thalidomide in Refractory Multiple Myeloma

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Antitumor Activity of Thalidomide in Refractory
Multiple Myeloma

• By Ezra Kassin

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Background

• Refractory Multiple Myeloma
• A malignant tumor in the bone marrow. Usually
  affecting flat bones (skull, pelvis, shoulder
  blade).
• The disease occurs when B lymphocytes multiply
  into clones of plasma cells.
• Healthy B lymphocytes are active in the
  formation of antibodies.
• Plasma cells have no infection fighting ability.
• They begin to invade and crowd out the functional
  cells in the bone marrow.

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• Multiple Myeloma accounts for 10 of all
  hematologic cancers.
• Conventional chemotherapy is ineffective .
• Melphalan-based high dose chemotherapy and stem
  cell support is the protocol.
• Many patients still relapse with this treatment
  and other therapies are limited.
• Death within three years of diagnosis is common.

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Thalidomide

• Developed in the 1950s as a sedative that
  appeared to be very nontoxic during testing.
• Women began taking it as a treatment for morning
  sickness and as a sedative.
• Sharp increase in babies born with stunted limbs.
• 1960s it was discovered that Thalidomide was a
  potent teratogen and antiangiogenetic drug.
• Banned worldwide after causing 12,000 babies to
  be born with no limbs or flipper like arms and
  legs, facial deformities and defective organs.

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• In 1998 Thalidomide was approved again to treat
  leprosy.
• New research is showing that Thalidomide can be
  an effective treatment for AIDS, different types
  of cancers and many other diseases.
• In Theory Cancer cells, like all cells needs a
  constant blood supply for tumor
  progression.Thalidomide Stops blood vessel growth
  to developing cells and they die from lack of
  nutrients.

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Thalidomide as Treatment for Multiple Myeloma

• Patients and Treatment
• Patients with Multiple Myeloma show an increase
  in vascularization of bone marrow.
• Leading to the spread of the cancer throughout
  the body.
• This lead researchers to use antiangiogenic drugs
  in treatment.

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• There were 84 patients with advanced myeloma who
  were previously treated with high dose
  chemotherapy
• Orally administered thalidomide was the sole
  treatment.
• 200 mg. A day was administered.
• The dose was increased every two weeks by 200 mg.
  
• The final dose was 800 mg.

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Evaluation

• Evaluations included complete blood counts
• test of renal liver function
• paraprotein levels
• of plasma cells and vascularity in bone marrow
  through biopsies.
• These tests were performed on a weekly basis for
  the first two months followed by monthly exams.

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Results

• Paraprotein levels
• In 27 patients (32) the paraprotein levels
  decreased by at least 25.
• Any paraprotein level less than 25 was
  considered non responsive to the Thalidomide.
• Two patients had a complete remission meaning
  greater than 90 reduction in paraprotein levels.

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• Bone Marrow Response
• A bone marrow response was defined as the
  presence of less than 5 of plasma cells in bone
  marrow.
• A paraprotein response was associated with a bone
  marrow response in 81 of the patients.

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• Microvascular Density of Bone Marrow
• The microvascular density and the percentage of
  plasma cells in bone marrow correlated throughout
  the treatment.

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Adverse Effects of Thalidomide

• Most adverse effects were mild to moderate.
• Constipation, fatigue, weakness, and tiredness
  occurred in one third or more of the patients.
• Less than 10 of the patients suffered serious
  side effects.
• Nine patients could not tolerate the drug.

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Activity on cancer cells

• Thalidomide suppresses the production of tumor
  necrosis factor.
• Increases the production of interleukin 10.
• Enhances cell mediated immunity by stimulating
  cytotoxic T cells.
• Interaction between thalidomide and T cells
  increase levels of cytokines such as interferon.
• Thalidomide increases lymphocytes, CD8 and CD4 T
  cells counts.

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Conclusion

• This study shows us that Thalidomide has
  substantial antitumor activity in myeloma
  patients.
• 10 of the patients had complete or nearly
  complete remission.
• 32 had a marked reduction in paraprotein levels
  which was accompanied by a reduction in plasma
  cells in bone marrow and an increase in
  hemoglobin.

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• Thalidomide is now being used in combination with
  chemotherapy as a treatment for many different
  types of cancers.
• The results in this experiment are very
  promising but researchers must be careful when
  using this powerful drug.
• They must remember the tragedy that occurred when
  the drug was first introduced 50 years ago.