Thalidomide, Radiation, and Peripheral Stem Cell Transplantation as Combination Treatment for Multiple Myeloma

Allison ReczekDepartment of Biological Sciences, York College of Pennsylvania

PROJECT SUMMARY:Multiple Myeloma (MM) is an incurable

hematological cancer that invades bone and most often leads to death. A review of the literature suggests that individually, thalidomide, radiation therapy and peripheral blood stem cell transplantation have marginal therapeutic effects. The objective is to use a combination treatment utilizing thalidomide, radiation and peripheral blood stem cell transplantation that will contribute to recovery from late stage multiple myeloma. The efficacy of the treatment will be tested in a Phase II Clinical Trial using hematologic factors, M-protein levels in serum and urine, and bone surveys to monitor patients’ responses to treatment. The goal is to destroy the myeloma cells and stimulate peripheral stem cells to repair the diseased bones.

INTRODUCTION:

Multiple Myeloma (MM) is a type of cancer formed by malignant plasma cells.

Phase II clinical trial is a small trial consisting of individuals who have the disease or condition. The purpose of a Phase II trial is to determine the therapeutic effect of the prescribed treatment.

Diagnosis of multiple myeloma is based on:

Increased numbers of abnormal, atypical, or immature plasma cells in the bone marrow.

Presence of M-protein in the urine or blood serum.

Bone lesions typical of those produced by multiple myeloma.

Stage III (Late Stage) MM is classified by:

>1.2 cells x 1012 (high cell mass)

Hemoglobin value <8.5 g/dL

Serum calcium value >12mg/dL

Advanced lytic bone lesions

High M-component production rate:

IgG value >7 g/dL; IgA value > 5 g/dL

Bence Jones protein >12 g/24h

Patients diagnosed with the disease often experience symptoms including severe bone pain, fatigue caused by anemia, and weight loss.

RESEARCH DESIGN AND METHODS:

Subject Selection and Baseline Values Established200 subjects will be selected.Subjects selected will be male, 65-70 years of age in Stage III of MM.Diagnosis for Stage III MM will be based on defined criteria as described. Baseline values will be determined for each of the tests for each patient.

Treatment

Thalidomide administered orally, starting at 200 mg/day, increasing 200mg/day every 2 weeks for 6 weeks

until maximum of 800 mg/day is reached.

GM-CSF administered at 5 mcg/kg a day for 1 week, starting at week 3 of thalidomide treatment.

Blood stem cell harvesting and aphoresis, beginning the day following the first GM-CSF injection and continuing for 1

week.

Radiation Therapy administered everyday beginning week 4, in conjunction with thalidomide drug.

Peripheral Stem Cell Transplantation will begin 2 days after final thalidomide and radiation treatment, allowing 2 to 4

weeks for engraftment.

Patient Response

Patients’ responses will be monitored and will be based on the results of the following:

Hematologic Tests

•Hemoglobin levelsM-protein levels

•In serum

•In urineBone surveys

•CT scans

•X-rays

Results will be compared to baseline values.

REVIEW OF LITERATURE:

For over 30 years, standard therapy for multiple myeloma consisted of melphalan and prednisone, producing overall response rates of 50%, but complete remission rates of less than 10% (Cool et al. 2002).

Single treatments have only shown marginal results (Rajkujmar et al. 2003).

Various chemotherapy regimens alone have failed to produce significant survival rates (Cool et al. 2002).

Autologous stem cell transplantation has yielded complete remission rates of 20-40% (Cool et al. 2002).

Once banned from the market in 1962, thalidomide was reintroduced in 1998 for treatment for leprosy. Today, this antiangiogenesis drug is thought to have various properties that may aid in slowing malignant cell growth (Richardson et al. 2003) (Figure 1):

Thalidomide is thought to directly inhibit the growth and survival of myeloma cells.

Thalidomide may modulate adhesion molecules involved in the growth and survival of myeloma cells.

Thalidomide may alter the production and activity of cytokines involved in the growth and survival of myeloma cells.

Figure 1. Thalidomide’s various effects on multiple myeloma.

Radiation is more effective against actively reproducing cells because these cells are highly radiosensitive.

Radiation treatment does not differentiate between normal cells and diseased cells.

Peripheral blood stem cell transplantation procedure has been shown to restore cells destroyed by other treatments (Rajkujmar et al. 2003).

HYPOTHESIS

Thalidomide, radiation, and peripheral blood stem cell transplantation, when used in combination, will provide an effective treatment against multiple myeloma.

Figure 1: Hyphothetical mechanism of how thalidomide works

EXPECTED RESULTS:

After completion of treatment, hemoglobin levels should return to a normal range of 13 – 18 g/dL.

The stem cells will provide new blood and immune cells and replace cells destroyed by treatment. The bone then can begin healing from the inside out.

A partial response indicates a >50 < 75% regression of the M-protein and the myeloma cells.

A complete response indicates a 75% reduction in M-protein levels in the blood, or a complete elimination of the M-protein from the blood, along with no evidence of myeloma cells in the bone marrow.

A patient will be considered in complete remission if myeloma cells are not evident after 30 – 36 months.

LITERATURE CITED:

Cool, R.M., Herrington, J.D. 2002. Thalidomide for the Treatment of Relapsed and Refractory

Multiple Myeloma. Pharmacotherapy. 22:1019-1028.

Duncombe, A. 1997. Bone marrow and stem cell transplantation. British Medical Journal. 314:119.

Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispenzieri, A., Fonesca, R., Rajkumar, S.V., Offord, J.R., Larson, D.R., Plevak, M.E., Therneau, T.M., Greipp, P.R. 2003. Review of 1027 Patients with Newly Diagnosed Multiple Myeloma. Mayo Clinic Proceedings. 78:21-33.

Making Treatment Decisions: Radiation Therapy. Available from: www.cancer.org

Rajkujmar, S.V., Gertz, M.A., Kyle, R.A., Greipp, P.R. 2003. Current Therapy for Multiple Myeloma. Mayo Clinic Proceedings. 77:813- 822.

Richardson, P., Hideshima, A.K. 2002. Thalidomide in multiple myeloma. Biomedicine and

Pharmacotherapy. 56:115-28.

Acknowledgements:

Thanks to Mrs. Marilyn Daly for her guidance and encouragement throughout the course of this project.