Multiple Myeloma Research Center

Home Research Education Resources Support Group

 

Actimid (CC4047) Amyloidosis BMT Bone Disease Diagnosis & Treatment Dental Care Drug Resistance Fatigue Glossary Interferon Immunomodulators Kyphoplasty Lenalidomide Multiple Myeloma Questions & Answers Revlimid Thalidomide Thalidomide Response Thalidomide Safety Update Thalidomide Toxicity Vitamins & Anemia Neovastat Opioid Therapy Vitamins Drug Info

Back Home Up Next

The role of Multidrug Resistance Anti-therapy in the Management of Multiple Myeloma

   The majority of patients will succumb to their disease (1,2 ). In the community, MM patients are usually treated with conventional-dose Melphalan and prednisone or a regimen consisting of Vincristine, doxorubicin, and Dexamethasone (VAD). With this approach, the median survival of MM patients is 30 to 36 months; however, therapy will eventually fail in nearly all of these patients secondary to drug-resistant disease or infectious complications. (3)

A major obstacle to the successful treatment of MM is the emergence of chemotherapy-refractory disease. Although 60% to 80% of patients treated with Melphalan and prednisone or VAD achieve an objective response to initial therapy, many patients will relapse. Those patients who relapse within 6 months of therapy will not respond to subsequent treatment with the same regimen, and will have a lower response rate to new therapy. The tumor cells in 90% of VAD-refractory patients exhibit a multidrug resistant (MDR) phenotype resulting from over expression of P-glycoprotein (P-gp). This protein is responsible for pumping the active drug out of the cancerous cell, thus compromising its exposure to the cytotoxic therapy. This in turn renders the myeloma cells resistant to Melphalan, Vincristine, and doxorubicin.(4-10)

Disabling this active protein pump in these tumors has presented a difficult challenge. The most widely studied agents include Verapamil, cyclosporine A, and the second-generation cyclosporine analogue Valspodar (Amdray; Novartis Pharmaceuticals Corporation, East Hanover, NJ), also known as PSC 833. However, the clinical applications of both Verapamil and cyclosporine A have been limited by severe heart, kidney, and immunosuppression at doses that could effectively inactivate the active pump. Currently, a variety of second-generation MDR modulators (pump inhibitors) are being investigated, some of which may prove to have a more favorable toxicity profile compared with these first-generation products. In contrast to cyclosporine A, Valspodar is a nonimmunosuppressive, non nephrotoxic cyclosporine derivative, which is approximately two- to tenfold more potent than cyclosporine A.(11) Preclinical and phase I clinical studies have shown that Valspodar reverses MDR at dose levels that are well tolerated in animals and humans.(12-14) The principle toxicity associated with administration of Valspodar is moderate, reversible ataxia (i.e., loss of coordination, unsteadiness, and/or mild dizziness).

Clinical trials have demonstrated the safety and efficacy of this novel MDR modulator in chemotherapy-refractory MM patients. Sonneveld et al reported the first phase I trial (a study evaluating the safety of the drug) of Valspodar in 22 patients with VAD- or Melphalan-refractory MM. (15) In this study, patients were treated with three cycles of VAD plus an escalating dose of Valspodar (2.5 to 15 mg/kg). The dose-limiting toxicities were myelosuppression (bone marrow suppression) and neuropathy (nerve damage. Because Valspodar inhibits the normal clearance of some chemotherapeutic agents (e.g., doxorubicin) via the liver and kidneys, it increases the drug levels in patients. Consequently, dose reductions, depending on the specific agent, are required. This does not, however, compromise the therapeutic efficacy of the chemotherapy regimen.

With respect to MDR modulation, Sonneveld et al reported partial responses in 10 of 22 (45%) patients, including 4 of 8 assessable Melphalan-refractory patients and 6 of 12 assessable VAD-refractory patients.

Subsequently, a phase II trial (a trial designed to evaluate the efficacy of the drug) in VAD-refractory MM patients was conducted and preliminary data are available. Based on a previous phase I dose-escalation study,(16)  patients on this trial received a reduced dose of VAD plus Valspodar every 28 days. Patients were treated for up to 6 cycles or until progression or unacceptable toxicity. As reported at the 1998 meeting of The American Society of Hematology, accrual to this study is complete, a total of 41 patients have been treated, and 36 patients are evaluable for safety. The primary chemotherapy-related toxicities were severe low white blood count and platelets in 36% and 11% of patients respectively. The most common Valspodar-associated toxicities were mild to moderate unsteady gate (36%), with no reports of severe symptoms. Objective responses were observed in 4 of 41 (10%) patients. Further more, a recent update has confirmed that another 15% of the patients have responded for a total of 25%. This study has further demonstrated that the combination of Valspodar and reduced-dose VAD is safe and can induce responses in VAD-refractory patients. However, continued follow-up is necessary to establish the efficacy of this regimen.

Based on these encouraging results, the Eastern Cooperative Oncology Group (ECOG) has recently initiated a randomized phase III (a study designed to compare new therapy to the standard) intergroup trial of modified VAD plus Valspodar versus full-dose VAD alone in patients with relapsing or refractory MM. The primary objective of this study is to determine if Valspodar improves the objective response rate and overall survival in this patient population. Event-free survival, P-gp expression, prognostic variables, and toxicity will also be assessed. Eligible patients will be those with a confirmed diagnosis of MM, and with clinical evidence of progression following initial chemotherapy. However, patients previously resistant to VAD are ineligible. Planned accrual for this study is 324 patients.

The aim of these studies is to develop an effective strategy to overcome multidrug resistance and ultimately, perhaps, to prevent the development of drug resistance in a variety of human malignancies. Valspodar is a prime example of an agent that has emerged from the culmination of intensive research into the molecular mechanisms of MDR and novel drug development.

 

References

   

  1. Attal, N Engl J Med, 1996; 335:91-97

  2. Jagannath, Blood, 1990;76:1860-1866

  3. Alexanian, N Engl J Med, 1994; 330:484-489

  4. Grogan, Blood, 1993; 81:490-495

  5. Epstein, Blood, 1989; 74:913-917

  6. Sonneveld, Br J Haematol, 1993; 83:63-67

  7. Grogan, Lab Invest, 1990; 63:815-824

  8. Pilarski, Blood, 1994; 83:724-736

  9. Cornelissen, J Clin Oncol, 1994;12:115-119

  10. Dalton, Blood, 1989;73:747-752

  11. Fisher, Eur J Cancer, 1996; 32A: 1082-1088

  12. Ford, Hematol Oncol Clin North Am, 1995; 9:337-361

  13. Twentyman, Eur J Cancer, 1991; 27:1639-1642

  14. Hausdorff, Proc Am Soc Clin Oncol, 1995; 14:181

  15. Sonneveld, Leukemia, 1996; 10:1741-1750

  16. Dalton, Blood, 1996; 88:662a

 
 
Home Up
Phone: 216-445-6830
Fax: 216-445-3434

Maps & Directions

 Cleveland Clinic Home  |   Contact Us  |   Disclaimer  |   Privacy Statement
 Cleveland Clinic 2005

Page Last Updated 08/20/2003 08:54:31 PM