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Phase II Trial Evaluating the Role of High Dose Intermittent Schedule ATRA in the Management of Multiple Myeloma


General Information:

There is no curative therapy available for multiple myeloma. Patients who fail standard therapy, usually do not respond or briefly respond to more toxic and less effective regimens.

The main growth factor for the Myeloma cell is Interleukin-6. In relapsed and advanced disease the level of this Myeloma growth factor is significantly elevated. Inhibiting the effect of the IL-6 on the Myeloma cells results in remissions. ATRA does suppress the IL-6 receptors on the Myeloma cells ( receptors are proteins responsible for binding the IL-6 to the Myeloma cell so that it could stimulate the cell to grow), as well as suppressing the level of the IL-6.

In patients who do not respond to ATRA, the addition of a- interferon could result in a response.

The drugs used in this treatment are approved by the Food and Drug Administration (FDA) and are commercially available.

Eligibility Criteria:

Induction Phase

Diagnosis of multiple myeloma.

Relapsed or refractory multiple myeloma of any stage.

Patients should not have received more than three chemotherapy regimens, and no more than two biologic regimens.

Patients with pancytopenia related to multiple myeloma will be eligible for treatment i.e. patients with > 50% plasma cells in the BM, or splenomegaly, or plasma cell leukemia.

ECOG performance status of less than or equal to 2.

18 years or older.

Signed consent form.

Enhancement Phase (Addition of a-Interferon)

Patients who demonstrate disease progression at 4 weeks.

Patients who achieve only stable disease after 8 weeks of therapy.

Ineligibility Criteria:

Induction Phase

Evidence of active infection requiring IV antibiotics.

Patients with solitary bone or extramedullary Plasmacytoma.

Patients who are HIV positive.

Women who are pregnant or breastfeeding.

Enhancement Phase (Addition of a-Interferon)

Patients who have received a- Interferon in previous treatment regimens.

Patients who are not expected to live longer than 12 weeks

Concurrent involvement in any other clinical trial using an investigational drug or device, or participation in any investigational drug study within 4 weeks prior to study registration. Exceptions may be made by the study investigators for participation in certain studies (e.g. antimicrobial studies) on a case by case basis.

Sero-positive for HIV antibody or any evidence of serious or active infection which is chronic or is requiring intravenous antibiotic treatment.

Severe hepatic disease (e.g. SGOT or SGPT, bilirubin, alkaline phosphatase more than 2.5 times the normal laboratory range).

Compromised renal function as evidenced by a serum creatinine > 2.0.

Other major organ system dysfunction (including cardiac, pulmonary, gastrointestinal, neurologic or psychiatric) that would impair tolerance of therapy.

Concomitant use of corticosteroids or colony stimulating factor agents.

Patients who fail to have a granulocyte count > 750/mL, platelet count > 75k/mL.

Allowable Concomitant Therapy

Standard radiation therapy to treat extra-skeletal and/or skeletal tumor sites. If radiation is needed during the study period, the investigator must document that there is no sign of progressive disease leading to radiation as a treatment. Comparisons of area to be radiated with baseline bone survey films must be provided to document lack of disease progression.

Erythropoietin for severe symptomatic anemia.

GM-CSF is the only growth factor that will be allowed if necessary in the induction phase.

Aredia and Immunoglobulin therapy will be allowed at any stage of the therapy.

Scientific Background:

All-Trans Retinoic Acid

  1. MULTIPLE MYELOMA is a neoplastic disease characterized by the growth and accumulation of malignant plasma cells. Because myeloma responds poorly to conventional chemotherapy and radiation therapy, the need exists for a new therapeutic approach. It is well known that interleukin-6 (IL-6) plays an important role in myeloma cell growth by means of the autocrine or paracrine mechanism both in vitro and in vivo. (1 2 3 4) This suggests that the functional blocking of IL-6 may be a new approach for myeloma therapy. Actually, Klein et al(4) reported that during treatment with antiIL-6 monoclonal antibody (MoAb) of a patient with plasma cell leukemia, myeloma cells in peripheral blood and bone marrow (BM) were significantly decreased and plasma M-protein disappeared.
  2. All trans retinoic acid (ATRA) derived from retinol (vitamin A) is known as a regulator of cell proliferation, cell differentiation, and embryonic development.( 5 6 7 8). Recently, Sidell et al (9) identified the antiproliferative action of ATRA on a myeloma cell line, AF10, as the result of down regulation of IL-6 receptor (IL-6R) and subsequent inhibition of IL6mediated autocrine growth. Therefore, ATRA is a possible modulator of IL6dependent growth systems on myeloma cells.
  3. Ogata et al showed the dose dependent growth inhibition by all trans retinoic acid (ATRA) of myeloma cells freshly isolated from patients. ATRA down regulated the cell surface expression of interleukin-6 receptor (IL-6R) and/or glycoprotein (GP) 130. The growth inhibitory activity of ATRA was well correlated with that of antigp130 antibody in every sample. Furthermore, ATRA inhibited the production of IL6 from both myeloma cells and marrow stromal cells, and recombinant IL-6 (rIL-6) could partially recover the myeloma cell growth that had been inhibited by ATRA. These data suggest that ATRA may inhibit the proliferation of myeloma cells both by the down regulation of IL-6R and gp130 expression on myeloma cells and by the inhibition of IL-6 production from myeloma and stromal cells. The inhibitory effect of ATRA on myeloma cell proliferation was observed in 10 of 14 samples obtained from eight patients, which suggests that ATRA may be a potent new therapeutic agent for some myeloma patients (10).
  4. Several recent studies did not demonstrate any activity for ATRA in advanced myeloma patients. Moreover, hypercalcemia, possibly related to increased levels of IL-6 and/or IL-6-R ,was a noticeable side effect (11,12,13). In all published myeloma clinical trials, ATRA was used as a low dose, continuous uninterrupted schedule. This could have possibly affected its efficacy (14).
  5. Phase 1 data from our institution, demonstrate that if ATRA is used on an every other week schedule, a Dose of 190 mg/m2 is well tolerated (15). In vitro response of Myeloma cells to ATRA is dose related i.e., the higher the dose the more complete the suppression of the malignant cells.
  6. We therefore will conduct a study using a higher dose ( ~ 4x studied dosages), and administer the ATRA in an intermittent schedule. These modifications to the dose and schedule provide a rational Pharmacological and Biologic plan for the management of Multiple Myeloma.

a-Interferon, ATRA, and Multiple Myeloma

a-Interferon and Myeloma:

  1. a-Interferon has been shown to prolong the plateau phase in patients with multiple myeloma (16,17)

ATRA and a-Interferon:

  1. Retinoids and a-Interferon appear to have antiproliferative and synergistic effect on different human cancer cell lines (18).
  2. Toma et al, evaluated the effect of 13cisretinoic acid (cRA) and all trans-retinoic acid (ATRA) used alone or in combination with interferon alpha2a (a-IFN -2a) on three established human cell lines Both retinoids significantly decreased cell proliferation (growth curves) and colony forming efficiency (CFE) in all cell lines, in a dose dependent way.

Bisphosphonates and Myeloma:

Aredia demonstrated a significant benefit relative to bony resorption and pathologic fractures in myeloma patients(19).adding the drug to the treatment protocol, in addition to the benefits related to MM, will insure the lower rate of hypercalcemia possibly related to the ATRA.


  1. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T: Autocrine generation and requirement of BSF2/IL6 for human multiple myelomas. Nature 332:83,1988
  2. Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R: Paracrine rather than autocrine regulation of myelomacell growth and differentiation by interleukin6. Blood 73:517,1989
  3. Anderson KC, Jones RM, Morimoto C, Leavitt P, Barut BA: Response patterns of purified myeloma cells to hematopoietic growth factors. Blood 73:1915,1989
  4. Klein B, Wijdenes J, Zhang XG, Jourdan M, Boiron JM, Bronchier J, Linnie J, Merlin M, Clement C, MorelFournier B, Lu ZY, Mannoni P, Sany J, Bataille R: Murine antiinterleukin6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 78:1198,1991
  5. Ross AC: Vitamin A: current understanding of the mechanisms of action. Nutr Today 26:6,1991
  6. De Luca L: Retinoids and their receptors in differentiation, embryo genesis, and neoplasia. FASEB J5: 2924, 1991
  7. Eichele G: Retinoids in embryonic development. Ann NY Acad Sci 678:22,1993
  8. Blomhoff HK, Smeland EB, Erikstein B, Rasmussen AM, Skrede B, Skjfnsberg C, Blomhoff R: Vitamin A is a key regulator for cell growth, cytokine production, and differentiation in normal B cells. J Biol Chem 267:23988,1992
  9. Sidell N, Taga T, Hirano T, Kishimoto T, Saxon A: Retinoic acid induced growth inhibition of a human myeloma cell line via down regulation of IL6 receptor. J Immunol 146:3809,1991
  10. Ogata A., Nishimoto N., Shima Y., Yoshizaki K., and Kishimoto T.: Inhibitory effect of all-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction. Blood, 84:3040-46, 1994.
  11. Musto P., Falcone A., Sajeva M.R., D'Arena G., Bonini A., and Carotenuto M.: All-trans retinoic acid for advanced multiple myeloma. Blood 85 (12):3769-70, 1995.
  12. Vesole D, Kombluth J, Jagannath S, Sznol M, Mattox S, Vaught L, Tricot G, and Barlogie B: Biological response modifiers (BRM) in refractory multiple myeloma (MM). Blood 82:263a, (abstr, suppl) 1993.
  13. Niesvizky R., Siegel D., Busquets X., Nicholls G., Muindi J., Warrell R., and Michaeli J.: Hypercalcemia and increased serum interleukin-6 levels induced by all-trans retinoic acid in patients with multiple myeloma. British Journal of Hematology; 89:217-18 1995.
  14. Adamson P., Bailey J., Pluda J., Poplack D., Bauza S., Murphy R., Yarchoan R., and Bali F.: Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule. Journal of Clinical Oncology; 13(5): 1238-41, 1995.
  15. Budd GT, et al: Phase 1 and Pharmacokinetics trial of trans- Retinoic acid and Tamoxifen advanced Breast Cancer. Proceedings of the American Society of Clinical Oncology., ( 4), 111, Abstr# 144, 1995.
  16. The Nordic Myeloma Study Group: Interferon-aa2b added to Melphalan-Prednisone for initial and maintenance therapy in multiple myeloma. Ann Intern Med.;124:212-222, 1996.
  17. Mandelli F., Avvisati G., Amadori S., Boccadoro M., Gernone A., Lauta V., Marmont F., Petrucci M., Tribalto M., Vegna M., Dammacco F., and Pileri A.: Maintenance treatment with recombinant interferon alpha-2b in patients with multiple myeloma responding to conventional induction chemotherapy. The New England Journal of Medicine;322(20):
  18. Toma S., Monteghirfo S., Tasso P., Nicolo G., Spadini N., Palumbo R., and Molina F.: Antiproliferative and synergistic effect of interferon alpha-2a, Retinoids and their association in established human cancer cell lines. Cancer Letters; 82(2):209-16, 1994.
  19. Berenson JR, et al: Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma. NEJM; 334,(8), 488-493, 1996.
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