Unusual Long Term Remission in Multiple Myeloma Using Conventional Therapy Combined with Danazol

Introduction and Case studies. The treatment of multiple myeloma (MM) has drastically changed over the past decade with significantly improved progression free as well as overall survival. Despite the advent of multiple treatment options, MM still has the inherent ability to become resistant. Relapses are frequent and the disease becomes refractory to treatment, leading to significant morbidity and mortality. Long term remissions lasting over a decade without relapses are rare in MM with conventional treatment.

We report here prolonged remission lasting for decades in two patients with MM who were treated with conventional alkylating agents and steroids, combined with danazol as adjuvant and maintenance therapy. Both achieved complete remissions with undetectable M proteins and remarkable clinical improvement and better quality of life. The remissions were maintained now over two decades.

Our first case was a 51 year old man who presented with severe back pain and noticeable loss of height. Work up revealed many lytic lesions and multiple collapsed vertebrae with diffuse osteoporosis on skeletal bone survey. Hematologic studies revealed high levels of IgG-lambda M protein of 6 grams. He was treated with melphalan, prednisone, monthly Aredia and danazol 200 mg three times daily (TID). He achieved a complete remission (CR) with marked clinical improvement. His remission was maintained with danazol 200 mg TID and Intron-A (interferon alfa-2b, recombinant) 5 million units three times a week. Danazol was later reduced to three times a week in combination with interferon, doses of which he remains on today. He remains in CR now for over 21 years without signs of relapse. He resumed all of his normal activities and is currently working without any limitation as a full time college professor. He refuses to stop danazol nor Intron-A.

Our second case was a 41 year old man with 3 year history of progressive polyneuropathy that rendered him severely paraplegic, bedridden and unable to feed himself because of weakness. Work up revealed an IgG lambda M protein and multiple sclerotic bone lesions on bone survey. Excisional bone biopsy showed neoplastic plasma cell proliferation. Diagnosis of osteosclerotic multiple myeloma with POEMS syndrome was made. He was treated initially with plasmapheresis and infusions of IVIG without any long tern benefit. Subsequently, he received palliative radiation therapy to relieve bone pain and was treated with chlorambucil 3 mg PO daily, hydrocortisone 20 mg PO daily, danazol 200 mg PO TID and monthly Aredia which was later changed to Zometa. He achieved a CR with remarkable clinical recovery. His strength improved significantly with the ability to walk and feed himself as well as resumption of his normal daily activities (Muscle Nerve. 1997, 8:1035). He stopped danazol and remains in remission now over 22 years.

Conclusion/Discussion: The use of immunomodulators (IMiDs) have changed the approach to the treatment of MM. While the mechanism of action is not fully understood, IMiDs appear to possess anti-myeloma properties including immunomodulation, anti-angiogenesis, and anti-proliferative activities (Leukemia. 2010, 24:22).

Danazol, an attenuated androgen, is widely used in the treatment of ITP (NEJM. 1983, 308:1396). We previously showed that danazol carries inherent immunomodulatory action, increasing T-helper cells as well as the proportion of T-helper to T-suppressor cells among patients treated for ITP (Clin Imm Immunopath. 1987, 42:287). Administration of danazol in patients for ITP for over a year, even with withdrawal, yielded long term remissions while relapses were more frequent in those that took it for less than 6 months (Ann Intern Med. 1989, 111:723). Similar observation was made in other autoimmune disease such as immune hemolytic anemia (Acta Hematol. 1990, 84:122). Collectively, long term administration of danazol appears to induce prolonged unmaintained remission in autoimmune diseases like ITP. We postulate that danazol may induce similar immunomodulation in MM and contributed to decades of remission in our patients. Danazol has not yet been tested in the treatment of MM systematically but deserves further investigation through a large prospective clinical trial.