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Possible Usefulness of Biaxin for Type I Cryoglobulinemia

Last updated 11/21/2001
Type I cryoglobulinemia is produced by monoclonal gammopathy of undetermined significance (MGUS), or its malignant forms, multiple myeloma or macroglobulinemia. Promising results have been found using Biaxin (Clarithromycin) to reduce the monoclonal immunoglobulins in multiple myeloma. Combining Biaxin with low dose Thalidomide and Dexamethasone have produced even better results.

Dr. Brian Durie has found that about 50% of myeloma patients respond to Biaxin with a greater than 50% reduction in monoclonal component, a response which is comparable to standard therpy with melphalan and prednisone. Responders typically show a response within a month of beginning therapy, and show a 17% decline per month in monoclonal component thereafter. Dr. Durie reports (as of June 1998) that adding pulsed dexamethsone (Decadron) to the Biaxin treatment has produced the most dramatic decreases in monoclonal component. The dosages he has been using are: Biaxin, 500 mg twice a day; and dexamethsone 8 mg once a day, for two days in a row, repeated every two weeks.

In at least one case, a patient with MGUS Type I cryoglobulinemia has responded to the Biaxin/Dexamethasone regime. After 3 weeks on Biaxin alone, cryoglobulin production began to decrease, plateauing at about 60% of the pre-treatment level after 3 months on Biaxin alone. After addition of pulsed dexamethasone (8 mg X 2 days every 2 weeks), the cryoglobulin production fell to about 45% of pre-treatment levels, reducing the patient's need for apheresis from twice a week to every 8 days in order to maintain a cryocrit value of around 8%. More experiments would appear to be worthwhile.

References are below:


"Don shared with us about an exciting treatment that Dr. Durie has him on. Don had sent his blood to Dr. Durie in the past because he fit a profile of people that Dr. Durie was doing research about. Don was found to be positive for the SV-40 (green monkey virus) and Adenovirus-5. Dr. Durie is working on the hypothesis that certain viruses trigger the proliferation of myeloma. He put Don on a regimen of pulsed Dexamethasone, high-dose Biaxin® (a powerful antibiotic which inhibits protein formation in viruses), and Zantac (which Don says actually has an anti-myeloma effect of its own). This protocol was created by a rheumatologist (who has myeloma) who does research work with Dr. Durie. The exciting part is that Don's IGA has dropped from 4600, when he started this protocol, to 1020 which is the lowest it's ever been. I hope that Don is able to keep us informed about his progress."

Below is the currently published studies on Clarithromycin in myeloma:

  1. Clarithromycin (Biaxin) Adds to the Efficacy and Toxicity of Steroid Therapy in Multiple Myeloma.

    Robert A. Vescio, Nelida N. Sjak-Shie, Steven J. Manyak, Hank Yang, James R. Berenson.€Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. American Society of Hematology 2001 Meeting.

    Recently, Durie et al (Blood 90:579a, 1997 (abstr, suppl 1)) reported that some patients with multiple myeloma (MM) appeared to clinically respond with disease status improvement when treated with the antibiotic clarithromycin for upper respiratory tract infections. They observed 6/23 complete and 7/23 partial responses in their MM patient cohort. Several responding patients were on concurrent anti-myeloma agents, including steroids, raising the concern that the observed clinical benefit was primarily due to steroid therapy, not the addition of the clarithromycin. Two subsequent studies using single agent clarithromycin failed to document significant clinical benefit using this antibiotic as a single agent in MM patients with progressive disease. However, the triple drug combination of clarithromycin, thalidomide and dexamethasone designed by Dr. Coleman and colleagues has produced very high response rates for this disease (>85%). Our group noted a dramatic reduction in the paraprotein levels of a patient whose disease was progressing on both thalidomide and steroids after clarithromycin was initiated to treat bronchitis. Based upon this observation, we treated additional MM patients with clarithromycin to assess its activity. clarithromycin 500 mg po BID was added to the treatment regimen of 11 MM patients with disease progression and documented resistance to multiple forms of therapy. Six patients had relapsed post autologous stem cell transplant, nine patients were resistant to steroid therapy, eight patients either failed or could not tolerate the addition of thalidomide, and two patients were started on steroids and clarithromycin simultaneously. Significant reductions in serum and urine paraprotein levels ranging from 18 to 86% were documented in 8/11 patients, stabilization of the paraprotein levels was noted in 1/11, and progressive disease occurred in the other two patients. Response duration ranged from 2 to 8 months. All observed responses occurred in the setting of concurrent clarithromycin and steroid therapy with/without thalidomide. Improvements in clinical parameters such as anemia and bone marrow plasmacytosis were also noted in responding patients. Unfortunately, the addition of clarithromycin also potentiated steroid-induced side effects in some patients including hyperglycemia (4/11), confusion (2/11) and proximal muscle weakness (5/11). These side effects occurred even in patients previously tolerant of an equivalent dose of corticosteroids. clarithromycin and other macrolide antibiotics are known to prolong the half-life of corticosteroids. Thus, some of the beneficial as well as detrimental consequences of this antibiotic may be explained by this effect. Nevertheless, even some patients refractory to high-dose dexamethasone responded to the addition of clarithromycin. Alternatively, macrolide antibiotics are known to have immunomodulatory properties and can suppress various cytokines such as IL-6 known to promote MM cell growth. Our results demonstrate the beneficial effect of clarithromycin in MM patients when combined with corticosteroids. Laboratory and further clinical studies should be undertaken to better understand the mechanism behind this surprising effect. Keywords: clarithromycin\ Multiple myeloma\ Steroids

  2. BLT-D (Biaxin, Low-Dose Thalidomide and Dexamethasone) Produces Consistent Responses in Myeloma and Waldenstrom's Macroglobulinemia.

    Morton Coleman, John P. Leonard, Weill Medical Coll of Cornell Univ and New York Presbyterian Hosp, New York, NY.

    Seventeen patients with myeloma (13) or Waldenstrom's macroglobulinemia (4) have been treated at our center with a non-myelosuppressive combination of Biaxin (clarithromycin) 500mg po BID, low dose thalidomide (THAL) 50mg po QD, and dexamethasone (DXM) 40mg po Q wk. Rx also included pyridoxine 100mg po BID and omeprazole 20 mg po BID for 2 days with DXM. Dose modifications were as follows: Biaxin reduced to 250mg po BID for GI sx; THAL escalated as tolerated by 50 mg biweekly to a max of 200mg/day; and DXM decreased for endocrine intolerance to 40mg Q 10 d, Q 2 wks or 20 mg Q 2 wks as maximally tolerated. Therapy is ongoing, with duration of 3-24 wks, median/mean of 12 wks. Of 17 patients, 1 is post-stem cell transplant, 3 received "high-dose" non-transplant chemotherapy, 9 conventional chemotherapy, and 4 previously untreated. Three patients have not completed a min of 6 wks of rx and thus are not assessable. Of 14 evaluable patients, all responded: 3 complete remission with no evidence of disease, 5 complete remission with normal Ig levels but a persistent monoclonal spike, and 6 partial remission with a greater than 75% reduction of the monoclonal spike. Responses were mirrored by similar improvement in bone marrow status. Improvement in blood counts and/or normal immunoglobulins was observed in most patients. Responses occurred by 6 wks, and are ongoing and proportionate to medication doses (improvement with incr drug dose, less improvement with lower doses). Resistance has not been encountered; Responses were unrelated to prior chemosensitivity or resistance. Three patients required a reduced Biaxin dose due to GI intolerance or C. difficile, all patients required a reduction in THAL dosing (median tol dose 100 mg/d), and 14 patients required reduction in DXM dosing. All patients sustained grade 1-3+ reversible neurotoxicity including peripheral and/or autonomic neuropathy and drowsiness requiring dose reduction. Withdrawal of rx resulted in rapid return of disease suggesting that response may be cytokine-mediated. BLT-D administered daily is a highly effective regimen in virtually all myeloma and Waldenstrom's macroglobulinemia patients evaluated to date. Results are dependent on a balance of treatment intensity with quality of life.


    Morton Coleman, Robert M. Gelfand, John P. Leonard. Center for Lymphoma and Myeloma and Division of Hematology/Oncology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY. American Society of Hematology 1999 Proceedings, Abstract 4604.

    Thalidomide, clarithromycin, and dexamethasone (TCD), agents that are not traditionally considered chemotherapy and are non-myelosuppressive, are reported to have some therapeutic activity in plasma cell myeloma. These drugs were administered in combination to 5 myeloma patients who were not eligible or unwilling to receive myelosuppressive chemotherapy. Three of the 5 were previously untreated and 2 were heavily pretreated. TCD was given as follows: oral thalidomide 50-200 mg daily as tolerated with pyridoxine (B6) 100 mg daily, oral clarithromycin 500-1000 mg daily as tolerated, and dexamethasone 40 mg once every 7 to 10 days as tolerated. Four of 5 patients demonstrated rapid decrements in their monoclonal immunoglobulin spikes within 14 weeks of initiating therapy, with reductions of 95% (IgA), 75% (IgG), 70% (IgG) and 50% (IgA) respectively. Improvement in hematologic parameters and/or performance status occurred in three of the five patients. All patients required dose modification of thalidomide dosing to low levels due to symptoms associated with neuropathy. Transient elevations of C-reactive protein occurred in two patients. It is premature to determine if protein responses will be sustained and herald improvement in bone and/or marrow status and survival. Given the low likelihood of response to the low doses of the individual medications administered, these data suggest that the combined use of the drugs may have added efficacy and warrants further evaluation. Neurologic toxicity from thalidomide may be augmented by the combined use of these agents.

  4. Clarithromycin (Biaxin®) as primary treatment for myeloma.

    B. G. M. Durie, L. Villarete, A. Farvard, M. Ornopia and H. B. Urnovitz. Cedars Sinai Comprehensive Cancer Center, Los Angeles; Chronic Illness Research Foundation, Berkeley, CA. 1997. Blood 90 (10 SUPPL. 1 PART 1): 579A.

    We report the results of Clarithromycin (Biaxin®) antibiotic treatment in patients with active multiple myeloma. This trial was begun based upon results in MALT lymphoma with t(11:14)(q12:q32) associated H. pylori infection, as a result of the detection of a circulating nucleotide sequence, which contains the same Bcl-I/JH 5/6 break point region, in patients with active myeloma. A basic schedule of 500 mg B.I.D. was utilized with ongoing dosages/schedule dependent upon initial response. 30 patients are currently enrolled with the longest follow-up being approximately 1 year. Treatment has been well tolerated with no untoward complications. Thus far using SWOG response criteria there have been: 6 C.R.s (>=75% regression); 7 P.R.s (>=50%); 6 stable; 4 mixed and 7 too early to evaluate. Response has been documented by improvement in clinical status, hemoglobin, serum and urine M-component, S beta2M, bone marrow plus follow up MRI and other scans. The first patient (previously untreated), with IgA-kappa myeloma is in full clinical remission at approx. 1 yr: IgA from 4.3 g/dl to 300 mg/dl; plasma cells from 65% to 1%; MRI to normal. Other dramatic responses have also occurred in 2 patients relapsing after stem cell transplant and 1 patient refractory to both VAD and melphalan. Thus far patients with IgA and IgG, kappa subtype have been the best responders; versus lambda, Bence Jones, and non-secretory patients in whom efficacy has been less. High levels of circulating nucleotide have been associated with more transient response and dose escalation is currently being explored in this subgroup. One patient with Waldstrom's is also showing evidence of lymph node reduction and reduced IgM. Nucleotide levels clear with successful treatment. However, caution is required because rebound can occur early if Biaxin® is stopped before full response is achieved. Based upon the initial results a study is now planned comparing alternate weekly cycles of Biaxin® versus a a continuous 6-8 week course with dose escalation if necessary. The initial clinical efficacy of Biaxin® is dramatic and justifies further studies, both to evaluate potential mechanisms behind its efficacy (e.g. ? target of RNA polymerase III inhibition) as well as to determine the best patients and schedule(s) for therapy.

Negative studies:


    K. J. Shannon, H. P.G. Dave, G. P. Schechter. Hematology Section, VA Medical Center, Washington, DC; Hematology/Oncology, George Washington University Medical Center, Washington, DC. American Society of Hematology 1999 Proceedings, Abstract 4630.

    As there are only limited effective agents for use in progressive MM, the report of Durie et al. (Blood 90:579a, 1997) demonstrating successful treatment of MM with clarithromycin was tantalizing and warranted further investigation. Interleukin-6 (IL-6) has been shown to be a potent plasma cell growth factor, and excessive IL-6 levels may have an etiologic role in plasma cell dyscrasias. Macrolide antibiotics such as erythromycin and clarithromycin have been demonstrated to inhibit IL-6 production, which provides a theoretical basis for its use in MM. We performed a phase 2 study using clarithromycin in symptomatic patients with MM who were intolerant of or had failed standard therapy. Clarithromycin 500mg bid was administered qd x 7d on alternate weeks for a planned 4 months or until complications and/or progression. Patients also received monthly pamidronate therapy, but no other agents known to be effective in MM were given. Five patients were enrolled in this single institution study and completed a mean of 11 +/- 6 weeks of treatment. All patients had IgG MM, were a mean age of 76 years, and had received a mean of 2.4 different courses (range 2 - 3) and 7.4 cycles (range 4 - 10) of prior chemotherapy. This included melphalan and prednisone, high dose dexamethasone, cyclophosphamide, or interferon. During treatment, monoclonal paraproteinemia and serum IL-6 concentrations were followed, in addition to C-reactive protein (CRP), b2 microglobulin (b2M), hematocrit, WBC, renal, hepatic and electrolyte parameters. There were no apparent side effects to therapy. During treatment, 3 patients died: 1 of CHF and pneumonia (who had very poor pre-existing cardiac function), 1 of newly-diagnosed advanced renal cell carcinoma, and 1 from progressive MM. Results reveal no statistically significant change in monoclonal protein or CRP levels during therapy. This study of elderly patients with progressive or refractory MM fails to show a benefit from clarithromycin therapy. At the conclusion of the study period, there were no significant changes in M-spike, CRP, or b2M. The above findings and the recent report of Stewart et al. (Blood 93, 4441, 1999) suggest that clarithromycin is not a useful salvage therapy for MM patients who have failed standard treatment.

  2. Lack of Response to Short-Term Use of Clarithromycin (BIAXIN) in Multiple Myeloma.

    A.K. Stewart, S. Trudel, B.M. Al-Berouti, D.M. Sutton, J. Meharchand, and C. Shustik. Blood 1999 93: 4441-4442.

  3. Lack of efficacy of clarithromycin in advanced multiple myeloma. Intergroupe Francais du Myelome.

    Moreau P, Huynh A, Facon T, Bouilly I, Sotto JJ, Legros L, Milpied N, Attal M, Bataille R, Harousseau JL. Leukemia 1999 Mar;13(3):490-491.