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:
From http://myeloma.org/TheIMF/Support/imf_supstn.html
"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:
Recently, Durie et al (Blood 90:579a, 1997
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.
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.
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.
COMBINATION NON-MYELOSUPPRESSIVE THERAPY (THALIDOMIDE, CLARITHROMYCIN, DEXAMETHASONE) FOR PLASMA CELL MYELOMA: A PRELIMINARY REPORT.
Clarithromycin (Biaxin®) as primary treatment for myeloma.
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.