To the Editor:

In multiple myeloma (MM), interleukin-6 (IL-6) has been identified as a major cytokine involved in proliferation of the tumor clone and in tumor-associated toxicities.1,2 The central role of IL-6 as a growth factor for MM suggests that strategies to block its effects could be exploited therapeutically.

Preclinical studies have demonstrated that the macrolide antibiotic clarithromycin has immunomodulatory properties mediated in part by suppression of IL-6 and other cytokines.3 Preliminary clinical experience has subsequently also suggested efficacy of clarithromycin in the treatment of MM.4 Durie et al4 reported 6 complete and 7 partial responses from a group of 23 evaluable patients treated with clarithromycin as a single agent. This observation, even in abstract form, has generated widespread patient and physician interest in the use of clarithromycin as a novel therapy in this disease.

To further explore the use of this agent in myeloma, we have treated 23 patients with clarithromycin. The regimen consisted of clarithromycin at 500 mg administered orally twice daily on a 2 weeks on, 1 week off schedule as previously described.4 No concurrent chemotherapy, including the use of steroids, was allowed. Bisphosphonate treatment was permitted during the treatment period. Response to clarithromycin treatment was assessed using National Cancer Institute of Canada criteria.

Table 1 shows the demographic characteristics, prognostic variables, and prior treatment modalities for enrolled patients. Twenty-three myeloma patients with varying disease status were treated. Five patients were treatment naı̈ve at the time of initiation of therapy. Of these 5 patients, 2 had smouldering myeloma, 2 had asymptomatic stage 1 disease, and 1 patient with active myeloma had consistently refused all conventional therapies over a 1-year period before beginning clarithromycin. The status of the remaining patients at the time of treatment included relapsed disease (n = 3), plateau phase (n = 3), stable residual disease after bone marrow transplantation (n = 1), relapsed disease posttransplant (n = 3), and refractory disease (n = 8). Five of the 23 patients had rapidly progressive myeloma at the time of initiation of treatment.

Table 1.

Characteristics of Patients at Initiation of Treatment

Characteristics Number Range
Sex  
 Male  13 
 Female  10  
Age (yr)  49  32-78  
Stage  
 I 5  
 II  2  
 III  16  
Isotype 
 IgGκ/λ 10/5 
 IgAκ/λ  3/2  
 IgDκ 1  
 Biclonal  1  
Previous treatment  
 Untreated  
 Standard chemotherapy  10  
 Transplant  
Characteristics Number Range
Sex  
 Male  13 
 Female  10  
Age (yr)  49  32-78  
Stage  
 I 5  
 II  2  
 III  16  
Isotype 
 IgGκ/λ 10/5 
 IgAκ/λ  3/2  
 IgDκ 1  
 Biclonal  1  
Previous treatment  
 Untreated  
 Standard chemotherapy  10  
 Transplant  

Of the 23 patients enrolled, 3 received clarithromycin for less than 1 month and were thus inevaluable at the time of analysis. One patient discontinued treatment because of rapid progression of disease and 2 discontinued therapy because of drug toxicity before completing the first cycle of treatment: 1 because of gastrointestinal intolerance and 1 because of a potential drug interaction with Dilantin.

The median duration of therapy for the remaining 20 evaluable patients was 3.2 months (range, 1 to 6 months). Of the 20 patients, there were no partial or complete remissions using standard response criteria. Ten patients had stable disease and 10 patients progressed on therapy. No patients with rapidly progressing myeloma at the time of initiation of clarithromycin displayed stable disease on treatment.

In this phase II pilot study, we were unable to confirm activity of short-term treatment with clarithromycin. However, it is possible that a small treatment effect may have been missed because 11 of the 20 evaluable patients on this trial had relatively chemotherapy-insensitive disease (smouldering, plateau phase, or refractory myeloma). Nevertheless, these results suggest that clarithromycin is not an effective single agent therapy for myeloma.

REFERENCES

REFERENCES
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B
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R
Interleukin-6 in human multiple myeloma.
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1995
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Multiple myeloma: Increasing evidence for a multistep transformation process.
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Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells.
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4
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