Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma

Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
American Journal of Hematology (Impact Factor: 3.8). 09/2010; 85(9):664-9. DOI: 10.1002/ajh.21777
Source: PubMed


The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, P = 0.071), and progression-free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results.

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Available from: Shaji K Kumar, Dec 12, 2014
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    • "Therefore, enhanced cytotoxicity could be explained in terms of loading excess ER-stress in CML cells. Interestingly, BiRD therapy consisting of Baixin (CAM), Revlimid (lenalidomide) and dexamethasone resulted in high complete and overall response rates in MM, although the molecular mechanism for using CAM was not clarified (46,47). CAM has immunomodulatory properties, partially mediated by the suppression of interleukin-6 and other inflammatory cytokines. "
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    ABSTRACT: The specific 26S proteasome inhibitor bortezomib (BZ) potently induces autophagy, endoplasmic reticulum (ER) stress and apoptosis in multiple myeloma (MM) cell lines (U266, IM-9 and RPMI8226). The macrolide antibiotics including concanamycin A, erythromycin (EM), clarithromycin (CAM) and azithromycin (AZM) all blocked autophagy flux, as assessed by intracellular accumulation of LC3B-II and p62. Combined treatment of BZ and CAM or AZM enhanced cytotoxicity in MM cell lines, although treatment with either CAM or AZM alone exhibited almost no cytotoxicity. This combination also substantially enhanced aggresome formation, intracellular ubiquitinated proteins and induced the proapoptotic transcription factor CHOP (CADD153). Expression levels of the proapoptotic genes transcriptionally regulated by CHOP (BIM, BAX, DR5 and TRB3) were all enhanced by combined treatment with BZ plus CAM, compared with treatment with each reagent alone. Like the MM cell lines, the CHOP+/+ murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and upregulation of CHOP and its transcriptional targets with a combination of BZ and one of the macrolides. In contrast, CHOP-/- MEF cells exhibited resistance against BZ and almost completely canceled enhanced cytotoxicity with a combination of BZ and a macrolide. These data suggest that ER stress-mediated CHOP induction is involved in pronounced cytotoxicity. Simultaneously targeting two major intracellular protein degradation systems such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome system by a macrolide antibiotic enhances ER stress-mediated apoptosis in MM cells. This result suggests the therapeutic possibility of using a macrolide antibiotic with a proteasome inhibitor for MM therapy.
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    • "Furthermore, clinical experience with lenalidomide indicates that early use in MM therapy is associated with a higher response rate and, possibly, prolonged survival [30]. To further improve the outcome of lenalidomide, combination regimens (BiRd, VRD, RAD, VDCR, and VRDD) [31] [32] [33] [34] [35] have been evaluated or are under investigation in both old and young MM patients, in transplant and non transplant settings. MM has been chosen for this article with the purpose of showing our current knowledge on the mechanisms of antitumor activity of lenalidomide. "
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    • "A case-matched study compared clarithromycin-lenalidomide plus low-dose dexamethasone (BiRd) with Rd as initial therapy for newly diagnosed MM patients [15]. Seventy-two patients treated with either BiRd or Rd were included in this retrospective analysis. "
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