A novel combination of bortezomib, lenalidomide, and clarithromycin produced stringent complete response in refractory multiple myeloma complicated with diabetes mellitus – clinical significance and possible mechanisms: a case report

Abstract

BackgroundIn general, dexamethasone is a required component drug in various combination chemotherapies for treating multiple myeloma, and its efficacy has been widely recognized. However, administration of dexamethasone is known to cause various adverse effects including hyperglycemia which requires insulin therapy. During the course of treatment, we developed a novel effective dexamethasone-free combination regimen and evaluated it for its effect in multiple myeloma.Case presentationWe report a case of 68-year-old Japanese woman with refractory advanced Bence-Jones-λ type multiple myeloma associated with diabetes mellitus. Various combination regimens were carried out, but the response to some regimens was insufficient or others containing dexamethasone, although effective, were inappropriate to continue due to aggravation of diabetes mellitus. Thus, we developed a dexamethasone-free, short dosing-period regimen consisting of bortezomib, lenalidomide, and clarithromycin. This regimen was found to be highly effective and succeeded in achieving stringent complete response.ConclusionsThe successful dexamethasone-free regimen clearly shows that dexamethasone is not a requisite component in treating multiple myeloma, and it can be substituted with clarithromycin. This regimen is particularly useful for treating patients with multiple myeloma associated with diabetes mellitus.

Possible mechanisms of action of clarithromycin and its clinical application as a repurposing drug for treating multiple myeloma

“…Moriya et al [93] experimentally demonstrated that combined treatment of CAM and Bor resulted in increased cytotoxicity as compared to the use of Bor alone. The effectiveness of this combined treatment with CAM, Len and Bor was recently demonstrated at the clinical level [106]. The apoptosis-inducing effect was further enhanced when vorinostat (HDAC6 inhibitor), which is known to inhibit aggresome formation, was added to Bor and CAM [94] (Figure 2).…”

Autophagy-related mechanisms for treatment of multiple myeloma

“…The combination of Suberoylanilide hydroxamic acid (Vorinostat), 17-allylamino-17-demethoxy-geldanamycin (Tanespimycin), and Clonazepam overcame the complication of peripheral neuropathy by inducing autophagy via HSP70 or LAMP-2A [165] . Moreover, the efficacy of the combination of Clarithromycin, a high-spectrum antibiotic, in MM and various cancers has been previously reported [166] . Clarithromycin's suppression of autophagy by reducing cytokines such as IL-6, which is an important factor in MM development and drug resistance, makes it a possible candidate.…”

“…Clarithromycin’s suppression of autophagy by reducing cytokines such as IL-6, which is an important factor in MM development and drug resistance, makes it a possible candidate. It was shown that the combination of Bortezomib, Lenalidomide, and Clarithromycin would also be suitable for therapy without Dexamethasone in MM patients with diabetes [ 167 ] . The combination of Vorinostat, Bortezomib, and Clarithromycin in MM cells causes cell death and upregulation of CHOP genes that stimulate ER stress [ 137 ] .…”

Autophagy: A Potential Therapeutic Target to Tackle Drug Resistance in Multiple Myeloma

“…According to an experimental study by Moriya et al, using CAM and bortezomib together led to more cytotoxic effects than monotherapy with Bortezomib [ 93 ]. Recently, clinical studies showed the efficacy of combination therapy, including bortezomib, CAM, and lenalidomide [ 143 ]. Once vorinostat (HDAC6 antagonist), which is recognized to prevent aggresome synthesis, was combined with bortezomib and CAM, the apoptosis-inducing impact was improved further [ 139 ] ( Figure 4 ).…”