Results of a recent Phase 2 clin­i­cal trial in Denmark raise questions about the future role of the antibiotic clarithro­mycin (Biaxin) in the treat­ment of multiple myeloma.

Previous research has suggested that adding clarithromycin to standard myeloma treat­ment regi­mens could im­prove treat­ment efficacy without a sig­nif­i­cant increase in side effects.

As a result, clarithromycin-containing regi­mens such as “BiRd” (Biaxin, Revlimid, and dexa­meth­a­sone) have been employed by some myeloma specialists to treat both newly diag­nosed and re­lapsed patients.

The recent Danish trial, however, found that adding clarithromycin to the com­bi­na­tion of Velcade (bor­tez­o­mib), cyclophosphamide (Cytoxan), and dexa­meth­a­sone (VCD) did not im­prove the efficacy of that regi­men in newly diag­nosed, trans­plant-eligible myeloma

Furthermore, the addi­tion of clarithromycin was asso­ci­ated with a greater number of serious side effects, particularly gastro­in­tes­ti­nal side effects, but also in­fec­tion-related and blood cell count-related side effects.

Based on their findings, the researchers who carried out the Danish trial do not recommend further investigation of clarithromycin-Velcade com­bi­na­tions as treat­ment for multiple myeloma.

Background

A number of clin­i­cal studies over the past 15 years have suggested that combining the antibiotic clarithro­mycin (Biaxin) with standard myeloma treat­ment regi­mens – particularly regi­mens con­taining immuno­modu­la­tory agents such as thalido­mide, Revlimid, and Pomalyst (poma­lido­mide) –could im­prove treat­ment efficacy without a sig­nif­i­cant increase in side effects.

One study, for example, found that adding clarithromycin to the com­bi­na­tion of Revlimid and dexa­meth­a­sone could sub­stan­tially increase treat­ment response in newly diag­nosed multiple myeloma (reference; Beacon news story about a related study). Another study found that the com­bi­na­tion of clarithro­mycin, Pomalyst, and dexa­meth­a­sone led to promising response rates in re­lapsed multiple myeloma (related Beacon news story and forum discussion).

Preclinical research also has suggested that combining clarithromycin with Velcade could im­prove Velcade’s ability to treat multiple myeloma.

No pre­vi­ous study, however, has assessed the impact of clarithromycin on the efficacy and safety of myeloma treat­ment regi­mens by ran­domly assigning patients in a clin­i­cal trial to receive treat­ment with, or without, clarithro­mycin in addi­tion to other myeloma treat­ments. Organizing a trial in that way is the best way to determine the impact a drug has on patients.

Danish researchers therefore decided to organize a ran­dom­ized, placebo-controlled trial to test the impact of adding clarithro­mycin to Velcade, cyclophosphamide, and dexa­meth­a­sone (VCD) as in­duc­tion (initial) ther­apy in newly diag­nosed multiple myeloma patients who were eligible for stem cell trans­plan­ta­tion.

Study Design

The trial the Danish researchers organized included 58 newly diag­nosed, trans­plant-eligible myeloma patients with a median age of 63 years. The researchers originally planned to enroll 160 patients in the trial. The study was halted early, however, due to safety concerns.

Patients in the study were ran­domly assigned to receive either 500 mg of clarithromycin or a placebo (sugar pill) twice daily. All patients also were admin­istered 1.3 mg/m² of sub­cu­tane­ous Velcade on days 1, 4, 8 and 11, 500 mg/m² of cyclophosphamide on days 1 and 8, and 40 mg of oral dexa­meth­a­sone on days 1, 2, 4, 5, 8, 9, 11 and 12 in a 21-day treat­ment cycle.

The patients in the study originally were scheduled to receive three cycles of induction ther­apy before proceeding to stem cell trans­plan­ta­tion. However, the induction ther­apy was extended to four treat­ment cycles due to changes in the Danish guidelines for the treat­ment of multiple myeloma while the trial was ongoing.

Study Results

The trial results show that the addi­tion of clarithromycin did not im­prove the efficacy of the Velcade-based treat­ment com­bi­na­tion. Specif­i­cally, 44 per­cent of the patients who received clarithro­mycin plus the Velcade com­bi­na­tion achieved a very good partial response (VGPR) or better, compared to 52 per­cent of patients who received the Velcade com­bi­na­tion alone.

Almost all patients in both treat­ment groups ex­peri­enced side effects of any grade (96 per­cent of patients who received clarithro­mycin and the Velcade com­bi­na­tion, versus 90 per­cent of patients who received the Velcade com­bi­na­tion alone).

The rate of serious (grade 3 or higher) side effects was sig­nif­i­cantly higher, however, in patients who received clarithro­mycin and the Velcade com­bi­na­tion compared to those who received the Velcade com­bi­na­tion alone (59 per­cent versus 32 per­cent).

The difference in serious effects was particularly noticeably for serious gastro­in­tes­ti­nal side effects (26 per­cent versus 3 per­cent) and serious blood stream in­fec­tions (19 per­cent versus 3 per­cent).

The frequency of periph­eral neu­rop­athy and low blood cell counts also was higher in the patients who received clarithro­mycin. Almost half of the patients who received clarithro­mycin as part of their treat­ment ex­peri­enced low platelet counts, for example, compared to less than a quarter of the patients who received the placebo instead of clarithro­mycin.

The side effects ex­peri­enced by the patients who received clarithromycin had a real impact on their quality of life. The researchers who conducted the trial surveyed the patients about their quality of life at the beginning of the study, after two months of treat­ment, and six months after the start of the study. Patients who in the clarithro­mycin group had sub­stan­tially lower quality of life during their induction ther­apy.

Based on the noticeably higher incidence of serious side effects in the clarithromycin-treated patients, the study safety board recommended halting the clin­i­cal trial.

In their report summarizing the trial results, the Danish researchers offer a poten­tial explanation for the impact clarithro­mycin had on the frequency and severity of side effects seen in the trial partic­i­pants. The authors note that clarithro­mycin interferes with the body’s processing of Velcade, increasing the length of time the drug is in the body. This has the same effect as increasing the dose of the drug, and higher doses of Velcade generally are asso­ci­ated with more side effects, such as neu­rop­athy, gastro­in­tes­ti­nal upset, and lower blood cell counts.

For more in­­for­ma­tion, please see the study by Gregersen, H. et al., “A ran­dom­ized placebo-controlled phase II study of clarithro­mycin or placebo com­bined with VCD in­duction ther­apy prior to high-dose mel­phalan with stem cell sup­port in patients with newly diag­nosed multiple myeloma,” in Experimental Hematology & Oncology, August 13, 2018 (full text).

The researchers also have published an analysis of the quality of life data from the trial. See Nielsen, L.K., et al., “Clarithro­mycin added to bor­tez­o­mib-cyclophosphamide-dexamethasone im­pairs health-related quality of life in multiple myeloma patients,” European Journal of Haematology, September 19, 2018 (abstract).