The results of a recent retrospective analysis show that long-term treat­ment with the combination of Revlimid, clarithromycin (Biaxin), and dexa­methasone – commonly abbreviated "BiRd" – is effective and safe in newly diagnosed myeloma patients.

Furthermore, the study did not find any significant association between long-term Revlimid ^[1] (lenalidomide) therapy and an increased risk of developing secondary cancers.

“We did expect these results. It was our sense from following patients who have been treated with lena­lido­mide [Revlimid] long-term and have not received any genotoxic therapy that we did not see increased rates of second primary malignancies,” said Dr. Ruben Niesvizky from Weill Cornell Medical College and one of the study investigators.

Dr. Niesvizky added that the emergence of secondary cancers might be related to the sequential or con­current use of Revlimid with chemotherapy drugs such as melphalan ^[2] (Alkeran) or doxorubicin ^[3] (Adria­mycin), rather than long-term exposure to Revlimid itself.

In the current study, none of the patients who received high-dose melphalan followed by a transplant were given Revlimid maintenance therapy after their transplant.

The authors of the current study point out that it does have some limitations, including its retrospective nature and the relatively small number of study participants.  They also believe that further evaluation of the relationship between long-term Revlimid therapy, treatment with alkylating agents such as melphalan, and the development of secondary cancers is still needed.

Revlimid has proven effective in both previously untreated and relapsed/refractory myeloma patients. The addition of clarithromycin ^[4] (Biaxin), an antibiotic used to treat bacterial infections, to Revlimid has been shown to improve response rates and survival times. Clarithromycin also has shown promising results when combined with Pomalyst ^[5] (pomalidomide) and dexamethasone ^[6] (Decadron) for relapsed/refractory patients (see related Beacon ^[7] news).

However, some studies investigating long-term Revlimid therapy have raised concerns of a possible relationship between long-term Revlimid usage and increased rates of secondary cancers (see related Beacon ^[8] news articles).

In the current follow-up analysis, researchers from Weill Cornell Medical College in New York City sought to investigate the effects of long-term treatment with Revlimid in previously untreated myeloma patients.

The Phase 2 trial that yielded the data for this study enrolled 72 newly diagnosed myeloma patients between December 2004 and November 2006.

Patients in the study received 25 mg of Revlimid on days 1 to 21, 500 mg of clarithromycin twice daily, and 40 mg of dexamethasone weekly on a 28-day treatment cycle. Patients could choose to receive an autologous stem cell transplant after reaching a maximum response, or to continue with the combination regimen.

Patients who opted for a stem cell transplant did not receive any maintenance therapy after the transplant.

The initial study results published in 2008 showed that 90 percent of the patients achieved a partial response or better, compared to 79 percent of patients in a comparable study where only Revlimid and dexamethasone were the treatment regimen.

After a median follow-up of 6.6 years, 14 percent of patients were still receiving Revlimid; 65 percent had relapsed and gone on to receive second-line therapy.

Approximately half of the study participants (46 percent) elected to have a stem cell transplant, followed by observation only.

Patients who chose to have a stem cell transplant received a median of 10 cycles of Revlimid, clarithro­mycin, and dexamethasone, compared to 26 cycles for patients who received continuous therapy of Rev­limid, clarithromycin, and dexamethasone with no transplant.

The overall response increased to 93 percent after a median of 6.6 years of follow up.

At the time of the analysis for the current study, the median progression-free survival time across all patients in the trial was 4.3 years, and the median overall survival has not been reached. The five-year overall survival rate was 75 percent.

The current analysis also showed that the patients who elected to have a stem cell transplant (with no follow-up maintenance therapy) did not experience any survival improvement versus the patients who did not have a transplant and continued with their therapy.

In fact, patients who received a transplant had a median progression free survival of 47 months versus 60 months for the patients who opted, instead, for continuing treatment with Revlimid, clarithromycin, and dexamethasone.

The five-year overall survival rate, however, was 75 percent for both groups of patients.

The researchers found 12 cases of secondary cancers (16.7 percent) among the study participants.  The types of secondary cancer include skin (6), colon (2), prostate, pancreas, metastatic melanoma, and lung carcinoid. There were no secondary cancers that were blood cancers, such as myelodysplastic syndromes ^[9] or acute myeloid leukemia.

The median time to secondary cancer diagnosis was 35 months.

The development of secondary cancers was not associated with chromosomal abnormalities, the number of Revlimid treatment cycles, treatment with a stem cell transplant, or disease stage.

Furthermore, the investigators pointed out that the rate of secondary cancers observed in this study (2.85 percent per year) was not significantly different from the rate expected for similarly aged individuals without myeloma (2.1 percent per year).

For more information, please see the study in the journal Blood ^[10] (abstract).