Results of a small Phase 2 study show that the four-drug combination therapy of Revlimid, Velcade, Doxil, and dexamethasone may be an effective and tolerable treatment option for relapsed and refractory multiple myeloma patients.

According to the study investigators, the four-drug regimen compares favorably to the three-drug combination without Revlimid in that it improves response rates without a significant increase in side effects.

The investigators recommend that future trials further investigate the number and specific types of previous treatments to identify those in which the Revlimid, Velcade, Doxil, and dexamethasone combination may work best as subsequent treatment.

In recent years, the use of novel agents such as Velcade ^[1] (bortezomib) and Revlimid ^[2] (lenalidomide) has become the standard of care for multiple myeloma patients. Combination regimens containing these agents have led to greater response rates than any anti-myeloma drug alone.

Doxil ^[3] (doxorubicin liposomal) is an anticancer agent marketed by the Johnson & Johnson (NYSE: JNJ) subsidiary Janssen Biotech.  It kills myeloma cells by damaging their DNA.

Doxil has the same active ingredient as the chemotherapy agent doxorubicin ^[4](Adriamycin), but in Doxil the active ingredient is coated so that it stays in the body longer. Doxil has been in short supply during the past year due to manufacturing problems.  To alleviate this shortage, the U.S. Food and Drug Administration last month decided to allow the temporary importation of Lipodox, a version of Doxil marketed by Sun Pharma.

Doxil has demonstrated promising anti-myeloma activity in relapsed or refractory patients when administered in combination with Velcade and dexamethasone ^[5] (Decadron) (see related Beacon ^[6] news). To further improve the efficacy of this regimen, clinical studies are being conducted to assess the addition of a fourth drug.

In an earlier Phase 1/2 trial evaluating the addition of Revlimid to Velcade, Doxil, and dexamethasone in newly diagnosed myeloma patients, the four-drug regimen, sometimes referred to as RVDD or DVD-R, led to a high response rate (96 percent) but poor tolerability. More recent studies have modified the dosing and scheduling of drug administration in this combination with the hope of maintaining efficacy while reducing the side effects.

The results indicated that lower doses of Velcade in addition to lower doses and more frequent administration of Doxil during a longer treatment cycle led to comparable response rates while improving tolerability.

Based on these findings, researchers led by Dr. James Berenson at the Institute for Myeloma and Bone Cancer Research sought to evaluate the efficacy and safety of this modified four-drug regimen in relapsed or refractory multiple myeloma patients.

A total of 40 relapsed and/or refractory myeloma patients with a median age of 70 years were enrolled in the trial. The patients had received a median of three prior lines of therapy, including 43 percent who had received a Velcade, Doxil, and dexamethasone combination and 25 percent who had prior treatment with Revlimid, Velcade, Doxil, and dexamethasone.

The patients received up to eight 28-day cycles of 4 mg/m² of Doxil, 1 mg/m² of Velcade, and 40 mg of dexamethasone on days 1, 4, 8, and 11 plus 10 mg of Revlimid on days 1 through 14.

The median follow-up time was 11 months.

Overall, 49 percent of the study participants responded to the four-drug combination: 21 percent of patients achieved a complete response, 10 percent a very good partial response, and 18 percent a partial response. An additional 36 percent of patients achieved a minimal response.

By comparison, results of a previous trial had shown that among relapsed and refractory patients who received a similar treatment schedule with Velcade, Doxil, and dexamethasone, 4 percent achieved a complete response, 11 percent a very good partial response, 29 percent a partial response, and 18 percent a minimal response.

The researchers noted that for the current study, 77 percent of patients who had progressed on a prior regimen of Velcade, Doxil, and dexamethasone achieved at least a minimal response with the four-drug combination. Furthermore, of the patients who were previously treated with this four-drug regimen, 60 percent achieved at least a minimal response after receiving this combination with a modified dose and schedule of drug administration.

The median time to the best response was two months, and the median duration of response was 12 months.

The median progression-free survival time was nine months, and median overall survival time has not been reached yet.

The most commonly observed side effects included fatigue (40 percent), low platelet counts (35 percent), low white blood cell counts (35 percent), anemia (30 percent), nerve damage in the extremities, also called peripheral neuropathy, (25 percent), and pneumonia (15 percent).

For more information, please see the study in the journal Leukemia ^[7] (abstract).