The results of a recent Phase 2 clinical trial suggest that siltuximab in com­bi­na­tion with dexa­metha­sone may be effective for some multiple myeloma patients resistant to prior dexa­metha­sone-containing treatments. However, siltuximab in combination with high-dose dexa­metha­sone may be associated with a high rate of serious side effects.

Dr. Peter Voorhees from the Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, presented these results at the 2011 American Society of Hematology (ASH) conference in San Diego last month.

Although Dr. Voorhees and his colleagues concluded that the combination of siltuximab and dexa­metha­sone was well tolerated, Dr. Craig Hofmeister from the Ohio State University College of Medicine described the combination as a “toxic regimen.”

Dr. Hofmeister, who was not involved with the study, cautioned that siltuximab and similar drugs predispose patients to infection.  In this particular trial, 4 percent of patients died due to infections.  He also indicated that siltuximab has yet to demonstrate anti-myeloma activity that outweighs harm, although he stated that it was unclear whether siltuximab or high-dose dexa­metha­sone was responsible for the serious side effects observed in this trial.

Siltuximab is a compound that blocks the activity of IL-6, a protein that facilitates myeloma cell growth and resistance to dexa­metha­sone ^[1] (Decadron). It is being developed by Janssen Biotech, a Johnson & Johnson company (NYSE: JNJ), and has been investigated for the treatment of prostate cancer, ovarian cancer, metastatic renal cell cancer, and Castleman's disease (the overgrowth of lymphatic cells). Siltuximab in combination with Velcade ^[2] (bortezomib), dexa­metha­sone, or melphalan ^[3] (Alkeran) has demonstrated anti-myeloma activity in preclinical trials.

In this Phase 2 study, researchers investigated the combined effects of siltuximab and dexa­metha­sone for the treatment of relapsed and/or refractory multiple myeloma.

The trial included 53 heavily pretreated myeloma patients; however, only 49 patients were treated with siltuximab plus dexa­metha­sone and were included in the analyses.

Prior to the start of the trial, the participants had been treated with a median of four lines of therapy.  All had previously been treated with Velcade and a steroid; almost all had previously received an immuno­modu­la­tory agent – such as Revlimid ^[4] (lenalidomide) or thalidomide ^[5] (Thalomid) – and an alkylating agent – such as melphalan; and two-thirds underwent an autologous stem cell transplant.

Eighty-six percent of the participants were resistant to their last therapeutic regimen.  Of the 44 patients with prior exposure to dexa­metha­sone, 73 percent were resistant to their last dexa­metha­sone-containing regimen.

The first 14 patients enrolled in the study received 6 mg/kg of siltuximab intravenously on days 1 and 15 of a 28-day cycle. After one or two cycles, 10 of these patients added 40 mg of dexa­metha­sone on days 1 to 4, 9 to 12, and 17 to 20 due to progressive disease or a low response. The remaining 39 patients received siltuximab and dexa­metha­sone each cycle, since none of the first 14 patients achieved at least a partial response with siltuximab monotherapy.

Patients remained on this treatment regimen for a median of four cycles. Of the 47 patients evaluated, 17 percent achieved a partial response, and 6 percent demonstrated a minimal response. Out of the patients who reached at least a minimal response, two-thirds were not able to achieve a minimal response with a previous dexa­metha­sone-containing regimen.

The median duration of response was 5.9 months, with three patients maintaining their responses for more than 9 months. The overall median progression-free survival time was 3.7 months, and the median overall survival time was 20.4 months.

Seventy-four percent of the patients experienced severe to life-threatening side effects, including low platelet counts (12 percent), fatigue (8 percent), abnormal liver function (8 percent), pneumonia (6 percent), low white blood cell counts (4 percent), and anemia (2 percent).

Twenty-five percent of the patients discontinued treatment due to side effects, and 10 percent of patients died during the study due to progressive disease or infection.

For more information, see abstract 3971 ^[6] on the ASH 2011 meeting website.