Siltuximab May Be Effective In Certain Patients With Advanced Multiple Myeloma (ASH 2011)
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 (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 (bortezomib), dexamethasone, or melphalan (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 (lenalidomide) or thalidomide (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 on the ASH 2011 meeting website.
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- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
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This seems to be quite a toxic regimen with little success to show for it. Immunotherapy and genetically engineered approaches will be the answer one day (soon we all hope) for Myeloma and many other cancers. Of course, basic science to look for etiology, and prevention will be important. Keep on working on it!
Dr. Hofmeister's point is well taken. To clarify, we should have stated that the toxicity/side effect profile was in line with what would be expected of high-dose dexamethasone alone, an intervention that in and of itself is highly immunosuppressive. That being said, infection did stand out as an important toxicity of our regimen. Given the role of IL-6 in immune system function, it is certainly possible that the addition of siltuximab increased the risk of infection. An on-going randomized study of melphalan/prednisone/bortezomib with placebo or siltuximab will help clarify this issue.
Our study enrolled patients several years ago. With emerging data on the increased risk of toxicity with high-dose dexamethasone, high dose steroids are falling out of favor in myeloma. In line with this trend, on-going studies with siltuximab are appropriately utilizing lower doses of steroids than what were used in our study.
Although the activity of the regimen was not as robust as we would have liked, we did see responses in patients who would not have been expected to respond to dexamethasone alone and in patients with refractory disease. This would suggest that siltuximab may make the dexamethasone work better in select patients. On-going randomized studies (like the one noted above) will help determine whether siltuximab will enhance the efficacy of proteasome inhibitor/steroid-based therapy.
Thank you for your thoughtful response. Best wishes on your investigations! Jan
Well maybe if you could identify which patients are likely to benefit, this treatment might make sense. Otherwise, it strikes me as yet another poisonous regimen at the expense of patients suffering from an incurable cancer.
I also have NEVER head that high dose DEX is associated with similar toxicity. Immunosuppressive - maybe. Poisonous - no.
Hi Dr. Voorhees, Thanks for the update on your findings. Is it true that dexamethasone is destructive of bone? I did hear that from other patients when I was taking it, and since MM has the effect of destroying bone also, wonder about that issue.
did I read this right? seventy four percent experienced severe to life threatening or serious side effects yet Dr voorhees and his colleagues concluded that the combination was well tolerated. where is the logic or better yet the patient benefit in this thinking?
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