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Daratumumab Shows Promise As Treatment For Relapsed / Refractory Multiple Myeloma (ASCO 2012)
By: Howard Chang; Published: June 7, 2012 @ 3:13 pm | Comments Disabled
Interim results of an ongoing early-stage clinical trial indicate that daratumumab is safe as a treatment for relapsed and refractory multiple myeloma. In addition, daratumumab showed promising activity in the trial participants.
Dr. Torben Plesner of Vejle Hospital in Denmark presented the preliminary results of the Phase 1/2 study at the 48th annual meeting of the American Society of Clinical Oncology (ASCO) on Monday.
“The efficacy [of daratumumab] looks very promising,” said Dr. Andrzej Jakubowiak, the director of the myeloma program at the University of Chicago, who was not involved in the study.
Dr. Leif Bergsagel from the Mayo Clinic in Arizona, who also was not involved in the study, agreed with Dr. Jakubowiak’s assessment of daratumumab.
“It appears to be the most promising monoclonal antibody for multiple myeloma to date and one of the most promising truly novel agents for multiple myeloma. It appears to have low toxicity and ought to combine well with other regimens,” said Dr. Bergsagel.
Dr. Plesner and his colleagues will evaluate the long-term safety and efficacy of daratumumab in the Phase 2 part of the trial. He added that additional studies with myeloma patients are planned that will look at continuous daratumumab therapy as well as daratumumab in combination with Revlimid [1] (lenalidomide) or Velcade [2] (bortezomib) plus dexamethasone [3] (Decadron).
“What we have observed from treatment with daratumumab as a single agent for a short period of time may be improved by prolonged treatment with the antibody and combinations with other anti-myeloma drugs,” said Dr. Plesner.
Daratumumab [4] is being developed by the Danish pharmaceutical company Genmab. It belongs to the same class of drugs – called monoclonal antibodies – as elotuzumab [5] and siltuximab [6]. Specifically, daratumumab binds a protein called CD38, which is found on the surface of multiple myeloma cells. It then signals for the immune system to kill the myeloma cells.
In the current Phase 1 part of the study, researchers sought to investigate the safety profile of daratumumab and to determine the maximum tolerated dose of the drug in relapsed or refractory myeloma patients.
To date, the study has enrolled 29 relapsed or refractory myeloma patients.
All patients had relapsed after receiving at least five prior lines of therapy, including Velcade, Revlimid, and thalidomide [7] (Thalomid); 67 percent of patients had also received a stem cell transplant before entering the study.
Patients received varying doses of daratumumab ranging from 0.005 mg/kg up to 16 mg/kg for eight weeks.
After some patients developed infusion-related reactions, dexamethasone was added to the treatment regimen.
According to Dr. Plesner, patients received a total of 200 mg of dexamethasone over an eight-week period, which is equivalent to 25 mg of dexamethasone per week per patient. Dr. Plesner explained that this dose is less than what is referred to as “low-dose” dexamethasone (40 mg per week).
At the most recent follow-up, researchers found that 24 percent of patients have achieved a partial response. An additional 14 percent of patients have achieved a minimal response, and 24 percent of patients have stable disease.
“Since the patients enrolled in the trial have been heavily pretreated, we do not think that the responses observed are caused by dexamethasone,” said Dr. Plesner.
Dr. Bergsagel agreed with Dr. Plesner’s assessment of the response rates. “I would expect most of the patients entered in this study would have had a lot of dexamethasone in their previous regimens, and I think it unlikely they would have much of a response to dexamethasone alone at this point,” he explained.
Of the patients who received 1 mg/kg or below of daratumumab, 47 percent experienced a reduction in their blood or urine monoclonal protein levels.
Monoclonal proteins are produced by abnormal plasma cells and are often measured in blood and urine tests to track the progress of multiple myeloma. Reductions in monoclonal protein levels typically signify a decrease in the number of active myeloma cells in the body.
Of the three patients who received 2 mg/kg of daratumumab, one patient experienced a 67 percent reduction of monoclonal proteins in the blood and a 55 percent reduction of monoclonal proteins in the urine.
Dr. Plesner pointed out that starting at 4 mg/kg, more systematic responses to treatment could be observed with a marked reduction in monoclonal protein levels.
“Importantly, biochemical responses were accompanied by clearance of myeloma cells from the bone marrow,” he added.
All three of the patients who received 4 mg/kg of daratumumab experienced reductions in their blood monoclonal protein levels by 49 percent, 64 percent, and 100 percent, respectively. These patients also experienced a significant reduction in the percentage of plasma cells in the bone marrow (80 percent, 89 percent, and 97 percent).
Similarly, all three of the patients who received 8 mg/kg of daratumumab also experienced reductions in their blood monoclonal protein levels by 4 percent, 39 percent, and 100 percent, respectively.
Two out of three patients who received 16 mg/kg of daratumumab experienced reductions in their monoclonal protein levels. One patient had a 50 percent reduction of blood monoclonal proteins, and the other patient had a 33 percent reduction of urine monoclonal proteins.
“The signs of response we see primarily from a dose level of 4 mg/kg and upwards has caused a good deal of optimism among investigators,” said Dr. Plesner.
The most common treatment-related side effects included fever (31 percent of patients), cough (21 percent), high blood pressure (14 percent), and nausea (14 percent).
The most common blood-related side effects included low white blood cell counts (21 percent) and low red blood cell counts (17 percent).
Fourteen percent of patients experienced severe side effects, including low red blood cell and platelet counts, abnormal liver function tests, spasms of the airways making breathing difficult, and an inflammatory syndrome.
Two patients experienced a dose-limiting toxicity that required a reduction in daratumumab dosing.
The maximum tolerated dose has not been established yet.
For more information, please see the slide deck [8] for Dr. Plesner’s presentation, which he has made available as a courtesy to The Beacon’s readers, and abstract 8019 [9] at the ASCO 2012 meeting [10] website.
Article printed from The Myeloma Beacon: https://myelomabeacon.org
URL to article: https://myelomabeacon.org/news/2012/06/07/daratumumab-shows-promise-as-treatment-for-relapsed-refractory-multiple-myeloma-asco-2012/
URLs in this post:
[1] Revlimid: https://myelomabeacon.org/resources/2008/10/15/revlimid/
[2] Velcade: https://myelomabeacon.org/resources/2008/10/15/velcade
[3] dexamethasone: https://myelomabeacon.org/resources/2008/10/15/dexamethasone/
[4] Daratumumab: https://myelomabeacon.org/tag/daratumumab/
[5] elotuzumab: https://myelomabeacon.org/tag/elotuzumab/
[6] siltuximab: https://myelomabeacon.org/tag/siltuximab/
[7] thalidomide: https://myelomabeacon.org/resources/2008/10/15/thalidomide
[8] slide deck: http://bit.ly/KlFNK3
[9] abstract 8019: http://abstract.asco.org/AbstView_114_96350.html
[10] ASCO 2012 meeting: http://chicago2012.asco.org/
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