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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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