Elotuzumab Combination Continues To Show Promise As Treatment For Multiple Myeloma (ASCO 2012)
Elotuzumab in combination with Revlimid and dexamethasone continues to show promise in relapsed and refractory myeloma patients, according to updated results from an ongoing Phase 2 clinical trial.
Response rates continued to be high, particularly among study participants receiving the lower elotuzumab dose. In addition, the rate of severe side effects remained low.
Dr. Philippe Moreau from the University Hospital in Nantes, France, presented the results last Monday at the 48th annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
“This combination seems to be highly active in relapsed and refractory myeloma patients,” said Dr. Andrzej Jakubowiak, the director of the myeloma program at the University of Chicago, during a presentation accompanying Dr. Moreau’s talk. “The data for this patient population is very convincing to me,” he added.
Elotuzumab, which is being developed by Bristol-Myers Squibb (NYSE: BMY), belongs to a class of drugs called monoclonal antibodies. Monoclonal antibodies work by identifying proteins on the surface of myeloma cells and signaling for the immune system to destroy the cancer cells. Other compounds in this class of drugs include daratumumab and siltuximab, which are in earlier phases of clinical development than elotuzumab.
The Phase 2 elotuzumab study included 73 relapsed / refractory myeloma patients with a median age of 63 years.
All patients were required to have had one to three previous lines of therapy. Fifty-five percent of patients had received at least two prior therapies. Sixty percent of patients had received prior treatment with Velcade (bortezomib), and 62 percent had received prior treatment with thalidomide (Thalomid). Patients who previously had received Revlimid (lenalidomide) were not eligible to participate in the trial.
Thirty-six patients received 10 mg/kg of intravenous elotuzumab on days 1, 8, 15, and 22 of the first two 28-day treatment cycles, and on days 1 and 15 of subsequent cycles. The remaining 37 patients received 20 mg/kg of intravenous elotuzumab on the same days.
The patients also received 25 mg of Revlimid on days 1 to 21, along with 40 mg of dexamethasone (Decadron) orally once per week or 28 mg dexamethasone orally plus 8 mg dexamethasone by intravenous infusion on elotuzumab dosing days.
The overall response rate was 84 percent for all patients.
Preliminary results of the study presented at the American Society of Hematology’s annual meeting in December indicated that the lower dose seems to be more effective than the higher dose (see related Beacon news).
Dr. Moreau confirmed that trend during his presentation on Monday: The overall response rate continued to be higher among patients who received 10 mg/kg of elotuzumab (92 percent), compared to patients who received 20 mg/kg of elotuzumab (76 percent).
Among patients treated with just a single previous line of therapy, all patients who received 10 mg/kg and 82 percent of patients who received 20 mg/kg of elotuzumab responded.
“[These results] indicate that this combination could also be effective in frontline treatment,” said Dr. Moreau.
Among patients who received two or more prior lines of therapy, the response rates remained high for both dosing groups (85 percent and 70 percent, respectively).
According to Dr. Moreau, the response rate was also high among patients with high-risk chromosomal abnormalities. However, he pointed out that the share of patients with high-risk chromosomal abnormalities was small in this study (14 percent), so results need to be interpreted cautiously.
Dr. Moreau also mentioned that patients showed a rapid response to treatment. The median time to response was one month, and the median time to best response was 2.5 months.
According to Dr. Moreau, the high response rate was also associated with a prolonged response duration. After a median follow-up time of 17.2 months, the median progression-free survival has not been reached yet for patients in the 10 mg/kg treatment group and was 19 months for patients in the 20 mg/kg treatment group.
“These data are really encouraging when compared to those achieved with Revlimid and high-dose dexamethasone,” said Dr. Moreau.
The median progression-free survival for patients with high-risk chromosomal abnormalities was nine months, which Dr. Moreau also described as encouraging.
According to Dr. Moreau, the treatment was well tolerated at both dose levels. The most common severe side effects were blood-related and included low red blood cell counts, low white blood cell counts, and low platelet counts.
Dr. Moreau pointed out that only one patient developed infusion-site reactions, a common side effect of monoclonal antibodies.
The researchers observed four cases of second cancer among the trial participants.
The main reason for treatment discontinuation was disease progression.
Two Phase 3 trials of elotuzumab in combination with Revlimid and dexamethasone have been initiated in both newly diagnosed and relapsed and refractory myeloma patients.
One of these trials will include 750 newly diagnosed myeloma patients who are ineligible for stem cell transplantation. The other one will include 640 relapsed and refractory myeloma patients who have received between one to three prior therapies. The lower dose from the Phase 2 trial (10 mg/kg) will be used in the Phase 3 trials.
Elotuzumab is also being investigated in a Phase 2 trial in combination with Velcade and dexamethasone in relapsed and refractory myeloma patients. This trial will include 150 relapsed and refractory myeloma patients.
Patients will be evaluated for response in all three trials. Progression-free survival and overall survival will also be tracked.
For more information on the Phase 2 trial results, please see abstract 8020. For a description of the new trials, please see abstracts TPS8112, TPS8113, and TPS8114 on the ASCO meeting website.
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- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
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This is very encouraging data! The ongoing phase 3 studies should be instrumental for FDA approval of this important option for recurrent MM disease, probably in 2013. Now we need studies of elotuzumab with pomalinomide and dex, and other monoclonal antibodies. Maybe even lower doses will be most efficacious, and should be studied.
Why were patients who had been previously treated with Revlimid not a part of this study? Thank you.
Hello Joanne,
That is a very good question. We have forwarded your question to one of the study investigators and will post a reply as soon as we hear back from him.
Just wondering if this is the reason:
"The patients also received 25 mg of Revlimid on days 1 to 21, along with 40 mg of dexamethasone (Decadron) orally once per week or 28 mg dexamethasone orally plus 8 mg dexamethasone by intravenous infusion on elotuzumab dosing days."
Hadn't they already shown that elotuzumab doesn't have efficacy unless it is given with Revlimid...so patients refractory to Revlimid would show no effect?
I think there are data that elotuzumab and Revlimid both have more activity against myeloma cells if they are administered together than either one has on their own. Wasn't there a poster or presentation at ASCO about that?
It's not clear to me that patients who have stopped responding to Revlimid in the past wouldn't respond to this combination. I once heard a myeloma expert say that, after you have had several treatments as a myeloma patient, there is always a chance you'll respond to a previous treatment that you've received, although the response may not last very long.
In this case, though, the design of the trial was such that patients only had a couple of previous therapies. So, given that restriction, the patients best suited to be treated with this combination almost certainly would be patients who hadn't yet been treated with Revlimid. The investigator may well have considered it unethical to treat patients with this combination if they've already received treatment with Revlimid.
"Notably, the 22 patients who had NOT been previously treatment with Revlimid achieved an overall response rate of 95 percent (73 percent partial response, 23 percent very good partial response). After 8 months, the median time to disease progression has not yet been reached, as only 39 percent of patients have progressed."
http://www.myelomabeacon.com/news/2010/06/21/elotuzumab-combinations-show-encouraging-results-in-multiple-myeloma-asco-2010/
Thanks for digging up that article, suzierose.
Those results are interesting because, if I did the math right, it means that a third of the patients who previously had been treated with Revlimid still responded to the elotuzumab-Revlimid combination. I'm not sure I would have predicted that so many of those patients would have responded.
Of course, one third is a lot less than 95 percent, which -- as you suggested -- probably explains why Revlimid-treated patients were excluded from the later trial.
Hi Ricardo,
A third of the patients getting PR is not impressive..and neither is elotuzmab.
We've corresponded a bit with Dr. Lonial about why patients who previously had been treated with Revlimid were excluded from this trial.
The rationale has more to do with practical considerations than one might have expected. When the trial was being designed, there already were expectations that the elotuzumab combination might go on to be tested in two different Phase 3 trials -- one with newly diagnosed (previously untreated) myeloma patients, and one with recently relapsed/refractory patients. And, in fact, two Phase 3 trials of that sort have been started.
A very important question that comes up when planning Phase 3 trials is: How large will they have to be to provide results that will be considered statistically significant by government regulators like the Food and Drug Administration?
To answer that question, researchers look to results from earlier studies. Response rates from different sets of patients tested in earlier studies can give guidance on how large a Phase 3 trial should be. The more similar the previous trials have been in comparison to a planned Phase 3 trial, the better the previous trials will give guidance on how large the Phase 3 trial should be.
Thus, when planning the Phase 2 trial described above, the researchers excluded patients who had previous Revlimid treatment so that the Phase 2 trial could provide guidance on the size needed for the two different Phase 3 trials that were already in the early stages of planning: the trial with newly diagnosed myeloma patients (who also will have had no previous treatment with Revlimid), and the trial with recently relapsed myeloma patients (since the Phase 2 trial also had relapsed/refractory patients in it).
Thanks again for the question on this.
I have read in the comments using elotuzumab probably be approved next year, ie in 2013. Is this right? Is there a date certain about it, in particular as regards paritir of when it will begin marketing. Also, what other components are developing monoclonal or already available for the treatment of multiple myeloma? In the short term, what are the new treatments for multiple myeloma more hopeful?