ASCO 2012 Multiple Myeloma Update – Day Four: Immunotherapy For Myeloma
Today is the fourth day of the American Society of Clinical Oncology (ASCO) 2012 annual meeting, and the meeting continued to be filled with interesting results from clinical trials in multiple myeloma patients.
The day included a session of oral presentations in the late morning that featured results from three clinical trials involving immunotherapy agents.
The three compounds, elotuzumab, siltuximab, and daratumumab, belong to the class of drugs called monoclonal antibodies. They work by identifying proteins on the surface of myeloma cells and signal for the immune system to destroy the cancer cells. All three drugs are administered via infusion, rather than as a tablet or capsule.
The results presented during the session can be considered good news for myeloma patients. Two of the three drugs showed promising results in terms of both efficacy and tolerability, and one of those drugs -- elotuzumab -- is already in late stage clinical trials.
Elotuzumab
Elotuzumab, which is being developed by Bristol-Myers Squibb (NYSE: BMY), is the monoclonal antibody that is furthest along in clinical development for multiple myeloma.
During the session this morning, Dr. Philippe Moreau from the University Hospital in Nantes, France, presented updated results from a Phase 2 study of elotuzumab in combination with Revlimid (lenalidomide) and low-dose dexamethasone (Decadron) in patients with relapsed and refractory multiple myeloma (abstract).
The study included 73 patients. All patients were required to have had one to three previous lines of therapy. Patients previously treated with Revlimid could not participate in the trial.
Half of the patients received 10 mg/kg elotuzumab, while the other half received 20 mg/kg.
Preliminary results of the study presented at the American Society of Hematology’s annual meeting in December had already indicated that the lower dose seems to be more effective than the higher dose (see related Beacon news).
The results Dr. Moreau presented today confirmed that trend.
Overall, 92 percent of patients in the 10 mg/kg group and 76 percent in the 20 mg/kg group responded to treatment. Among patients with just a single previous line of therapy, 91 percent had a partial response or better. Median progression-free survival across all the patients in the trial has not yet been reached after a median follow-up time of 17.2 months.
Serious side effects occurred in a limited number of patients and consisted primarily of low white blood cell counts and low platelet counts. There were, however, four cases of second cancer among the trial participants.
In his review of the three presentations given during this session, Dr. Andrzej Jakubowiak from the University of Chicago said that the elotuzumab combination demonstrates "very promising" efficacy and very good tolerability. Phase 3 trials of the drug in combination with Revlimid are already ongoing in both newly diagnosed and relapsed and refractory myeloma patients.
Siltuximab
Siltuximab is being developed by Janssen Biotech, a Johnson & Johnson company (NYSE: JNJ). The antibody blocks the activity of IL-6, a protein that facilitates myeloma cell growth and resistance to dexamethasone.
Dr. Robert Orlowski from the MD Anderson Cancer Center in Houston presented results from a Phase 2 study comparing siltuximab plus Velcade (bortezomib) to Velcade alone (abstract).
The study included 286 multiple myeloma patients with one to three previous lines of therapy. Patients were not permitted to have been previously treated with Velcade.
Results showed that more patients on siltuximab plus Velcade responded to treatment (55 percent) than patients on Velcade alone (47 percent).
The median progression-free survival time was longer for patients receiving siltuximab plus Velcade (8.1 months), compared to patients receiving Velcade alone (7.6 months).
However, the median overall survival time was longer for patients receiving Velcade alone (36.9 months) compared to those receiving siltuximab plus Velcade (30.8 months).
More patients receiving siltuximab plus Velcade experienced severe or life-threatening side effects (91 percent) than patients receiving Velcade alone (74 percent).
Although the results of this trial were not what he and his colleagues initially expected, Dr. Orlowski noted that other trials investigating siltuximab as a potential treatment for myeloma are still ongoing or planned.
Dr. Orlowski has made his presentation available for download and viewing as a courtesy to The Beacon's readers.
Daratumumab
Daratumumab is being developed by the Danish pharmaceutical company Genmab. It is a monoclonal antibody that binds to the CD38 molecule, which is found on the surface of multiple myeloma cells. Daratumumab then signals for the immune system to kill the myeloma cells.
Dr Torben Plesner from Vejle Hospital in Vejle, Denmark, presented preliminary efficacy results from a Phase 1/2 study of daratumumab in relapsed and refractory myeloma patients (abstract).
Twenty-nine patients included in the study received varying doses of daratumumab up to 16 mg/kg, along with occasional doses of dexamethasone.
To participate in the trial, patients had to have at least two previous lines of therapy, and most patients had considerably more than that. All patients previously received treatment with Velcade and either Revlimid or thalidomide.
Treatment with daratumumab achieved a partial response in 24 percent of the patients, a minimal response in 14 percent of the patients, and stable disease in another 24 percent of the trial participants.
According to the researchers, the drug’s side effects at these doses are manageable. Specifically, 14 percent of patients experienced serious 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.
Dr. Plesner said that additional studies with myeloma patients are planned that will look at continuous daratumumab therapy and also daratumumab in combination with Revlimid or Velcade plus dexamethasone.
For further details, see the slide deck (PDF) for Dr. Plesner’s presentation, which he has made available as a courtesy to The Beacon’s readers.
In his discussion of the daratumumab results, Dr. Jakubowiak described the drug as "very active" with no significant toxicity issues. He also noted that the results may be even more promising than they seem at first glance. In Dr. Plesner's trial, the drug showed greater efficacy at its higher doses, and there seems to be scope to increase the dose beyond what has been tested in the trial so far.
Myeloma presentations from later today, Day 4, of the ASCO 2012 meeting also will be summarized in ASCO daily updates to be published later today or tomorrow. Additional coverage of key research results from the meeting will continue throughout the rest of the week in individual, topic-specific news articles.
For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2012 coverage.
Related Articles:
- bb2121 Continues To Impress As Potential New Multiple Myeloma Therapy (ASCO 2018)
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Darzalex May Affect Different Uninvolved Immunoglobulins Differently
- Two Darzalex Clinical Trials Halted; Little Impact Expected On Drug’s Use In Multiple Myeloma
- ASCO 2018 Update – Expert Perspectives On The Key Multiple Myeloma-Related Oral Presentations
Thanks for all of the great coverage.
It was disappointing that the above study on elotuzumab used relapsed patients that had not been exposed to Revlimid. We already know that Revlimid shows efficacy in relapsed patients that had not been exposed to Revlimid previously. Since most patients here in the US are treated with Revlimid early in disease course or as maintenance, few relapsed patients in the US will never have been exposed to Revlimid. The combo should work very well as Revlimid's ability to increase T and NK cells is synergistic with antibodies. I am concerned with 4 out of 73 developing a second cancer.
In the abstract on siltuximab Dr. Orlowski concludes: "S+B appears to be generally well tolerated but had a higher incidence of hematologic AEs." How could a therapy with 91% of patients experiencing severe or life-threatening side effects be considered generally well tolerated?
I know this has nothing to do with you as reporters, but I hope in the future Andrzej Jakubowiak will not be used to summarize therapies at future meetings. It is hard to take someone with the following Disclosure Statement all that serious when he is evaluating new therapies by Drug companies that are paying him.
Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.
https://ash.confex.com/ash/2011/webprogram/Paper36976.html
Mark: It is interesting that Velcade with "74% of patients experiencing severe or life threatening side effects" is considered to be well tolerated. Yikes! Small cohort problem?
I would also hope that for the star of the show elotuzumab some wise clinician would try and even lower dose not stop here.
Gary: I know you have expertise with respect to dosing with drugs. Do you think a lot of the side effects patients are having come from not having any therapy breaks? I did aggressive Induction and I had no problems with the first 2 cycles, mid-way through the 3rd the side effects hit me hard. Fortunately I am going on a little over 1 year with no myeloma therapy and I feel great. The break does the body good!
Hi Mark,
Your point about the patient population for the elotuzumab trial is well taken. However, there are a few considerations worth bearing in mind.
First, Revlimid still does not have approval in either the U.S. or Europe to be used as front line therapy. Yes, it is used frequently off label in the U.S. as a front line treatment, but that is much less so the case in Europe. So there is a conceivable role for the elotuzumab-Revlimid combination in relapsed/refractory patients.
Second, there may have been safety and ethics considerations behind the choice of the trial's patient population. Would it really have been justifiable, from a safety and ethics perspective, to test the combination in, say, newly diagnosed patients without first doing more extensive testing in relapsed patients, where the need for treatment alternatives is greater? And would it have been ethical to test the combination on patients who had already received Revlimid, knowing full well that the combination might not work as well for them as, say, a combination involving Velcade (or cafilzomib)?
One other point worth mentioning ... During his presentation yesterday, Dr. Moreau discussed some data from laboratory studies showing that elotuzumab and Revlimid together as a combination treatment have noticeably more activity against myeloma cell lines than either elotuzumab or Revlimid alone. This has been one of the rationales for doing clinical trials of the combination.
Dr. Orlowski has provided his siltuximab presentation to The Beacon and permitted us to make it available to our readers. It can be viewed here (PDF): http://bit.ly/LuCJNM .
Hi Mark,
You write:
"It was disappointing that the above study on elotuzumab used relapsed patients that had not been exposed to Revlimid. We already know that Revlimid shows efficacy in relapsed patients that had not been exposed to Revlimid previously."
But wouldn't this be an excellent reason in terms of a trial design to discern elotuzumab's efficacy not to include lenalidamide, unless there was an arm w/without elotuzumab, how could you assess what agent was effectively producing the response?
I agree with all that you wrote in your post subsequent to that.
Hi Beacon Staff:
you write:
"First, Revlimid still does not have approval in either the U.S. or Europe to be used as front line therapy."
Ok, while that is true, wasn't this a relapsed population, making this a moot point?
Based on how clinical trials are designed for the greatest benefit to the mfgr sponsoring the trial, there is also the well reasoned possibility that BMS had greater interest in demonstrating the effect of elotuzumab than any snynergism that lenalidomide might provide.
Hi Suzierose,
Thanks for your comment. We probably should have clarified a bit more our point about Revlimid's approved uses in the U.S. and Europe. What we wanted to make clear is that, worldwide, there are, in fact, many relapsed myeloma patients who are Revlimid-naive.
You are right, of course, that the designs of company-sponsored trials reflect commercial as well as scientific motivations. This is an important concern of the FDA and other regulatory authorities, who seek to ensure that drug approvals are based on sound, scientifically rationale trial designs.
In the case of the elotuzumab trial discussed in this article, it should be pointed out that there is little near-term commercial benefit to BMS from the trial design. Given the limited number of patients enrolled in the trial, it would be unlikely that the company would seek approval for elotuzumab based simply on these results.
Instead, the trial primarily establishes a rationale for investigating further, and in more detail, the elotuzumab, Revlimid, and dexamethasone combination -- something BMS is, in fact, doing in large-scale Phase 3 trial.
Hi Beacon Staff,
I see your point about the Revlimid-naive.
Looking further, I also saw your prior write up which shows that the mfgr, has had several trial designs that looked at combinations with Revlimid, which means this trial in lenalidamide naive patients, was designed to show efficacy without prior use intentionally. Which demonstrates the intent to show multiple types of patients that could respond to elotuzumab.
Which is a good thing overall, commercially and scientifically for diverse patient populations.
"Two of the studies are Phase 3 clinical trials investigating the combination of elotuzumab, Revlimid (lenalidomide), and dexamethasone (Decadron) compared to Revlimid plus dexamethasone alone.
One of these trials plans to test the combination in 750 newly diagnosed myeloma patients who are ineligible for stem cell transplantation (abstract). The other plans to test the combination in 640 relapsed and refractory myeloma patients (abstract).
Another ongoing study is a Phase 2 clinical trial investigating the combination of elotuzumab, Velcade, and dexamethasone compared to Velcade plus dexamethasone alone (abstract). The trial plans to test the combination in 150 relapsed and refractory myeloma patients."
BeaconStaff, Suzierose,
You make great points about the study. I certainly did not want to imply that therapies should not be used on relapsed patients - they are the ones that need it the most. IMO there is no current therapy that fully exploits Revlimids immunomodulatory abilities, so these therapies are indeed very important. I actually would like to see the Revlimid/elotuzumab therapy used without any DEX included. This is an interesting study and response from Dr. Constantine S. Mitsiades from Dana-Farber about future trials that use Revlimid (lenalidomide).
"The main message of the article by Hsu et al is not that lenalidomide is completely devoid of “immunomodulatory” activity in MM patients, but that with Dex administration, this immunostimulatory effect is severely compromised, if present at all. This suggests that other mechanisms are primarily responsible for the observed clinical responses with lenalidomide-Dex."
"Until more data become available, it is important to consider the specific goals for lenalidomide in each specific regimen. If the goal is to maximize direct anti–MM-cell cytotoxicity, inclusion of Dex with lenalidomide is compatible with the FDA approval of lenalidomide in combination with Dex and capitalizes on the demonstrated clinical potency of this doublet, without running counter to the data of Hsu et al. However, if adding lenalidomide to an investigational regimen seeks to augment immunologic responses of, for example, a monoclonal antibody which stimulates MM-cell killing by immune effector cells (rather than inhibition of surface receptors which trigger cell survival), Dex use should be viewed with caution. It may even be worth considering a Dex-sparing approach, unless specific data are available to inform a design through which the suppressive effect of Dex can be bypassed in the clinical context of the trial."
http://bloodjournal.hematologylibrary.org/content/117/5/1440.full
http://bloodjournal.hematologylibrary.org/content/117/5/1605.short
Mark
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