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ASCO 2012 Multiple Myeloma Update – Day Four: Immunotherapy For Myeloma

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Published: Jun 4, 2012 5:28 pm

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.

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10 Comments »

  • mark said:

    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

  • Gary said:

    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.

  • mark said:

    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!

  • Myeloma Beacon Staff said:

    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.

  • Myeloma Beacon Staff said:

    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 .

  • suzierose said:

    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. :)

  • suzierose said:

    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.

  • Myeloma Beacon Staff said:

    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.

  • suzierose said:

    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."

  • Mark said:

    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