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ASH 2012 Multiple Myeloma Update – Day Two: Late Afternoon Oral Session

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Published: Dec 10, 2012 5:40 am; Updated: Dec 16, 2012 6:40 pm

Yesterday was the sec­ond day of the 2012 American Society of He­ma­tol­ogy (ASH) annual meeting, which is being held in Atlanta.

The day's myeloma-related pre­sen­ta­tions began in the afternoon with three sessions of oral pre­sen­ta­tions.  Two of the sessions focused on re­­sults from clin­i­cal trials, most of which studied drugs that are still being devel­oped for the treat­ment of mul­ti­ple myeloma.  The third session, which focused on the biology of myeloma, ran simultaneously with one of the sessions about clin­i­cal trial re­­sults.

An up­date pub­lished yes­ter­day evening summarized the re­­sults for the first oral session about mul­ti­ple myeloma treat­ments (see re­lated Beacon news).  This article will summarize the highlights from the sec­ond oral session about myeloma treat­ments.

The sec­ond session kicked off with two pre­sen­ta­tions involving treat­ment regi­mens that in­clude main­te­nance ther­apy with thalido­mide.  These re­­sults are likely to be of pri­mary interest to Beacon readers outside of the U.S., where thalido­mide main­te­nance ther­apy is used much more fre­quently than in the U.S.

Three of the pre­sen­ta­tions from the late afternoon session con­cerned new myeloma ther­a­pies still under de­vel­op­ment.   The pre­sen­ta­tions about poma­lido­mide and elotuzumab made clear why there is sig­nif­i­cant interest in those drugs.  Results for the third drug in the group, oprozomib, were based on a trial that cur­rently has only a small num­ber of patients; the re­­sults, how­ever, sug­gest that side effects may be an issue with the drug.

Thalidomide Maintenance

Dr. Annamaria Brioli from the In­sti­tute of Cancer Re­search in London pre­sented the re­­sults from a study com­par­ing thalidomide (Thalomid) main­te­nance ther­apy versus no main­te­nance ther­apy (abstract). The re­­sults were part of a larger study which has been reported about extensively in the past.

The study in­cluded 818 mul­ti­ple myeloma patients of whom 408 re­ceived thalido­mide main­te­nance ther­apy and 410 re­ceived a placebo.

The median pro­gres­sion-free sur­vival time was 23 months for those in the thalido­mide main­te­nance group and 15 months for those who re­ceived a placebo.  The median over­all sur­vival times were 59 months and 58 months, re­spec­tively.

Dr. Brioli then reported that standard-risk patients who re­ceived thalido­mide main­te­nance had sig­nif­i­cantly longer pro­gres­sion-free sur­vival than those who re­ceived no main­te­nance (30 months and 20 months, re­spec­tively).  High-risk patients had similar pro­gres­sion-free sur­vival re­gard­less of whether they re­ceived main­te­nance ther­apy (11 months and 13 months, re­spec­tively), but their over­all sur­vival was neg­a­tively affected if they re­ceived thalido­mide main­te­nance ther­apy (35 months versus not yet reached).  Patients classified as ultra-high risk had poor pro­gres­sion-free and over­all sur­vival, re­gard­less of whether they re­ceived main­te­nance ther­apy.

Thalidomide main­te­nance appeared to im­prove pro­gres­sion-free sur­vival of patients who did not have the chromosomal ab­nor­mal­ity t(4;14) or who had t(4;14) but no addi­tional chromosomal ab­nor­mal­i­ties.

Patients with one or more extra chromosomes also appeared to gain a pro­gres­sion-free sur­vival ben­e­fit from thalido­mide main­te­nance.

VMPT-VT Versus VMP

The sec­ond pre­sen­ta­tion was given by Dr. Antonio Palumbo from the Uni­ver­sity of Torino in Italy.  Dr. Palumbo pre­sented four-year sur­vival re­­sults from a Phase 3 study com­par­ing two Velcade-based regi­mens (abstract; pre­sen­ta­tion slide deck made avail­able by Dr. Palumbo as a courtesy to the Beacon's readers).

The study in­cluded 511 newly diag­nosed mul­ti­ple myeloma patients with a median age of 71 years.

Half of the patients re­ceived initial ther­apy with Velcade (bor­tez­o­mib), melphalan (Alkeran), prednisone, and thalido­mide followed by main­te­nance ther­apy with Velcade and thalido­mide, known as VMPT-VT.  The other half re­ceived only initial ther­apy with Velcade, mel­phalan, and pred­ni­sone, known as VMP.

After a median follow-up of nearly four years, the median over­all sur­vival of the VMPT-VT group was not yet reached, as com­pared to 61 months for the VMP group.

Dr. Palumbo esti­mated that five years after the start of treat­ment, 61 per­cent of the VMPT-VT group would be alive, as com­pared to 51 per­cent of the VMP group.  He noted that patients younger than 75 years of age and patients who achieved a com­plete re­sponse after their initial ther­apy ben­e­fitted the most from the VMPT-VT ther­apy.

Among those who re­ceived main­te­nance ther­apy, the most common severe side effects were periph­eral neu­rop­athy (4 per­cent), blood-related side effects (3 per­cent), and in­fec­tion (1 per­cent).

Pomalidomide Plus Dexa­meth­a­sone

The next three pre­sen­ta­tions were about new drugs being devel­oped for the treat­ment of mul­ti­ple myeloma.  First, Dr. Martha Lacy from the Mayo Clinic in Rochester, Minnesota, pre­sented long-term follow-up re­­sults from six Phase 2 stud­ies of pomalidomide plus dexamethasone (Decadron) (abstract; presentation slide deck (pdf) made avail­able by Dr. Lacy as a courtesy to the Beacon's readers).

Pomalidomide is an immuno­modu­la­tory agent, meaning that it works by inducing a patient’s im­mune sys­tem to attack and destroy myeloma cells. It belongs to the same class of drugs as thalidomide (Thalomid) and Revlimid (lena­lido­mide).

Pomalidomide is being devel­oped by Celgene Corpo­ra­tion (NASDAQ: CELG), the same com­pany that mar­kets Revlimid and thalido­mide in the United States and inter­na­tionally.

The stud­ies in­cluded 344 myeloma patients who were a median of 4.4 years from their myeloma diag­nosis and who had been treated with a median of three prior ther­a­pies.  The median patient age was 64 years.

Overall, 35 per­cent of patients responded to the treat­ment, with 5 per­cent achieving a com­plete re­sponse, 12 a very good partial re­sponse, and 18 a partial re­sponse. The strongest predictor or re­sponse was the num­ber and type of pre­vi­ous ther­a­pies.

After a median follow-up of 10.4 months, 62 per­cent of patients are alive and 30 per­cent have not yet progressed.  The strongest predictor for time to pro­gres­sion and sur­vival were the num­ber and type of pre­vi­ous ther­a­pies, LDH levels and beta-2 microglobulin levels.

Severe side effects in­cluded low white blood cell counts (50 per­cent), low red blood cell counts (17 per­cent), low platelet counts (13 per­cent), pneu­monia (9 per­cent), and fatigue (8 per­cent).  In addi­tion, 3 per­cent of patients devel­oped blood clots in the vein.

Elotuzumab Plus Revlimid And Dexa­meth­a­sone

Next, Dr. Paul Richardson from the Dana-Farber Cancer In­sti­tute in Boston pre­sented re­­sults from a Phase 2 study of elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone (abstract; presentation slide deck made avail­able by Dr. Richardson as a courtesy to the Beacon's readers).

Elotuzumab, which is being devel­oped by Bristol-Myers Squibb (NYSE: BMY) and Abbott (NYSE: ABT), 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 study in­cluded 73 myeloma patients treated with a median of two prior lines of ther­apy.  The median patient age was 63 years.

Half of the study par­tic­i­pants re­ceived 10 mg/kg of elotuzumab, while the other half re­ceived 20 mg/kg of the drug.

The re­­sults showed that the out­comes of those treated with 10 mg/kg of elotuzumab were better than the out­comes of those treated with 20 mg/kg.

In par­tic­u­lar, 92 per­cent of the patients in the 10 mg/kg group responded to treat­ment, as com­pared to 76 per­cent in the 20 mg/kg group.

After a median follow-up of 21 months, median pro­gres­sion-free sur­vival has not been reached yet for the 10 mg/kg group and 19 months for the 20 mg/kg group.

Two-thirds of the patients ex­peri­enced at least one severe or life-threatening side effect.  The most common were low blood cell counts (10 per­cent to 20 per­cent).

The com­bi­na­tion using 10 mg/kg of elotuzumab is being fur­ther studied in Phase 3 stud­ies of newly diag­nosed myeloma patients.

Oprozomib

Dr. Michael Savona from the Sarah Cannon Re­search In­sti­tute in Nashville, Tennessee, then discussed re­­sults of a Phase 1b study of oprozomib (abstract).

Oprozomib is being devel­oped by Onyx Pharma­ceu­ticals (NASDAQ: ONXX), the com­pany that mar­kets Kyprolis (car­filz­o­mib).

Oprozomib is chemically very similar to Kyprolis, and also works similarly to Velcade.  All three of these drugs belong to the class of drugs known as pro­te­a­some in­hib­i­tors.  They work by preventing the breakdown of pro­tein in cancer cells, triggering their death.  Oprozomib, unlike Kyprolis and Velcade, can be taken orally.

Oprozomib is cur­rently being in­ves­ti­gated as a treat­ment for solid tumors as well as blood cancers.

Dr. Savona pre­sented initial re­­sults from 13 people with blood cancers who re­ceived be­tween 120 mg and 210 mg of oprozomib per day.  The study par­tic­i­pants had re­ceived a median of four pre­vi­ous treat­ment regi­mens.

Of the 10 patients eval­u­ated for re­sponse, nine achieved at least stable dis­ease.  Two patients with mul­ti­ple myeloma achieved a partial re­sponse and a minimal re­sponse.  An addi­tional patient with chronic lym­pho­cytic leukemia achieved a partial re­sponse.

The most common side effects were diarrhea (78 per­cent), nausea (78 per­cent), and vomiting (67 per­cent).

Myeloma pre­sen­ta­tions from the rest of Day 2 as well as Day 3 and Day 4 of the ASH 2012 meeting also will be summarized in ASH daily up­dates to be pub­lished at The Beacon the next few days.  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 ASH meeting, see The Beacon’s full ASH 2012 coverage.

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6 Comments »

  • suzierose said:

    Hmmmmm

    RE: Thalidomide Maintenance,

    "High-risk patients had similar progression-free survival regardless of whether they received maintenance therapy (11 months and 13 months, respectively), but their overall survival was negatively affected if they received thalidomide maintenance therapy (35 months versus not yet reached)."

    It seems that maintenance therapy with thalidomide does not increase PFS but it does DECREASE OS for high-risk patients.? So, the high risk patients who did not receive thalidomide maintenance had better OS!

    A real conundrum.

  • suzierose said:

    Re: Pomalidamide plus Dex,

    "The strongest predictor for time to progression and survival were the number and type of previous therapies, LDH levels and beta-2 microglobulin levels."

    What were the LDH levels and beta-2 microglobulin levels that correlated with longer time to progression and survival? And what number/type of previous therapy correlated with shorter time to progression and survival.

  • suzierose said:

    Re: Elotuzumab plus Dex and Rev

    "The results showed that the outcomes of those treated with 10 mg/kg of elotuzumab were better than the outcomes of those treated with 20 mg/kg.
    In particular, 92 percent of the patients in the 10 mg/kg group responded to treatment, as compared to 76 percent in the 20 mg/kg group."

    So less drug was more efficacious? How was this explained in terms of MOA? Why does less of a monoclonal AB work more effectively?. Is this about there being a finite number of receptor sites...hmmm perhaps, not since if all the receptors were saturated, then both doses should be equally effective and not less effective in higher doses.

    Is this about patient population variance? Do the myeloma cells vary that much in the patient population? Did the patients in the 10 vs 20 mg/kg arm have fewer prior therapies or different prior therapies from those in the 20mg/kg arm?

  • suzierose said:

    I located some of the additional details on Pom/Dex from Mayo:

    "Strongest predictors of nonresponse to pomalidomide/dexamethasone included > 3 previous treatment regimens, previous lenalidomide, and prior bortezomib"

    β2-microglobulin (> 5.5 vs ≤ 5.5 mg/dL)

    and

    LDH greater than Upper Limit of Normal (ULN)
    http://www.clinicaloptions.com/Oncology/Conference%20Coverage/Hematology%202012/Myeloma/Capsules/201.aspx

  • Myeloma Beacon Staff said:

    This article has been updated with links to presentation slide decks provided by Dr. Lacy and Dr. Palumbo.

  • Myeloma Beacon Staff said:

    This article has been updated with a link to the elotuzumab-Revlimid-dex presentation slide deck that Dr. Richardson discussed during his presentation.