The 2014 annual meeting of the American Society of He­ma­tol­ogy (ASH) starts tomorrow, De­cem­ber 5, in San Francisco, and will con­tinue until next Tuesday.

The ASH annual meeting is one of sev­er­al large med­i­cal conferences where myeloma-related re­search findings are pre­sented each year.  However, from a mul­ti­ple myeloma perspective, the ASH meeting is generally the most im­por­tant of the meetings.

At this year’s meeting, for example, some 500 myeloma-presentations are scheduled to take place.  The pre­sen­ta­tions will summarize cur­rent re­search on a wide range of topics, in­clud­ing the biology of the dis­ease and cur­rent and poten­tial new myeloma ther­a­pies.

As is the case at most scientific meetings, re­search re­­sults at ASH will be com­mu­ni­cated either in oral pre­sen­ta­tions or poster summaries.

Oral pre­sen­ta­tions are usually given for re­search that is con­sidered par­tic­u­larly im­por­tant, either because the subject itself is im­por­tant, or because the re­­sults are based on sub­stan­tial amounts of evi­dence (for example, a sizable clin­i­cal trial).

Poster re­search summaries are made avail­able during spe­cif­ic “poster sessions,” when re­searchers dis­play summaries of their stud­ies on posters in a large exhibition hall.

Compared to the re­search summarized during oral pre­sen­ta­tions, the findings in poster summaries generally are in earlier stages of devel­op­ment and may in­volve­ only laboratory re­search or clin­i­cal trials with just a small num­ber of patients.

The Beacon will be in attendance at ASH, providing daily coverage as the meeting progresses, followed by in-depth, topic-specific coverage once the conference has finished.

To mark the start of the conference tomorrow, The Beacon to­day takes an extended look at the ASH pre­sen­ta­tions re­lated to poten­tial new myeloma ther­a­pies – a topic that usually is of keen interest to Beacon readers.

As in pre­vi­ous years, re­search re­lated to lesser known agents that are in the early stages of clin­i­cal de­vel­op­ment will be pre­sented at the ASH meeting. However, the num­ber of early-stage myeloma treat­ments with such re­­sults is smaller this year than in recent years.  Potential new myeloma ther­a­pies in this category in­clude ulocuplumab, Imbruvica (ibrutinib),PRLX93936, PVX-410, and Jakafi (ruxolitinib). Studies involving these drugs are discussed in the first half of this article.

There also is an overview in this article of clin­i­cal trial re­­sults for poten­tial new myeloma treat­ments that are a bit fur­ther along in clin­i­cal devel­op­ment and that have shown promising re­­sults so far. These agents in­clude elotuzumab, SAR650984, dara­tu­mu­mab, ix­az­o­mib (MLN9708), and oprozomib.  Studies involving these drugs are discussed in the sec­ond half of this article.

Readers who are rel­a­tive­ly new to reviewing summaries of clin­i­cal trial re­­sults may wish to consult the Beacon’s “Tips For Making Sense Of The Re­search Results Presented At This Year’s ASH Annual Meeting,” which was pub­lished prior to the 2012 ASH meeting.

First Results For Early-Stage Potential New Therapies

Ulocuplumab

A poster pre­sen­ta­tion at the ASH meeting will summarize re­­sults from a Phase 1 study of ulocuplumab alone and in com­bi­na­tion with Revlimid (lena­lido­mide) and dexamethasone (Decadron), or in com­bi­na­tion with Velcade (bor­tez­o­mib) and dexa­meth­a­sone in re­lapsed and re­frac­tory myeloma patients (abstract).

Ulocuplumab (BMS-936564), which is being devel­oped by Bristol-Myers Squibb (NYSE:BMS), belongs to the same broad class of drugs as elotuzumab and dara­tu­mu­mab, called mono­clonal anti­bodies. Monoclonal anti­bodies work by identifying pro­teins on the surface of myeloma cells and signaling for the im­mune sys­tem to destroy those cells.

The ulocuplumab study in­cludes 44 patients who have re­ceived a median of four prior lines of ther­apy; 93 per­cent pre­vi­ously re­ceived Velcade, and 86 per­cent pre­vi­ously re­ceived Revlimid.

The over­all re­sponse­ rate for all patients was 50 per­cent, with 2 per­cent achieving a com­plete re­sponse­, 14 per­cent a very good partial re­sponse­, and 34 per­cent a partial re­sponse­. More patients re­ceiv­ing ulo­cu­plu­­mab in com­bi­na­tion with Revlimid and dexa­meth­a­sone responded (55 per­cent) than those re­ceiv­ing ulocuplumab in com­bi­na­tion with Velcade and dexa­meth­a­sone (40 per­cent).

Based on these findings, the trial arm of ulocuplumab in com­bi­na­tion with Revlimid was ex­panded.

Imbruvica

One of the oral pre­sen­ta­tions to be made at this year’s ASH meeting will summarize the initial re­­sults of a Phase 2 study of Imbruvica (ibrutinib) alone or in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of re­lapsed and re­frac­tory myeloma (abstract).

Imbruvica, which has been devel­oped by the bio­tech com­pany Pharmacyclics (NASDAQ:PCYC) in coop­er­a­tion with Johnson & Johnson (NYSE:JNJ), blocks a pro­tein called Bruton’s tyrosine kinase (Btk). Btk is found in anti­body-producing cells and in cells that break down bone tissue. The drug cur­rently is approved by the U.S. Food and Drug Admin­istra­tion for the treat­ment of chronic lym­pho­cytic leukemia.

So far, 69 myeloma patients who have re­ceived a median of four pre­vi­ous ther­a­pies have been en­rolled in the Imbruvica Phase 2 myeloma trial.

The re­­sults show that the re­sponse­ rate was highest among patients who re­ceived the highest Imbruvica dose in com­bi­na­tion with dexa­meth­a­sone (5 per­cent); all of these patients achieved a partial re­sponse­.

Imbruvica also is being in­ves­ti­gated in com­bi­na­tion with Kyprolis (car­filz­o­mib) in an on­go­ing Phase 1/2 study.

PVX-410

Initial re­­sults of a Phase 1/2 trial investigating the thera­peutic cancer vaccine PVX-410 in smol­der­ing mul­ti­ple myeloma patients also will be pre­sented at this year’s annual meeting (abstract).

PVX-410, which is being devel­oped the pharma­ceu­tical com­pany OncoPep, consists of four novel peptides that target spe­cif­ic tumor-associated an­ti­gens found on myeloma cells.

The study in­cludes 12 smol­der­ing mul­ti­ple myeloma patients who had been diag­nosed a median of 0.8 years before entering the trial. The patients re­ceived six admin­istra­tions of PVX-410 over a period of 10 weeks.

All 12 patients showed an im­mune re­sponse­ to the vaccine, with a third of the patients having an im­mune re­sponse­ to three or more of the four peptides. Based on these findings, PVX-410 is cur­rently being in­ves­ti­gated in com­bi­na­tion with three cycles of fixed‑dose Revlimid. The in­ves­ti­ga­tors hypothesize that co-administration of Revlimid will en­hance the im­mune re­sponse­ induced by PVX-410.

PRLX93936

Results from a Phase 1study to be pre­sented at the ASH meeting will show that PRLX93936 did not have sig­nif­i­cant ac­­tiv­ity in re­lapsed and re­frac­tory myeloma patients when used alone. However, the im­pact of adding dexa­meth­a­sone to treat­ment with the drug is still being in­ves­ti­gated (abstract).

PRLX93936 is being devel­oped by Prolexys Pharma­ceu­ticals. PRLX 93936 is a small-molecule anti-cancer treat­ment that targets the RAS pro­tein.

So far, 14 patients who have re­ceived a median of five prior lines of ther­apy have been en­rolled in the trial.  Among the 13 patients eval­u­ated for re­sponse­, the best re­sponse­ observed was a minor re­sponse­, which was seen in 18 per­cent of the patients;

Jakafi

Also on the agenda for the ASH meeting will be a pre­sen­ta­tion about Jakafi (ruxolitinib).  In par­tic­u­lar, re­searchers will present re­­sults of a pre­clin­i­cal study of the drug in com­bi­na­tion with Revlimid and dexa­meth­a­sone (abstract).

Jakafi belongs to a class of drugs known as JAK in­hib­i­tors. They work by in­hib­iting the ac­­tiv­ity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), which are commonly mutated and overactive in in­flam­ma­tory dis­eases, myeloproliferative disorders, and var­i­ous cancers. Jakafi is already approved by the FDA for the treat­ment of myelofibrosis, a disorder in which the bone mar­row is scarred.

The re­­sults of the pre­clin­i­cal study show that the com­bi­na­tion of Jakafi, Revlimid, and dexa­meth­a­sone leads to a marked re­duc­tion of myeloma cell con­cen­tra­tion and delays in dis­ease pro­lif­er­a­tion in human and animal cell lines.

New Results For Potential Treatments Fur­ther Along In De­vel­op­ment

Monoclonal Antibodies

Myeloma re­searchers have been par­tic­u­larly ex­cited in recent years about the class of poten­tial new myeloma ther­a­pies known as CD38 mono­clonal anti­bodies.  These drugs work by targeting a pro­tein known as CD38 that is fre­quently found on the surface of myeloma cells.

SAR650984

The first clin­i­cal trial re­­sults for one of the drugs in this class of ther­a­pies, SAR650984, were pre­sented at last year’s ASH (see re­lated Beacon news). At the time, Dr. Joseph Mikhael of the Mayo Clinic told The Beacon, “This drug was hands down the most promising new agent at ASH for myeloma.”

During this year’s ASH meeting, up­dated re­­sults of a Phase 1b trial of SAR650984 in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed and re­frac­tory mul­ti­ple myeloma will be pre­sented (abstract). The most recent re­­sults of the trial were pre­sented at the American Society of Clinical Oncology (ASCO) annual meeting this summer (see re­lated Beacon news).

The study so far in­cludes 31 myeloma patients who had re­ceived a median of six prior ther­a­pies.

The trial explored three dif­fer­en­t dose levels (3 mg/kg, 5 mg/kg, and 10 mg/kg) of SAR650984.

Overall, 65 per­cent of patients have responded to the treat­ment. The median pro­gres­sion-free sur­vival was 6.2 months.

Daratumumab

The first CD38 mono­clonal anti­body to attract the attention of myeloma re­searchers was daratumumab.  It is being devel­oped by the Danish bio­technology com­pany Genmab to­geth­er with Janssen Biotech, a Johnson & Johnson sub­sid­i­ary.

Results of two on­go­ing clin­i­cal trials involving dara­tu­mu­mab will be pre­sented at this year’s ASH meeting.

The first is a Phase 1/2 trial of daratumumab in com­bi­na­tion with Revlimid (lena­lido­mide), and dexa­metha­sone (Decadron) in re­lapsed myeloma patients (abstract). Results were pre­sented earlier this year at the ASCO annual meeting (see re­lated Beacon news).

Of the 20 patients evaluable for re­sponse­, 75 per­cent have so far responded to the three-drug treat­ment, with 15 per­cent achieving a com­plete re­sponse­, 45 per­cent a very good partial re­sponse or com­plete re­sponse, and 15 per­cent a partial re­sponse­.

The sec­ond study is a Phase 1b trial in which dara­tu­mu­mab was added to cur­rent back­bone treat­ments (abstract). In par­tic­u­lar, dara­tu­mu­mab was added to Velcade-dexamethasone (VD), Velcade-thalidomide-dexamethasone (VTD), Velcade-melphalan-prednisone (VMP), and Pomalyst-dexamethasone (POM-D).

Newly diag­nosed patients were in­cluded in the VD and VTD arms of the trial, irrespective of trans­plant eligibility. Patients in the VMP arm were newly diag­nosed and trans­plant in­eli­gible. Patients in the POM-D arm were re­lapsed and re­frac­tory to two or more lines of prior ther­apy, in­clud­ing at least two consecutive cycles of Revlimid and Velcade.

So far, 17 newly diag­nosed patients have been treated in the VD, VTD, and VMP arms of the trial. All patients re­ceived 16 mg/kg of dara­tu­mu­mab.  The median duration of treat­ment was 44 days.

According to the in­ves­ti­ga­tors, dara­tu­mu­mab was well tol­er­ated in all evaluable patients and did not re­­sult in sig­nif­i­cant addi­tional toxicity.

Elotuzumab

Elotuzumab, which is being devel­oped by Bristol-Myers Squibb and AbbVie (NYSE:ABBV), is the mono­clonal anti­body that is furthest along in clin­i­cal devel­op­ment and has shown very promising re­­sults so far. It re­ceived break­­through desig­na­tion earlier this year (see re­lated Beacon news).

Unlike SAR650984 and dara­tu­mu­mab, how­ever, elotuzumab does not target the CD38 pro­tein.  Instead, it targets a dif­fer­en­t pro­tein known as CS1.

During this year’s ASH meeting, final re­­sults from a Phase 2 study of elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone will be pre­sented (abstract).

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 patients 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. Median pro­gres­sion-free sur­vival is 32 months for the 10 mg/kg group and 25 months for the 20 mg/kg group.

Pneumonia was the most common severe or life-threatening side effect; it oc­curred in 12 per­cent of the patients.

Initial re­­sults of another elotuzumab study, a Phase 1b/2 study in which the drug is given in com­bi­na­tion with Revlimid, Velcade, and dexa­meth­a­sone to newly diag­nosed, high-risk patients, will also be pre­sented at the meeting (abstract).

So far, eight patients with a median age of 67 years have been en­rolled in the study.

Efficacy re­­sults are not yet avail­able, but the four-drug regi­men seems to be well tol­er­ated. The most common severe side effects in­cluded periph­eral neu­rop­athy (33 per­cent), low white blood cell counts (17 per­cent), and low platelet counts (17 per­cent).

Next-Generation Pro­te­a­some Inhibitors

Several stud­ies will be pre­sented at this year’s ASH meeting about two next-gener­a­tion pro­te­a­some in­hib­i­tors.  This class of drugs in­cludes Velcade and Kyprolis, and drugs in the class work work by preventing the breakdown of pro­tein in cancer cells, triggering their death.

Unlike Kyprolis and Velcade, both of the next gen­er­a­tion pro­te­a­some in­hib­i­tors can be taken orally.

Ixazomib

One of the newer pro­te­a­some in­hib­i­tors is ixazomib (MLN9708), which is being devel­oped by Millennium Pharma­ceu­ticals, the same com­pany that devel­oped Velcade. Results of sev­er­al trials investigating ix­az­o­mib as a poten­tial myeloma ther­apy have been pre­sented a num­ber of times at pre­vi­ous conferences such as ASH.

At this year’s ASH meeting, re­­sults from a Phase 2 study of ix­az­o­mib in com­bi­na­tion with Revlimid and dexa­meth­a­sone followed by ix­az­o­mib main­te­nance in newly diag­nosed myeloma patients will be pre­sented (abstract). The focus of the pre­sen­ta­tion will be on the main­te­nance part of the study.

Of the 50 patients who re­ceived induction ther­apy with ix­az­o­mib plus Revlimid and dexa­meth­a­sone, 42 per­cent re­ceived ix­az­o­mib main­te­nance ther­apy.

The re­­sults show that ix­az­o­mib main­te­nance im­proved re­sponse­s fol­low­ing ix­az­o­mib-Revlimid-dexamethasone induction ther­apy; 33 per­cent of patients im­proved their re­sponse­ during main­te­nance ther­apy.

Oprozomib

Results from two clin­i­cal trials for the sec­ond next-gener­a­tion pro­te­a­some in­hib­i­tor, oprozomib, will be pre­sented at the ASH annual meeting.

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

One of the oprozomib trials is a Phase 1/2 study that in­ves­ti­gates the ef­fi­cacy and safety of opromozib in patients with hema­to­logic malig­nan­cies (abstract).

The study in­cludes 106 patients with hema­to­logic malig­nan­cies (68 with mul­ti­ple myeloma) who were treated with oprozomib, using one of two dif­fer­en­t dosing schedules.

Approximately a third of the myeloma patients in both dosing groups (33 per­cent and 37 per­cent, re­spec­tive­ly) responded to treat­ment. Both dosing schedules are in­ves­ti­gated in the Phase 2 part of the trial.

Another Phase 1b/2 study in­ves­ti­gates the ef­fi­cacy and safety of oprozomib in com­bi­na­tion with dexa­meth­a­sone in re­lapsed and re­frac­tory myeloma patients (abstract).

The study in­cludes 29 patients who had re­ceived a median of three prior ther­a­pies. Patients re­ceived oprozomib admin­istered at the same two dosing schedules as in the oprozomib mono­therapy trial, plus 20 mg of dexa­meth­a­sone.

Almost half of the patients in the one dosing group (42 per­cent) responded to treat­ment, with 8 per­cent achieving a very good partial re­sponse­ and 15 per­cent achieving a partial re­sponse­, while none of the patients in the sec­ond dosing group responded to treat­ment.

Gastrointestinal tol­er­a­bil­ity in the study was im­proved com­pared to what was seen in the stud­ies of oprozomib by itself.

For more in­­for­ma­tion on ASH’s 56^th Annual Meeting, in­clud­ing the final pre­sen­ta­tion schedule and all meeting abstracts, please see the ASH annual meeting website.