The Beacon con­tinues today with its ‘ASH preview’ series about mye­lo­ma re­search that will be pre­sented at the American Society of Hema­tol­o­gy (ASH) meet­ing in early December.

Abstracts for the ASH presentations are now avail­able, although many con­tain pre­lim­i­nary in­­for­ma­tion that will be updated at the meet­ing.

The Beacon’s ASH preview articles are in­tended to highlight the meet­ing's most in­ter­est­ing myeloma-related studies.

The first and second previews, published earlier this week and last week, provide an overview of ASH abstracts about the newest poten­tial mye­lo­ma ther­a­pies just starting out in clin­i­cal trials.  Further previews will be published in the coming weeks prior to the conference.

Today’s preview con­tinues with the “new treat­ments” theme, but turns its attention to ther­a­pies that are among the furthest in devel­op­ment.   All of the ther­a­pies covered below are in at least Phase 2 clin­i­cal test­ing, and trial results for these ther­a­pies have been discussed at several major medical conferences in the past.

In particular, this article discusses abstracts for ARRY-520 (filanesib), dara­tu­mu­mab, ixazomib (MLN9708), pano­bino­stat, per­i­fo­sine (KRX-0401), and Zolinza (vorinostat).

Many of the results in this preview are promising, but there also are one or two disappointments.

In terms of good news, all of the re­lapsed myeloma patients in a small trial testing the com­bi­na­tion of dara­tu­mu­mab, Revlimid (lena­lido­mide), and dex­a­meth­a­sone (Deca­dron) responded to treat­ment, with half achieving a com­plete or very good partial re­sponse.

The efficacy data for ARRY-520 also look pos­i­tive.  The two drug com­bi­na­tion of ARRY-520 and Kyprolis (car­filz­o­mib), for example, yields an over­all re­sponse rate com­parable to that seen for the well-regarded three-drug com­bi­na­tion of Pomalyst (poma­lido­mide, Imnovid), Kyprolis, and dex­a­meth­a­sone in a similar patient pop­u­la­tion.

Similarly, in a trial of ixazomib com­bined with Revlimid and dex­a­meth­a­sone in newly diag­nosed patients, almost all patients responded to the treat­ment.  The depth of the re­sponses in that trial, how­ever, may not be as sig­nif­i­cant as may have been hoped.

In terms of not-so-good news, per­i­fo­sine failed to dem­onstrate efficacy in a Phase 3 study.  In fact, the ad­di­tion of per­i­fo­sine to Velcade (bor­tez­o­mib) plus dex­a­meth­a­sone ther­apy resulted in lower re­sponse rates and lower pro­gres­sion-free survival.

ARRY-520

Several studies involving ARRY-520 will be presented at this year’s ASH meeting.

ARRY-520 is being devel­oped by Array BioPharma (NASDAQ: ARRY).  The drug inhibits kinesin spindle pro­tein, which plays an im­por­tant role in actively dividing cells. Initial results for ARRY-520 were presented at last year’s ASH meeting, and they looked promising (see related Beacon news).

Results will be presented from a Phase 2 study of ARRY-520 with or without dex­a­meth­a­sone in patients with heavily pre­treated re­lapsed and refractory myeloma (abstract).

The first group of patients (39 per­cent of the study par­tic­i­pants) was treated with ARRY-520 alone; these patients had received a median of six prior lines of ther­apy.  The second group of patients (61 per­cent) was treated with ARRY-520 plus dex­a­meth­a­sone; patients in this group had received a median of nine prior lines of ther­apy.  In both study groups, 16 per­cent of patients responded to ther­apy.  Median over­all survival was 19 months for the first group and 11 months for the second group.

This level of single-agent efficacy appears to be in line with – if not greater than – what was seen with the two most recently ap­proved myeloma ther­a­pies, Kyprolis and Pomalyst, in their single-agent trials.

Another presentation at ASH will describe the initial findings from a Phase 1 study combining ARRY-520 with Kyprolis for re­lapsed and refractory multiple myeloma (abstract).  The study in­cludes 20 patients who had received a median of four prior lines of ther­apy.  Among the 19 patients evaluable for re­sponse, the over­all re­sponse rate was 58 per­cent, with 5 per­cent achieving a near com­plete re­sponse, 32 per­cent a partial re­sponse, and 21 per­cent a minor re­sponse.  An addi­tional 21 per­cent achieved stable disease.

The re­sponse rate to this com­bi­na­tion ther­apy is com­parable to what has been seen in a trial testing the com­bi­na­tion of Pomalyst, Kyprolis, and dex­a­meth­a­sone in re­lapsed and refractory patients (see related Beacon news).

An addi­tional presentation at ASH will summarize initial findings of a Phase 1 trial of ARRY-520 in com­bi­na­tion with Velcade (and, in many cases, dex­a­meth­a­sone) in re­lapsed and refractory multiple myeloma patients (abstract). So far, 41 patients who received a median of five prior ther­a­pies have been treated with varying doses of ARRY-520 and Velcade.  Although limited results are avail­able at this time, the com­bi­na­tion is registering an over­all re­sponse rate of about 30 per­cent at the higher doses of ARRY-520.

One poten­tial issue with ARRY-520 going for­ward may be the fact that, in com­bi­na­tion with drugs such as Kyprolis and Velcade, it tends to noticeably reduce white blood cell counts.  Indeed, in both the Kyprolis and Velcade com­bi­na­tion studies, patients were preventatively given Neupogen (filgrastim) to stimulate their white blood cell pro­duc­tion.  Even with that extra safety measure, one patient died in the ARRY-520+Kyprolis trial due to severe fever accompanied by low white blood cell counts (febrile neu­tro­penia).

Daratumumab

A presentation at ASH will summarize the initial findings of an ongoing Phase 1/2 trial investigating dara­tu­mu­mab in com­bi­na­tion with Revlimid and dex­a­meth­a­sone in re­lapsed and refractory multiple myeloma patients (abstract).

Daratumumab is being devel­oped by the Danish bio­technology com­pany Genmab together with Janssen Biotech, a Johnson & Johnson (NYSE: JNJ) sub­sid­i­ary. It is a mono­clonal anti­body that binds to myeloma cells and then signals the patient's immune sys­tem to kill the cells.

Other mono­clonal anti­bodies being tested as poten­tial myeloma ther­a­pies in­clude elotuzumab, IPH2101, MOR202, and SAR650984.  Daratumumab, MOR202, and SAR650984 are similar in that all three bind to CD38, a protein found on the surface of multiple myeloma and other blood cancer cells.

Daratumab has pre­vi­ously been tested as a single agent in a Phase 1/2 study, with en­cour­ag­ing results (see related Beacon news).

So far, six patients who had received a median of three prior ther­a­pies have been recruited for the dara­tu­mu­mab-Revlimid-dex­a­meth­a­sone study. Patients in the trial were permitted to have been treated with Revlimid in the past.  However, if they were pre­vi­ously treated with Revlimid, they must have had at least a min­i­mal re­sponse to the drug.

All patients have responded to the three-drug treat­ment, which is a very high re­sponse rate for such a group of patients.  Depth of re­sponse also has been promising, with 50 per­cent of the patients achieving a very good partial re­sponse or com­plete re­sponse. According to the investigators, side effects have been man­ageable.

Ixazomib

Three presentations will be given at the ASH meeting with clin­i­cal trial results for ixazomib (MLN9708).

Ixazomib belongs to the same class of drugs as Velcade and Kyprolis, called pro­te­a­some inhibitors. It is being devel­oped by Millennium Pharma­ceu­ticals, the same com­pany that devel­oped Velcade. However, unlike Velcade and Kyprolis, which are given by in­fusion or injection, ixazomib can be admin­istered orally. Initial results related to ixazomib were presented at the 2011 ASH meeting, and they looked promising (see related Beacon news).

The ixazomib presentation likely to attract the most attention is one describing the results of a Phase 1/2 study of ixazomib in com­bi­na­tion with Revlimid and dex­a­meth­a­sone in newly diag­nosed myeloma patients (abstract).  Among 58 patients from Phase 2 of the study who were evaluable for re­sponse, 93 per­cent responded, with 14 per­cent achieving a stringent com­plete re­sponse, 10 per­cent a com­plete re­sponse, 43 per­cent a very good partial re­sponse, and 26 per­cent a partial re­sponse.

Although the over­all re­sponse rate in this trial was quite high, the depth of re­sponse may dis­ap­point some meet­ing attendees.  The share of patients in the trial who achieved a very good partial re­sponse or better, 67 per­cent, is the same as was observed in a trial testing Velcade com­bined with Revlimid and dex­a­meth­a­sone in newly diag­nosed patients (see related article in Blood).  The 67 per­cent share is lower, how­ever, than was seen in a trial testing Kyprolis, Revlimid, and dex­a­meth­a­sone in new­ly diag­nosed patients, where 81 per­cent of the patients had at least a very good partial re­sponse (see related Beacon news and article in Blood).

The ixazomib, Revlimid, and dex­a­meth­a­sone regi­men does appear to have a lower rate of periph­eral neu­rop­athy (burning, tingling, or numbness in the hands or feet) than Velcade+Revlimid+dex­a­meth­a­sone (37 per­cent versus 80 per­cent, re­spec­tive­ly), but the rate is not as low as was observed with the com­bi­na­tion of Kyprolis, Revlimid, and dex­a­meth­a­sone (23 per­cent).

Initial results will also be presented at ASH for a Phase 2 study of newly diag­nosed myeloma patients who underwent stem cell trans­plan­ta­tion and then received ixazomib plus Revlimid as main­te­nance ther­apy (abstract). So far, 16 patients with a median age of 60 years have been enrolled, and only two have dis­con­tinued main­te­nance ther­apy. According to the investigators, the com­bi­na­tion seems to be well tol­er­ated.

A third ixazomib-related presentation will summarize results of a trial investigating the drug as a single agent in re­lapsed myeloma patients who are not resistant to treat­ment with Velcade (abstract).  This trial enrolled 33 patients with a median of two pre­vi­ous ther­a­pies.  Three quarters of the patients had never been treated with Velcade, while the remaining patients had been treated with Velcade, but for no more than six cycles, and not to the point of devel­op­ing resistance to it.

Patients in the trial initially received treat­ment with only ixazomib, but dex­a­meth­a­sone could be added if the re­sponse to ixazomib alone was minimal, or if the patients ex­peri­enced disease pro­gres­sion.

Thus far, the over­all re­sponse rate has been 16 per­cent among patients treated with ixazomib alone, and 34 per­cent in those treated with both ixazomib and dex­a­meth­a­sone.

Panobinostat

During one of the sessions at ASH, results from a Phase 1/2 study of panobinostat plus Kyprolis will be presented (abstract).

Panobinostat is being devel­oped by the pharma­ceu­tical com­pany Novartis (NYSE: NVS) for a variety of dif­fer­ent cancers.  It belongs to a class of drugs known as oral histone deacetylase (HDAC) inhibitors. Several HDAC inhibitors are being in­ves­ti­gated for the treat­ment of multiple myeloma, in­clud­ing Zolinza, ricolinostat (ACY-1215), and quisinostat.  The drugs in this class work by interrupting cell division and causing cell death. Panobinostat has shown en­cour­ag­ing results in com­bi­na­tion with Velcade and dex­a­meth­a­sone (see related Beacon news).

So far, 44 patients who had received a median of three prior ther­a­pies have been treated with one of four dif­fer­en­t doses. Overall, 64 per­cent of patients responded, with 31 per­cent achieving a com­plete re­sponse or very good partial re­sponse and 30 per­cent achieving a partial re­sponse.  In addi­tion, the over­all re­sponse rate was 67 per­cent for patients resistant to pre­vi­ous Velcade ther­apy and 66 per­cent for patients resistant to both Velcade and Revlimid ther­apy.  With a median follow-up time of 6.3 months, the one-year pro­gres­sion-free survival rate was 41 per­cent and the one-year over­all survival rate was 83 per­cent.

Perifosine

Researchers at the ASH meeting also will present the results of a terminated Phase 3 study of per­i­fo­sine (KRX-0401) plus Velcade and dex­a­meth­a­sone com­pared to Velcade plus dex­a­meth­a­sone alone (abstract).

Perifosine is an orally admin­istered drug that belongs to a new class of anti-cancer drugs known as Akt inhibitors.  Akt is a protein believed to play an im­por­tant role in the devel­op­ment and growth of cancer cells.  Perifsone was being devel­oped by the pharma­ceu­tical com­pany Aeterna Zentaris; how­ever, the com­pany dis­con­tinued devel­op­ment of the drug based on pre­lim­i­nary results from this study (see related Beacon news).

The study in­cluded 135 re­lapsed and refractory myeloma patients who had received one to four pre­vi­ous lines of ther­apy and who re­lapsed after pre­vi­ous Velcade ther­apy.  Perifosine did not im­prove re­sponse rates or pro­gres­sion-free survival.  The over­all re­sponse rates were 20 per­cent for the three-drug com­bi­na­tion in­clud­ing per­i­fo­sine, and 27 per­cent for Velcade plus dex­a­meth­a­sone alone.  Median pro­gres­sion-free survival was 5 months for the per­i­fo­sine com­bi­na­tion and 9 months for Velcade plus dex­a­meth­a­sone.

Perifosine appeared to im­prove over­all survival, with median over­all survival being 33 months for the per­i­fo­sine com­bi­na­tion and 19 months for Velcade plus dex­a­meth­a­sone, but the im­prove­ment was not sta­tis­ti­cal­ly sig­nif­i­cant.  Therefore, the trial was terminated based on a recom­men­da­tion from an in­de­pen­dent Data Safety Monitoring Board.

Zolinza

Preliminary results of an ongoing Phase 1/2 study of Zolinza in com­bi­na­tion with Velcade, doxorubicin (Adriamycin), and dex­a­meth­a­sone will be presented at ASH (abstract).

Zolinza (vorinostat), which is mar­keted by the U.S. pharma­ceu­tical com­pany Merck (NYSE: MRK), is an oral drug already approved in the United States for a certain type of lym­phoma. It also is approved for a similar use in Canada and Australia, but not in Europe.

Like panobinostat, Zolinza is an HDAC inhibitor. It has been in­ves­ti­gated in various com­bi­na­tions as a po­ten­tial treat­ment for multiple myeloma and has shown mixed results (see related Beacon news).

The study to be presented at ASH cur­rently in­cludes 18 myeloma patients who had received a median of three prior ther­a­pies. Overall, 65 per­cent of patients responded to the three-drug com­bi­na­tion.  Almost a quarter (22 per­cent) of patients ex­peri­enced severe side effects; how­ever, the investigators point out that the observed side effects were in line with the known safety profile of the in­ves­ti­gated drugs.

For in­­for­ma­tion about addi­tional studies that will be presented at ASH, see a list of all myeloma-related ASH abstracts, all abstracts about new treat­ments under devel­op­ment for myeloma, clinical trial results for new treat­ments, and preclinical research about new treat­ments.