As the third day of the 2011 American Society of Hematology (ASH) annual meeting came to an end, attendees could look back on an agenda that featured presentations about a wide range of potential new myeloma ther­a­pies.

The afternoon myeloma sessions were focused, in fact, on potential new ther­a­pies.

The Beacon's pre­vi­ous ASH 2011 update covered the afternoon presentations about carfilzomib and pomalidomide, two potential myeloma ther­a­pies that are in the late stages of devel­op­ment.

This update covers the afternoon's presentations about four other potential new myeloma ther­a­pies -- MLN9708, panobinostat, perifosine, and Zolinza.

There also were morning presentations on the third day of the ASH meeting that were about potential new myeloma ther­a­pies.  Those presentations were covered in an update published last week.

MLN9708

During the afternoon sessions, Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, presented trial results for the investigational drug MLN9708 (ixazomib).

Specifically, he presented results from a Phase 1 study of MLN9708 in patients with re­lapsed and refractory multiple myeloma (abstract).

MLN 9708 belongs to the same class of drugs as Velcade (bor­tez­o­mib). However, unlike Velcade, MLN9708 can be taken orally.

The primary objective of the study presented by Dr. Kumar was to determine the maximum tolerated dose and safety of MLN9708 when it is admin­istered once per week.

The study included 32 patients with a median age of 64.  The patients had received a median of six prior ther­a­pies.

During the trial, patients received a median of two treat­ment cycles. Three patients are cur­rently continuing treat­ment; all others have dis­con­tinued treat­ment, mainly due to disease pro­gres­sion (69 per­cent).

Of the 18 patients who have been evaluated thus far for their response to the drug, one reached a very good partial response and one reached a partial response, for an over­all response rate of 11 per­cent.

The majority of patients (72 per­cent) experienced treat­ment-related side effects.

However, only nine per­cent of the patients reported experiencing periph­eral neu­rop­athy, a con­di­tion char­ac­ter­ized by pain and tingling in the extremities.  None of the reported cases were severe.

(For complete coverage of the MLN9708-related presentations at the ASH meeting, see the related Beacon news article.)

Panobinostat

Also during the afternoon sessions, Dr. Paul Richardson from the Dana-Faber Cancer Institute in Boston reported on Phase 2 trial results for the investigational drug panobinostat (Farydak) in com­bi­na­tion with Velcade (abstract; presentation slide deck (pdf), made available by Dr. Richardson as a courtesy to The Beacon’s readers).

Panobinostat is an oral drug being developed by the pharma­ceu­tical com­pany Novartis as a potential treat­ment for a range of different cancers, including multiple myeloma.  It belongs to same class of drugs -- known as "HDAC-inhibitors" -- as Zolinza, another potential new myeloma drug discussed later in this article.

Laboratory studies have suggested that the com­bi­na­tion of panobinostat and Velcade may have an anti-myeloma effect stronger than the anti-myeloma effect of either drug on its own.

In addi­tion, 65 per­cent of the re­lapsed / refractory patients in a Phase 1 trial of the com­bi­na­tion achieved at least a partial response to treat­ment.

The Phase 2 trial summarized by Dr. Richardson included 55 myeloma patients with a median age of 61 years.  All patients were refractory to Velcade and had a median of four prior treat­ment regi­mens.  Almost 70 per­cent of the patients had received a stem cell trans­plant.

Overall, 29 per­cent of the patients in the trial achieved at least a partial response to treat­ment, with 4 per­cent reaching a near complete response and 25 per­cent achieving a partial response.

The most common side effects included low platelet counts (thrombocytopenia), fatigue, diarrhea, anemia, and nausea.  More than half the trial participants experienced low platelet counts to an extent considered severe or life-threatening.

Dr. Richardson explained, however, that most side effects could be man­aged by dose reductions or inter­rup­tions.

Peripheral neu­rop­athy was observed in 24 per­cent of patients, but all cases were classified as mild.

Dr. Richardson concluded that the com­bi­na­tion of panobinostat and Velcade looks like a promising treat­ment for patients with Velcade-refractory myeloma.

Perifosine

Dr. Paul Richardson also presented the final results of a Phase 1/2 trial of perifosine plus Velcade and dexamethasone (Decadron) in multiple myeloma patients who pre­vi­ously re­lapsed from, and/or were refractory to, Velcade (abstract; presentation slide deck (pdf), made available by Dr. Richardson as a courtesy to The Beacon’s readers).

Perifosine is an orally admin­istered drug that is being developed by Keryx Biopharmaceuticals and Aeterna Zentaris.  It 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 spread of cancer cells.

The Phase 1 stage of the study discussed by Dr. Richardson enrolled 18 patients. For the Phase 2 part of the trial, an addi­tional 66 patients were recruited for a total of 84 patients. The median patient age was 63 years, and patients had received a median of five prior ther­a­pies.

Of the 73 patients evaluable in regard to their response to treat­ment, 22 per­cent achieved a partial response or better to treat­ment.  Another 19 per­cent achieved a minor response, and 41 per­cent of the patients had stable disease for at least three months,

Median pro­gres­sion-free survival was 6.4 months.  Median over­all survival for all evaluable study patients was 25 months.

Severe side effects included low platelet counts, low white blood cell counts, anemia, pneu­monia and muscle or bone pain.  These generally occurred, however, in less than 20 per­cent of the patients in the trial.

Peripheral neu­rop­athy of any grade was experienced by 29 per­cent of the patients in the trial.

Dr. Richardson concluded that perifosine in com­bi­na­tion with Velcade and dexa­meth­a­sone has dem­onstrated durable activity in both heavily pre-treated Velcade-refractory and Velcade-relapsed patients, with man­ageable side effects.

He also noted that an inter­na­tional Phase 3 trial is cur­rently underway to con­firm the efficacy of this com­bi­na­tion ther­apy.

Zolinza

The last presentation to be covered in this update is one that was given by Dr. Meletios Dimopoulos from the University of Athens in Greece

He presented the results of a large Phase 3 trial comparing Zolinza (vorinostat) in com­bi­na­tion with Velcade to Velcade plus placebo in re­lapsed / refractory myeloma patients (abstract).

Zolinza is an oral drug already approved by the U.S. Food and Drug Administration as a treat­ment for a type of lym­phoma.  It is marketed by the pharma­ceu­tical com­pany Merck.  The drug also is approved for a similar use in Canada and Australia, but not in Europe.

Like two other drugs that have been in­ves­ti­gated as potential myeloma treat­ments -- panobinostat and Istodax (romidepsin) -- Zolinza belongs to a class of drugs known as HDAC-inhibitors.   These drugs have been shown to reduce the spread of cancer cells through their impact on the rate of cell division, the repair of DNA mistakes, and the timing of cell death.

The Zolinza Phase 3 study included 637 patients from 174 treat­ment centers across 33 countries.  Patients in the study had received a median of two prior ther­a­pies. Median patient age was 62 years.

Among the patients who received Velcade in com­bi­na­tion with Zolinza, 56 per­cent had a partial response or better.  In contrast, 41 per­cent of the patients who received Velcade plus placebo achieved a partial response or better.

In addi­tion, pro­gres­sion-free survival was longer (7.6 months) in patients who received Velcade and Zolinza than in patients treated with Velcade plus placebo (6.8 months).

Although the 25-day difference in these time spans is statistically significant, it was not clear to many of the physicians attending the presentation that it is clinically significant.

In addi­tion, the difference in over­all survival between the two groups of patients in the study is not statistically significant.  Dr. Dimopoulos noted, however, that there is a trend toward a survival advantage for the Velcade-Zolinza com­bi­na­tion.

Side effects were more frequently observed in the patients receiving the Zolinza-Velcade com­bi­na­tion.  About half the patients receiving the com­bi­na­tion had to reduce their dose, or dis­con­tinue treat­ment, as a result of side effects.  Only a quarter of the patients receiving Velcade plus placebo had to reduce their dose or dis­con­tinue treat­ment.