Yesterday was the third day of the American Society of He­ma­tol­ogy (ASH) 2011 Annual Meeting in San Diego, and it was packed full with mul­ti­ple myeloma-related pre­sen­ta­tions. Presentations started early in the morn­ing and con­tinued through the afternoon.

The morn­ing pre­sen­ta­tions about po­ten­tial new myeloma ther­a­pies will be covered in this up­date, and pre­sen­ta­tions from the rest of the day will be covered in addi­tional up­dates.

MLN9708

During the first talk of the day, Dr. Paul Richardson from the Dana-Farber Cancer In­sti­tute in Boston pre­sented re­­sults from a Phase 1 study of MLN9708 (ixazomib) in patients with pre­vi­ously treated myeloma (abstract).  MLN9708 belongs to the same class of drugs as Velcade (bor­tez­o­mib); how­ever, MLN9708 can be taken orally.

The goal of the study was to identify the best dosing for MLN9708. The study in­cluded 62 patients who had re­ceived a median of four prior ther­a­pies.

Among the patients for whom data is avail­able so far, 13 per­cent have responded to the treat­ment, in­clud­ing one patient who achieved a com­plete re­sponse.

About 60 per­cent of patients have dis­con­tinued ther­apy, mainly due to dis­ease pro­gres­sion.

The most common side effects were fatigue, low platelet counts, and gastro­in­tes­ti­nal issues such as nausea, diarrhea, and vomiting. Only 8 per­cent of the trial par­tic­i­pants ex­peri­enced periph­eral neu­rop­athy, and none of the neu­rop­athy cases were classified as serious.

Overall, Dr. Richardson said that MLN9708 showed good ac­­tiv­ity in heavily pre-treated patients, that it has an “excellent tol­er­a­bil­ity profile,” and that the drug will con­tinue to be devel­oped, with trials planned looking at com­bi­na­tions of MLN9708 with other drugs as well as trials in dis­eases other than myeloma.

Later in the morn­ing Dr. Jesus Berdeja, from the Sarah Cannon Re­search In­sti­tute in Nashville, Tennessee, also gave a pre­sen­ta­tion about MLN9708.  He pre­sented re­­sults of a Phase 1/2 trial looking at MLN9708 com­bined with Revlimid (lena­lido­mide) and dexamethasone (Decadron) in pre­vi­ously untreated myeloma patients.

The core objective of the study is to better under­stand the best dosing of MLN9708, but it also is in­tended to shed more light on the ef­fi­cacy and safety of the drug.

Thus far, the study has en­rolled 10 patients.  The median num­ber of com­pleted treat­ment cycles to date for all patients is three, and six patients are still on treat­ment.  Trial par­tic­i­pants wishing to undergo a stem cell trans­plant can do so after six cycles of the com­bi­na­tion ther­apy.

Results so far show that all nine patients with re­sponse data have achieved a partial re­sponse or better, in­clud­ing one com­plete re­sponse and three very good partial re­sponses.  In addi­tion, all patients achieved a 50 per­cent or greater de­crease in mono­clonal (M)-protein by the end of the first cycle and reached best re­sponse by the end of the fourth cycle.

To date, no patients have progressed, and one patient with a very good partial re­sponse dis­con­tinued treat­ment to undergo a stem cell trans­plant.

The most common side effects were rash (40 per­cent of patients), vomiting (30 per­cent), fatigue (30 per­cent), diarrhea (20 per­cent), con­sti­pa­tion (20 per­cent), and nausea (20 per­cent). One patient (10 per­cent) reported mild periph­eral neu­rop­athy. The only serious side effect attributed to the drug was fainting (10 per­cent).

According to Dr. Berdeja, MLN9708 in com­bi­na­tion with Revlimid and dexa­meth­a­sone appears to be generally well tol­er­ated in pre­vi­ously untreated mul­ti­ple myeloma patients.

Marizomib

Dr. Richardson gave another pre­sen­ta­tion about marizomib (NPI-0052), which is also in the same class of drugs as Velcade.  Dr. Richardson pre­sented com­bined data from U.S. and Australian Phase 1 stud­ies of marizomib (abstract).  The goal of both stud­ies was to de­ter­mine the best dose and dosing schedule for the drug.

At the time the data was analyzed, 44 patients had par­tic­i­pated in the U.S.study and 25 patients had par­tic­i­pated in the Australian trial.  The par­tic­i­pants had re­ceived a median of six prior ther­a­pies.

Most of the trial par­tic­i­pants re­ceived dexa­meth­a­sone in addi­tion to marizomib.

Overall, 19 per­cent of par­tic­i­pants responded to the treat­ment.

During the testing of dif­fer­en­t doses for marizomib, dose-limiting side effects such as hallucinations, cog­ni­tive changes, and loss of bal­ance were reversible.  Other side effects in­cluded fatigue, nausea, vomiting, dizzi­ness, headache, diarrhea, con­sti­pa­tion, insomnia, weight loss, and short­ness of breath.  No patients ex­peri­enced low red or white blood cells, low platelet counts, or periph­eral neu­rop­athy.

Based on the re­­sults of the stud­ies, Dr. Richardson stated that 0.5 mg/m² of marizomib twice weekly should be studied fur­ther, alone or in com­bi­na­tion with dexa­meth­a­sone or Revlimid.

Elotuzumab

Dr. Sagar Lonial from the Winship Cancer In­sti­tute at the Emory Uni­ver­sity School of Medicine in Atlanta gave the next pre­sen­ta­tion.  He summarized re­­sults of a Phase 2 study of elotuzamab com­bined with Revlimid and low-dose dexa­meth­a­sone in patients with re­lapsed/refractory mul­ti­ple myeloma (abstract).

The study in­cluded 73 myeloma patients who had at least one, but no more than three, pre­vi­ous lines of ther­apy.  The patients in the study had a median time since initial myeloma diag­nosis of 4.5 years, and none had pre­vi­ously been treated with Revlimid.

Patients re­ceived either 10 mg/kg or 20 mg/kg elotuzumab by in­tra­venous in­fusion.  Patients were also treated with Revlimid and dexa­meth­a­sone.

The over­all re­sponse rate was actually higher in the (10mg/m²) lower-dose regi­men than the (20mg/m²) higher-dose regi­men – 92 per­cent and 73 per­cent, re­spec­tively.  The median time to re­sponse was 1.0 month.

After a median follow-up time of 11.4 months, 22 per­cent of patients ex­peri­enced dis­ease pro­gres­sion in the 10 mg/kg dose group and 30 per­cent in the 20 mg/kg dose group.

The most common serious or severe side effects were low lym­pho­cyte levels (a type of white blood cell) in 16 per­cent of patients, low platelet levels (16 per­cent of patients), low white blood cell levels (15 per­cent of patients), and low red blood cell levels (11 per­cent of patients).

In addi­tion, 63 per­cent of patients ex­peri­enced in­fusion reac­tions, despite re­ceiv­ing preventative treat­ment.  The most common in­fusion reac­tions in­cluded nausea (18 per­cent), headache (14 per­cent), fever (14 per­cent), and dizzi­ness (12 per­cent).

The lower, 10mg/kg dose of elotuzumab is being tested fur­ther in com­bi­na­tion with Revlimid and dexa­meth­a­sone in two large, Phase 3 trials. One is in newly diag­nosed myeloma patients; the other is in re­lapsed/refractory patients.

Treanda

Next, Dr. Suzanne Lentzsch from the Uni­ver­sity of Pittsburgh School of Medicine pre­sented re­­sults from a Phase 1/2 study of Treanda (bendamustine) in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed/refractory mul­ti­ple myeloma patients (abstract).

Treanda is an al­kyl­at­ing agent, which is a class of drugs that in­cludes myeloma treat­ments such as melphalan (Alkeran) and cyclophosphamide (Cytoxan). It cur­rently is approved by the U.S. Food and Drug Admin­istra­tion as a treat­ment for cer­tain types of leukemia and lym­phoma, and it is approved in some Euro­pean countries as a treat­ment for myeloma.

The goal of the trial was to de­ter­mine the max­i­mum tol­er­ated dose of the Treanda-Revlimid-dexamethasone com­bi­na­tion, as well as its ef­fi­cacy at the max­i­mum tol­er­ated dose.

The study in­cluded 36 patients, who had a median of three prior ther­a­pies.  Among 25 patients assessed for treat­ment re­sponses, the over­all re­sponse rate was 52 per­cent, with 24 per­cent achieving a very good partial re­sponse.

The re­searchers esti­mated that the median pro­gres­sion-free sur­vival would be 6.1 months and that the over­all sur­vival rate at one year after start of ther­apy would be 93 per­cent.

Twenty-four per­cent of patients ex­peri­enced severe low white blood cell counts during the course of the study, and 7 per­cent ex­peri­enced severe low platelet levels.  As a re­­sult, Dr. Lentzsch be­lieved patients should also re­ceive treat­ment with Neupogen (filgrastim) or Neulasta (pegfilgrastim) to help prevent such side effects.

Otherwise, Dr. Lentzsch con­sidered the three-drug regi­men to be "safe and well-tolerated" in re­lapsed/refractory myeloma patients up to 80 years of age.  She noted that the re­sponses observed during the trial were fast and that the regi­men was ef­fec­tive even in patients who pre­vi­ously had been treated with Revlimid.

BT-062

Dr. Sundar Jagannath from Mount Sinai Medical Center in New York City then pre­sented re­­sults from a Phase 1 study of BT-062 in patients with re­lapsed/refractory mul­ti­ple myeloma (abstract).

BT-062 com­bines an anti­body and a drug to kill cancer cells. The anti­body identifies the cancer cells, de­livers the drug right to them so it can be highly ef­fec­tive, and alerts the im­mune sys­tem to the cancer cells so it can defend against them.

The goal of the BT-062 trial was to in­ves­ti­gate the safety and ef­fi­cacy of BT-062 and to find its max­i­mum tol­er­ated dose.

The trial in­cluded 32 patients who had failed treat­ment with a drug in the same class as Revlimid and thalidomide (Thalomid) and who also failed treat­ment with a drug in the same class as Velcade. Prior to the start of the trial, par­tic­i­pants had a median of seven pre­vi­ous anti-myeloma ther­a­pies and were a median of six years from their initial diag­nosis with myeloma.

Of the 28 patients whose re­sponse to treat­ment could be eval­u­ated, the over­all re­sponse rate was 4 per­cent (one patient achieved a partial re­sponse).  An addi­tional 8 per­cent had a minor re­sponse and 38 per­cent had stable dis­ease.

Side effects in­cluded mouth sores, hand-foot syn­drome, blurred vision, and dry eyes, with the last two side effects primarily reported at very high doses. Most patients stopped the study due to dis­ease pro­gres­sion, not side effects.

According to Dr. Jagannath, re­­sults from the study sug­gest that BT-062 is safe and shows evi­dence of clin­i­cal ac­­tiv­ity. Based on the re­­sults, a Phase 1/2 study has been ini­ti­ated in mul­ti­ple myeloma patients to fur­ther eval­u­ate the safety and ef­fi­cacy of BT-062. However, it will use a more fre­quent dosing schedule, based on re­­sults from another clin­i­cal trial that sup­port such dosing.

Zolinza

Dr. David Siegel from the Hackensack Uni­ver­sity Medical Center in New Jersey pre­sented re­­sults from a Phase 3 study of Zolinza (vorinostat) in com­bi­na­tion with Velcade in re­lapsed/refractory mul­ti­ple myeloma patients (abstract).  Dexamethasone could be added to the regi­men if needed.

Zolinza, already approved for cu­tane­ous T-cell lym­phoma, is a histone deacetylase (HDAC) in­hib­i­tor.  This class of drugs in­creases the pro­duc­tion of pro­teins that slow cell division, repair DNA mistakes, and con­trol cell death. Re­searchers hope that this should help the body prevent cells from multiplying out of con­trol and becoming can­cer­ous.

The study in­cluded 143 patients who had re­ceived a median of four prior mul­ti­ple myeloma ther­a­pies.

Of the 142 patients who have been treated so far, 17 per­cent have responded to treat­ment. Median over­all sur­vival is 11.2 months with a two-year over­all sur­vival rate of 32 per­cent.

The most common side effects were mostly blood and gastro­in­tes­ti­nal prob­lems; periph­eral neu­rop­athy was infrequent, with severe periph­eral neu­rop­athy oc­curring in 2 per­cent of patients.

According to Dr. Siegel, this com­bi­na­tion may offer a new treat­ment op­tion for heavily pre­treated myeloma patients.

For more detailed coverage of yes­ter­day’s myeloma-related pre­sen­ta­tions and re­search at the ASH meeting, see the ASH 2011 Day Three thread in The Myeloma Beacon dis­cus­sion forum.

The Beacon is pub­lishing up­dates from Day Four of ASH in the Beacon’s myeloma forums.  As always, the news from each day will also be summarized in daily up­dates like this one.