During the upcoming annual meeting of the American Society of Hematology (ASH), which will be held December 8 through 11 in Atlanta, results will be presented from clin­i­cal trials involving a number of poten­tial new drugs under devel­op­ment for the treat­ment of multiple myeloma.

In particular, results for newer, lesser known agents that are in the early stages of clin­i­cal devel­op­ment will take center stage. These agents in­clude ARRY-520 ^[1] (filanesib ^[2]), BHQ880 ^[3], circularly permuted TRAIL ^[4], daratumumab ^[5], dinaciclib ^[6], lorvotuzumab mertansine ^[7], oprozomib ^[8], and tabalumab ^[9].

According to the recently released ASH abstracts, the agents showed varying degrees of activity in re­lapsed and refractory myeloma patients, except for BHQ880, which was tested for its ability to prevent bone disease in smol­der­ing myeloma patients. So it will be in­ter­est­ing to see and hear how the myeloma experts attending the ASH meeting react to the initial findings for these com­pounds.

The current article summarizes the pre­lim­i­nary results from these agents, based on the data avail­able in the meeting abstracts.  The results that seem particularly noteworthy are described first.

ARRY-520

Array BioPharma (NASDAQ: ARRY) is devel­op­ing ARRY-520.  The drug inhibits kinesin spindle protein, which plays an im­por­tant role in actively dividing cells.  It is being studied alone and in com­bi­na­tion with other drugs for several blood cancers.

During the ASH meeting, there will be one oral presentation and two posters about ARRY-520 studies.

The oral presentation will be given by Dr. Jatin Shah from M.D. Anderson Cancer Center in Houston, who will present results from a Phase 2 study of ARRY-520.

As of the date at which the abstract was written, 32 patients were treated with ARRY-520.  They had received a median of six pre­vi­ous lines of ther­apy.  In addi­tion, 18 patients were treated with ARRY-520 plus dexamethasone ^[10] (Decadron).  These patients had received a median of 10 pre­vi­ous lines of ther­apy.

Among those treated with only ARRY-520, 16 per­cent achieved a partial response.  Among those treated with ARRY-520 plus dexa­meth­a­sone, 22 per­cent achieved at least a partial response.

Given that patients receiving the com­bi­na­tion were sig­nif­i­cantly more heavily pre­treated than the patients treated only with ARRY-520, yet were more likely to respond to treat­ment, the researchers suggested that the com­bi­na­tion should be further studied.

During one of the meeting’s poster sessions, initial results from a Phase 1 study of ARRY-520 in com­bi­na­tion with Kyprolis ^[11] (car­filz­o­mib) will be presented.  The abstract is based on eight patients who had been treated with a median of four prior ther­a­pies.

Among the six patients who com­pleted at least one cycle of treat­ment, 17 per­cent achieved a near com­plete response, and 67 per­cent have stable disease and are continuing treat­ment.

The other poster about ARRY-520 will show that levels of a protein called alpha 1-acid glycoprotein (AAG) in the blood can be used to predict how well a patient is likely to respond to ARRY-520.  None of the patients with a high level of AAG prior to ARRY-520 treat­ment responded to the drug.

Tabalumab

Tabalumab (also known as LY2127399 ^[12]) is being devel­oped by Eli Lilly (NYSE: LLY).  It is an anti­body that targets a protein called BAFF, which plays an im­por­tant role in the devel­op­ment of B cells.  Excessive levels of BAFF lead to ab­nor­mally high levels of anti­body pro­duc­tion.  Therefore, tabalumab may be effective for multiple myeloma as well as auto­immune diseases.  Preclinical studies have indicated that tabalumab is effective against myeloma and also helps prevent bone destruction.

Dr. Noopur Raje from the Massachusetts General Hospital in Boston will discuss results of a Phase 1 study of tabalumab in com­bi­na­tion with Velcade and, in some cases, dexa­meth­a­sone.

The study in­cluded 48 multiple myeloma patients who had been treated with a median of three prior ther­a­pies.  Three-quarters of the par­tic­i­pants were treated with tabalumab plus Velcade; the remaining quarter also received dexa­meth­a­sone.

In total, 46 per­cent of patients responded to the ther­apy, with 4 per­cent achieving a com­plete response, 8 per­cent a very good partial response, and 33 per­cent a partial response.

Among 14 patients assessed, the median time to pro­gres­sion was 4.9 months.

The researchers also found that patients who responded to the tabalumab com­bi­na­tion ther­apy were more likely to have low levels of BAFF in their blood prior to treat­ment.

A Phase 2/3 study ^[13] of the same drug com­bi­na­tion is cur­rently recruiting par­tic­i­pants.  Tabalumab will be tested at two dif­fer­en­t doses in com­bi­na­tion with Velcade and dexa­meth­a­sone as com­pared to Velcade plus dexa­meth­a­sone alone.

Oprozomib

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

It works similarly to Kyprolis as well as Velcade ^[14] (bor­tez­o­mib).  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.

At ASH, Dr. Michael Savona from the Sarah Cannon Research Institute in Nashville, Tennessee, will discuss results of a Phase 1b study of oprozomib.

The abstract for the study in­cludes initial results from nine people with blood cancers who were treated with one of three dif­fer­en­t doses of oprozomib.  The study par­tic­i­pants had received a median of four pre­vi­ous treat­ment regi­mens.

All eight of the patients eval­u­ated for response to oprozomib 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.

Daratumumab

The Danish pharma­ceu­tical com­pany Genmab is devel­op­ing dara­tu­mu­mab together with the Johnson & Johnson (NYSE: JNJ) sub­sid­i­ary Janssen Biotech.  The drug is a mono­clonal anti­body that binds to the CD38 molecule, which is found on the surface of multiple myeloma and other blood cancer cells.  Once it is bound to the CD38 molecule on cancer cells, dara­tu­mu­mab signals for the immune sys­tem to kill the cells.

Dr Torben Plesner from Vejle Hospital in Vejle, Denmark, will present intermediate efficacy results from a Phase 1/2 study of dara­tu­mu­mab in re­lapsed and refractory myeloma patients (preliminary results ^[15] were presented at the American Society of Clinical Oncology meeting in June).

Study par­tic­i­pants received escalating doses of dara­tu­mu­mab ranging from 0.005 mg/kg to 24 mg/kg.

The abstract is based on data from 32 heavily pre­treated myeloma patients who received a median of 6.3 prior treat­ment regi­mens.

Daratumumab’s pre­lim­i­nary efficacy evaluation is based on the change in mono­clonal (M) protein in the blood or urine.

Of the patients receiving up to 2 mg/kg of dara­tu­mu­mab, 20 per­cent of patients achieved a reduction in M-protein ranging from 12 per­cent to 55 per­cent. Among the patients receiving at least 4 mg/kg, 78 per­cent achieved a reduction in M-protein of 33 per­cent to 100 per­cent.

In addi­tion, all patients treated with at least 4 mg/kg of dara­tu­mu­mab showed a marked reduction in the per­cent­age of plasma cells in the bone marrow ranging from 80 per­cent to 100 per­cent.

Dinaciclib

Dinaciclib is being devel­oped by Merck (NYSE: MRK).  It is a small molecule that inhibits enzymes called cyclin-dependent kinases, which regulate the cell cycle and are often overactive in cancer cells.  Inhibition of these enzymes and inter­rup­tion of the cell cycle causes the cell to die.

Dr. Shaji Kumar from the Mayo Clinic in Rochester, Minnesota, will discuss results of a Phase 1/2 study of dinaciclib at the ASH meeting.

The results are from 29 patients with re­lapsed multiple myeloma who had received a median of four pre­vi­ous lines of ther­apy.

Among the 27 patients eval­u­ated for response, 11 per­cent responded, with 7 per­cent achieving a very good partial response and 4 per­cent achieving a partial response.

Almost half (48 per­cent) are still alive after a median follow-up time of 11.8 months.

Researchers are planning an upcoming Phase 1 clinical trial ^[16] that will study dinaciclib in com­bi­na­tion with Velcade and dexa­meth­a­sone.

Circularly Permuted TRAIL

Circularly Permuted TRAIL (CPT) is being devel­oped by Beijing Sunbio Biotech as a treat­ment for multiple myeloma and other blood cancers.  It activates re­cep­tors in the body called TRAIL that cause cells to die.  Preclinical studies have shown that CPT kills cancers cells but not most healthy cells.

During the ASH meeting, there will be one oral presentation and two posters about CPT studies.

Results of a Phase 2 study of CPT will be presented by Dr. Wenming Chen from the Chaoyang Hospital of Capital Medical University in Beijing.

The abstract for Dr. Chen’s presentation is based on results from 27 people with re­lapsed or refractory multiple myeloma.  It does not state the median number of pre­vi­ous ther­a­pies.

Overall, 33 per­cent of the study par­tic­i­pants responded to CPT treat­ment, in­clud­ing 4 per­cent who achieved a near com­plete response and 30 per­cent who achieved a partial response.

In the Phase 1b study, which will be presented by poster at the ASH meeting, 27 patients were treated with one of five dif­fer­en­t doses of CPT and then eval­u­ated for response.  Among the patients treated with at least 8 mg/kg of CPT, 17 per­cent to 33 per­cent of the patients responded.

Results of a Phase 2 study of CPT in com­bi­na­tion with thalidomide ^[17] (Thalomid) will also be presented by poster.  As part of this study, 43 myeloma patients who pre­vi­ously did not respond to thalido­mide were treated with CPT in com­bi­na­tion with thalido­mide.

Among the 41 patients who were eval­u­ated for response, 22 per­cent responded to the com­bi­na­tion ther­apy, with 5 per­cent achieving a com­plete response, 7 per­cent a near com­plete response, and 10 per­cent a partial response.

Lorvotuzumab Mertansine

Lorvotuzumab mertansine (IMGN901 ^[18]) is being devel­oped by the U.S. bio­tech com­pany ImmunoGen (NASDAQ: IMGN).  It is a chemo­ther­apy agent (mertansine) attached to an anti­body (lovortuzumab) that directs the chemo­ther­apy to the cancer cell.  The lorvotuzumab portion of the drug recog­nizes the CD56 protein found on the surface of myeloma cells.  Approximately 70 per­cent of myeloma patients have myeloma cells with the CD56 protein.

Dr. Jesus Berdeja from the Sarah Cannon Research Institute in Nashville will discuss results of a Phase 1 study of lorvotuzumab mertansine in com­bi­na­tion with Revlimid and dexa­meth­a­sone.

The study in­cluded 44 multiple myeloma patients who had been treated with a median of two prior ther­a­pies; 32 of the patients have been eval­u­ated for response.

Overall, 59 per­cent of the par­tic­i­pants responded to the com­bi­na­tion ther­apy, in­clud­ing 3 per­cent who achieved a stringent com­plete response, 3 per­cent com­plete response (CR), 25 per­cent very good partial remission, and 28 per­cent partial remission.

BHQ880

BHQ880 is an anti­body that targets DKK-1, a protein that inhibits bone for­ma­tion and is overabundant in people with multiple myeloma.  BHQ880 there­fore helps to restore bone for­ma­tion.  Several ongoing Phase 2 studies are investigating the effect BHQ880, alone or in com­bi­na­tion with Zometa, has on myeloma bone disease.

During the ASH meeting, Dr. Nikhil Munshi from the Dana-Farber Cancer Institute in Boston will present results of a Phase 2 study of BHQ880 in higher-risk smol­der­ing multiple myeloma patients.

At the time the abstract was prepared, 25 patients had been enrolled.  Among the five patients eval­u­ated for bone strength after six months of treat­ment, 80 per­cent ex­peri­enced in­creased bone strength according to quantitative computed tomography.  No sig­nif­i­cant changes in bone strength were noted via DEXA scans, how­ever.

BHQ880 did not have any anti-myeloma effects.

For more in­for­ma­tion, please see abstracts 449 ^[19], 4082 ^[20], and 1868 ^[21] (ARRY-520); 331 ^[22] (BHQ880); 78 ^[23], 1857 ^[24], and 2958 ^[25] (CPT); 73 ^[26] (dara­tu­mu­mab); 76 ^[27] (dinaciclib); 728 ^[28] (lorvotuzumab mertansine); 203 ^[29] (oprozomib); and 447 ^[30] (tabalumab) on the ASH meeting website.