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New Multiple Myeloma Treatments On The Horizon (ASH 2012)

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Published: Nov 19, 2012 1:03 pm

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 (filanesib), BHQ880, circularly permuted TRAIL, daratumumab, dinaciclib, lorvotuzumab mertansine, oprozomib, and tabalumab.

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 (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 (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) 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 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 (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 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 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 (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) 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, 4082, and 1868 (ARRY-520); 331 (BHQ880); 78, 1857, and 2958 (CPT); 73 (daratumumab); 76 (dinaciclib); 728 (lorvotuzumab mertansine); 203 (oprozomib); and 447 (tabalumab) on the ASH meeting website.

Photo by Alexander van Dijk on Flickr – some rights reserved.
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5 Comments »

  • suzierose said:

    How is stable disease being defined in these studies vs. CR/VGPR/PR?

  • Julie Shilane (author) said:

    The abstracts are brief and therefore do not explicitly state the response criteria used. The standard, however, is to use the International Myeloma Working Group Uniform Response Criteria, which can be found in this journal article: http://www.nature.com/leu/journal/v20/n9/full/2404284a.html
    and specifically in this table: http://www.nature.com/leu/journal/v20/n9/fig_tab/2404284t5.html#figure-title

  • suzierose said:

    Ahhhh, TRAIL is an acronym for TNF-related apotosis- inducing ligand.

    What happens to normal cells when cyclin dependent kinases are inhibited?. Dinaciclib is not selective for cancer cells, which means it will inhibit DNA synthesis and mitosis in both normal and cancer cells. There are specific cyclin dependent kinases dependent on which phase of the cell cycle they regulate..does Dinaciclib inhibit a specific cyclin-dependent kinase? i.e. D,E, A, or B?

    If the destruction of bone is inhibited by BHQ880, does that mean the myeloma is controlled (even if not eradicated) in terms of symptomatic illness, will a patient still die? Given that bone destruction accounts for all of the CRAB effects that treatment is aimed at preventing, other than anemia?

  • suzierose said:

    Thanks Julie,

    Based on the table:
    SD (not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates)

    This was kinda what I was wondering, what were the time to progression numbers,particularly as these trials for oprozomib and ARRY-520 don't appear to have been long enough to have considerable length for time to progression...or perhaps I am misunderstanding how time to progression is being used to classify patients with stable disease.

  • Stan said:

    Reuters is reporting more positive study results for Pomalidimide.
    "The company had previously reported that the drug improved survival, but the new data, the result of an interim analysis, show that no matter what occurs during the remainder of the trial, the improvement in overall survival will be highly significant" Are links allowed here? I guess I'll find out! http://www.reuters.com/article/2012/11/19/us-celgene-pomalidomide-idUSBRE8AI0UU20121119