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ASH 2014 Multiple Myeloma Update - Day One: Oral Sessions

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Published: Dec 7, 2014 9:07 am

This year’s meeting of the American Society of Hematology (ASH) began yesterday morning in San Francisco.

Myeloma-related presentations were made during several sessions throughout the day.

The day started out with a session designed to better educate physicians about multiple myeloma and how to treat the disease.

Two sessions of oral presentations devoted solely to multiple myeloma ran simultaneously in the middle of the day. One of the sessions focused on the biology of the disease. The other one included presentations on new myeloma ther­a­pies for both newly diagnosed and re­lapsed and refractory patients, which will be summarized in this article. Additional myeloma-related presentations were given during a session focused on donor (allogeneic) trans­plan­ta­tion.

During the same time slot, Dr. Jesus San Miguel from the University in Navarra, Spain, gave the Ham-Wasserman Lecture, during which he spoke about the scientific and clinical progress in multiple myeloma (abstract). The Ham-Wasserman Lecture is named after two distinguished hematologists who are both past presidents of ASH and who contributed extensively to ASH. The lecture is traditionally given by an individual from outside the United States who has made a major contribution to the field of hematology.

Myeloma-related research was also made public during a poster session in the evening about the biology of myeloma as well as preclinical and clinical studies testing new and existing treat­ments for myeloma. The poster session will be summarized in a separate article to be published later today.

Education Sessions

During the morning’s Education Session, titled ‘Myeloma: Controversies in Therapy,’ three myeloma experts discussed the role of au­tol­o­gous stem cell trans­plan­ta­tion for the treat­ment of multiple myeloma.  The Beacon will have further details on this session after it is repeated again today; here, however, is a quick overview.

The first talk was given by Dr. Philippe Moreau from the University Hospital in Nantes, France.  Dr. Moreau provided an overview of data supporting the use of au­tol­o­gous stem cell trans­plan­ta­tion in first response, including preliminary data from the ongoing joint French-U.S. clinical trial comparing early versus late trans­plan­ta­tion in newly diagnosed myeloma patients (abstract).

Dr. Paul Richardson from the Dana-Farber Cancer Institute in Boston presented an opposing view, arguing against a one-size-fits-all approach to trans­plan­ta­tion in newly diagnosed patients (abstract).

The final talk of the session was given by Dr. Joseph Mikhael from the Mayo Clinic, who described a "practical approach to re­lapsed multiple myeloma" (abstract).

In a separate session later in the morning, Dr. Robert Orlowski from the M.D. Anderson Cancer Center discussed how to sequence ther­apy for multiple myeloma patients.

Oral Presentations About New Myeloma Therapies

Yesterday's midday oral session about new myeloma ther­a­pies included four myeloma-related presentations; the other two focused on the treat­ment of amyloidosis.

Imbruvica Alone Or In Combination with Dexamethasone In Relapsed And Refractory Myeloma

Dr. Ravi Vij from the Washington University School of Medicine in St. Louis, gave the first talk during the session.  He presented preliminary results of a Phase 2 study of Imbruvica (ibrutinib) alone or in com­bi­na­tion with dex­a­meth­a­sone (Decadron) for the treat­ment of re­lapsed and refractory myeloma (abstract, presentation slides [PDF] courtesy of Dr. Vij).

Imbruvica, which has been developed by the bio­tech com­pany Pharmacyclics (NASDAQ:PCYC) in coop­eration with Johnson & Johnson (NYSE:JNJ), blocks a protein called Bruton’s tyrosine kinase (Btk). Btk is found in anti­body-producing cells and in cells that break down bone tissue. The drug cur­rently is approved by the U.S. Food and Drug Ad­min­is­tra­tion for the treat­ment of chronic lymphocytic leukemia.

Overall, a total 69 myeloma patients were included in the study.  The patients had received a median of four pre­vi­ous ther­a­pies.

Patients received escalating doses of Imbruvica with or without dexa­meth­a­sone.

The results show that the response rate was highest among patients who received the highest Imbruvica dose in com­bi­na­tion with dexa­meth­a­sone (5 per­cent); all of these patients achieved a partial response. An addi­tional 20 per­cent of patients in this treat­ment group achieved a minor response. In addi­tion, 25 per­cent if patients achieved stable disease despite the fact that they were progressing at the time of enrollment.

The median pro­gres­sion-free survival was 5.6 months.

Overall, 57 per­cent of patients experienced severe side effects. Overall, 22 per­cent of patients required dose modifications and 10 per­cent dis­con­tinued treat­ment.

Dr. Vij pointed concluded that further devel­op­ment of Imbruvica in com­bi­na­tion with other agents is warranted, and the drug is, in fact, cur­rently being in­ves­ti­gated in com­bi­na­tion with Kyprolis (car­filz­o­mib) in an ongoing Phase 1/2 study.

Kyprolis Plus Panobinostat In Relapsed And Refractory Myeloma

The second talk was given by Dr. Jonathan Kaufman from Emory University. He presented results of a Phase 1 trial investigating Kyprolis in com­bi­na­tion with panobinostat in re­lapsed and refractory multiple myeloma patients (abstract, presentation slides [PDF] courtesy of Dr. Kaufman).

Panobinostat is an investigational treat­ment that is cur­rently being reviewed by the Food and Drug Administration (FDA) in com­bi­na­tion with Velcade (bor­tez­o­mib) and dexa­meth­a­sone as a potential treat­ment for myeloma. The FDA announced last month that it has extended its review of the drug by three months (see related Beacon news).

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 histone deacetylase (HDAC) inhibitors. Several HDAC inhibitors have been in­ves­ti­gated for the treat­ment of multiple myeloma, including Zolinzaricolinostat (ACY-1215), and quisinostat.  The drugs in this class work by interrupting cell division and causing cell death.

The panobinostat study included 26 myeloma patients with a median of 65 years who had received a median of three prior ther­a­pies. The majority of patients (88 per­cent) had pre­vi­ously received a trans­plant and 62 per­cent were resistant (refractory) to Velcade.

Overall, 46 per­cent of patients responded to treat­ment, with 4 per­cent of patients achieving a complete response, 19 per­cent a very good partial response, and 23 per­cent a partial response. The over­all response was similar among patients who were refractory to Velcade (44 per­cent).

The median pro­gres­sion-free survival was 11.4 months.

The most common severe side effects included anemia (38 per­cent), low platelet counts (38 per­cent), low white blood cell counts (19 per­cent), and fatigue (12 per­cent).

Panobinostat Plus RVD In Newly Diagnosed Myeloma

Next, Dr. Jatin Shah from the MD Anderson Cancer Center in Houston presented results from a Phase 1 of panobinostat in com­bi­na­tion with Revlimid (lena­lido­mide), Velcade, and dexa­meth­a­sone (RVD) in newly diagnosed, trans­plant-eligible patients (abstract).

The study included 31 newly diagnosed patients with a median age of 61 years.

Dr. Shah stated that the panobinostat-RVD com­bi­na­tion was highly active in the patient population. Of  the 22 patients who completed four treat­ment cycles, 95 per­cent responded, with 50 per­cent achieving a complete or near complete response, 27 per­cent a very good partial response, and 18 per­cent a partial response.

According to Dr. Shah, the com­bi­na­tion was well tolerated with limited severe toxicity. The most common severe side effects were blood-related and included low platelet counts (29 per­cent), anemia (13 per­cent), and low white blood cell counts (13 per­cent).

Opromozib In Relapsed And Refractory Myeloma

Dr. Ravi Vij, who presented earlier in the session, also gave the final myeloma-related talk during the session. He presented updated results of a Phase 1/2 study of opromozib in patients with hema­to­logic malignancies (abstract, presentation slides [PDF] courtesy of Dr. Vij).

Oprozomib is being developed by Onyx Pharmaceuticals (NASDAQ: ONXX), the com­pany that markets Kyprolis.  Oprozomib is a proteasome inhibitor like Velcade and Kyprolis.  These drugs work by preventing the breakdown of protein in cancer cells, triggering their death.  Oprozomib, unlike Kyprolis and Velcade, can be taken orally.

The study included 129 patients with hema­to­logic malignancies, of whom 87 had multiple myeloma. Dr. Vij’s presented the results for the myeloma patients.

The myeloma patients were initially diagnosed a median of four to five years prior to starting par­tic­i­pa­tion in the trial. Patients who pre­vi­ously treated with Kyprolis were not initially permitted to take part in the trial, but this exclusion was elim­i­nated for the Phase 2 part of the trial

Oprozomib was admin­istered in two different dosing schedules: days 1 to 5 of a 14-day cycle (5/14 schedule), and days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule). In addi­tion, during the Phase 2 part of the trial, a "step-up" dosing schedule was introduced, using a lower dose of oprozomib during the first cycle of treat­ment, followed by a higher dose in sub­se­quent cycles.

Oprozomib's formulation also changed as the trial progressed. At first, oprozomib was admin­istered as a powder in a capsule twice a day. A year later, a tablet formulation of oprozomib was introduced, which was admin­istered once a day. This summer, an extended-release tablet of oprozomib was introduced, which is also being admin­istered once a day.

Overall, 31 per­cent of patients on the 2/7 dosing schedule responded to treat­ment, compared to 23 per­cent on the 5/14 dosing schedule (results for patients on the step-up dosing schedule are not included in these results). The over­all response rate among patients who were refractory to Kyprolis was 18 per­cent.

The most common non-blood-related side effects included diarrhea, nausea, and vomiting.  Concerns about the drug's gastro­in­tes­ti­nal side effects have been a key reason different dosing schedules and formulations have been pursued during the trial.  More than a quarter of the patients on one dosing schedule, for example, dis­con­tinued par­tic­i­pa­tion in the trial due to side effects, and two patients in the trial died due to to severe gastro­in­tes­ti­nal bleeding.

Double Auto Transplant Versus Auto-Allo Transplant In Newly Diagnosed Higher-Risk Myeloma

During a session that ran concurrently with the one on myeloma ther­a­pies, Dr. Stefan Knop from the University Medical Center in Wuerzburg, Germany, presented results of a German study investigating two different stem cell trans­plan­ta­tion regi­mens for myeloma patients with the del(13q) chromosomal ab­nor­mal­ity.

In particular, patients in the study received either two back-to-back au­tol­o­gous (own) stem cell trans­plants or an initial au­tol­o­gous trans­plant followed by an allogeneic (donor) trans­plant (abstract, presentation slides [PDF] courtesy of Dr. Knop).

The study included 199 patients with a median age of 53 years; 73 patients received the auto-auto trans­plant sequence, while the remaining 126 of the patients received the auto-allo sequence.

The study results show that patients with del(13q) may benefit from the auto-allo approach. Specifically, at a median follow-up up of 7.6 years, auto-allo patients had significantly longer pro­gres­sion-free survival (34.5 months) than the auto-auto patients (21.8 months). The benefit in pro­gres­sion-free survival for patients who received the allo trans­plant was independent of the donor source (matched related or matched unrelated donor).

Median over­all survival did not differ significantly between the two treat­ment groups (71.8 months for auto-auto patients and 70.2 months for auto-allo patients).

The two-year non-relapse mortality among the auto-allo patients was 12 per­cent, compared to 4 per­cent among the auto-auto patients.

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Additional myeloma presentations from the rest of Day 1 of the ASH 2014 meeting, as well as presentations from Day 2 and Day 3, will be summarized in addi­tional ASH daily updates to be published at The Beacon the next few days.  Further coverage of key research results from the meeting will con­tinue after the meeting in individual, topic-specific news articles.

Unless other­wise noted, all presentation and poster summaries in the Beacon's ASH-related articles report results presented at this year's meeting.  These data are often more recent or extensive than what is contained in the presentation and poster abstracts.  In addi­tion, Beacon ASH-related articles will be updated on an ongoing basis in the coming weeks with links to the actual slides and posters presented at the meeting (when available and subject to permission of the lead author).

For more in­­for­ma­tion on ASH’s 56th Annual Meeting, including the final presentation schedule and all meeting abstracts, please see the ASH annual meeting website.

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3 Comments »

  • Nancy Shamanna said:

    Thanks Beacon Staff for this interesting coverage of MM preseantations. (I am just paraphrasing here ).. From the paper by Dr. R. Vij, a way of looking at Ibrutinib, which is to inhibit an enzyme that is essential for B cell receptors. The BTK enzyme is over expressed on myeloma cells, just as it is in other blood cancers CLL and MCL. So there is some overlap between these blood cancers, which the researchers are working with.

    'Introduction: Multiple myeloma (MM) remains an incurable disease in need of new therapies with unique targets. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), an essential enzyme in the B-cell receptor signaling pathway. While BTK is essential for the development and function of B cells and is down-regulated in plasma cells, the expression of BTK in malignant plasma cells is increased 4-fold and comparable to BTK expression levels in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In addition, pre-clinical models show that BTK inhibition with ibrutinib led to direct inhibition of both osteoclast bone resorption and the release of osteoclast-derived tumor growth factors (Tai et al, Blood 2012). Taken together these data suggest that ibrutinib may have a role in the treatment of MM.'

  • Mike Burns said:

    Thanks for the report, Beacon Staff. I am particularly interested in data that may have been presented by Dr. Moreau in the first talk you described. I am in the U.S. version of the early vs. late transplantation trial and have been looking for preliminary results from either the French or U.S. side of the trial without much success so far. So if you have any pointers to additional data, I sure would appreciate them.

  • Myeloma Beacon Staff said:

    Thanks for the feedback on the article, Nancy and Mike.

    Mike - We completely understand your interest in any results Dr. Moreau might have presented from the ongoing IFM/DFCI 2009 trial. It's an important trial.

    However, despite there having been indications that Dr. Moreau might present some results from the trial during the education session, this turned out not to be the case. He and Dr. Richardson both mentioned the trial and its significance on several occasions, but no results were presented.

    Indeed, Dr. Moreau suggested during his education session presentation that the first results of the trial may not be made public until a year from now, at next year's ASH meeting.