ASH 2014 Preview: New Multiple Myeloma Treatments On The Horizon

The 2014 annual meeting of the American Society of Hematology (ASH) starts tomorrow, December 5, in San Francisco, and will continue until next Tuesday.
The ASH annual meeting is one of several large medical conferences where myeloma-related research findings are presented each year. However, from a multiple myeloma perspective, the ASH meeting is generally the most important of the meetings.
At this year’s meeting, for example, some 500 myeloma-presentations are scheduled to take place. The presentations will summarize current research on a wide range of topics, including the biology of the disease and current and potential new myeloma therapies.
As is the case at most scientific meetings, research results at ASH will be communicated either in oral presentations or poster summaries.
Oral presentations are usually given for research that is considered particularly important, either because the subject itself is important, or because the results are based on substantial amounts of evidence (for example, a sizable clinical trial).
Poster research summaries are made available during specific “poster sessions,” when researchers display summaries of their studies on posters in a large exhibition hall.
Compared to the research summarized during oral presentations, the findings in poster summaries generally are in earlier stages of development and may involve only laboratory research or clinical trials with just a small number of patients.
The Beacon will be in attendance at ASH, providing daily coverage as the meeting progresses, followed by in-depth, topic-specific coverage once the conference has finished.
To mark the start of the conference tomorrow, The Beacon today takes an extended look at the ASH presentations related to potential new myeloma therapies – a topic that usually is of keen interest to Beacon readers.
As in previous years, research related to lesser known agents that are in the early stages of clinical development will be presented at the ASH meeting. However, the number of early-stage myeloma treatments with such results is smaller this year than in recent years. Potential new myeloma therapies in this category include ulocuplumab, Imbruvica (ibrutinib),PRLX93936, PVX-410, and Jakafi (ruxolitinib). Studies involving these drugs are discussed in the first half of this article.
There also is an overview in this article of clinical trial results for potential new myeloma treatments that are a bit further along in clinical development and that have shown promising results so far. These agents include elotuzumab, SAR650984, daratumumab, ixazomib (MLN9708), and oprozomib. Studies involving these drugs are discussed in the second half of this article.
Readers who are relatively new to reviewing summaries of clinical trial results may wish to consult the Beacon’s “Tips For Making Sense Of The Research Results Presented At This Year’s ASH Annual Meeting,” which was published prior to the 2012 ASH meeting.
First Results For Early-Stage Potential New Therapies
Ulocuplumab
A poster presentation at the ASH meeting will summarize results from a Phase 1 study of ulocuplumab alone and in combination with Revlimid (lenalidomide) and dexamethasone (Decadron), or in combination with Velcade (bortezomib) and dexamethasone in relapsed and refractory myeloma patients (abstract).
Ulocuplumab (BMS-936564), which is being developed by Bristol-Myers Squibb (NYSE:BMS), belongs to the same broad class of drugs as elotuzumab and daratumumab, called monoclonal antibodies. Monoclonal antibodies work by identifying proteins on the surface of myeloma cells and signaling for the immune system to destroy those cells.
The ulocuplumab study includes 44 patients who have received a median of four prior lines of therapy; 93 percent previously received Velcade, and 86 percent previously received Revlimid.
The overall response rate for all patients was 50 percent, with 2 percent achieving a complete response, 14 percent a very good partial response, and 34 percent a partial response. More patients receiving ulocuplumab in combination with Revlimid and dexamethasone responded (55 percent) than those receiving ulocuplumab in combination with Velcade and dexamethasone (40 percent).
Based on these findings, the trial arm of ulocuplumab in combination with Revlimid was expanded.
Imbruvica
One of the oral presentations to be made at this year’s ASH meeting will summarize the initial results of a Phase 2 study of Imbruvica (ibrutinib) alone or in combination with dexamethasone for the treatment of relapsed and refractory myeloma (abstract).
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.
So far, 69 myeloma patients who have received a median of four previous therapies have been enrolled in the Imbruvica Phase 2 myeloma trial.
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.
Imbruvica also is being investigated in combination with Kyprolis (carfilzomib) in an ongoing Phase 1/2 study.
PVX-410
Initial results of a Phase 1/2 trial investigating the therapeutic cancer vaccine PVX-410 in smoldering multiple myeloma patients also will be presented at this year’s annual meeting (abstract).
PVX-410, which is being developed the pharmaceutical company OncoPep, consists of four novel peptides that target specific tumor-associated antigens found on myeloma cells.
The study includes 12 smoldering multiple myeloma patients who had been diagnosed a median of 0.8 years before entering the trial. The patients received six administrations of PVX-410 over a period of 10 weeks.
All 12 patients showed an immune response to the vaccine, with a third of the patients having an immune response to three or more of the four peptides. Based on these findings, PVX-410 is currently being investigated in combination with three cycles of fixed‑dose Revlimid. The investigators hypothesize that co-administration of Revlimid will enhance the immune response induced by PVX-410.
PRLX93936
Results from a Phase 1study to be presented at the ASH meeting will show that PRLX93936 did not have significant activity in relapsed and refractory myeloma patients when used alone. However, the impact of adding dexamethasone to treatment with the drug is still being investigated (abstract).
PRLX93936 is being developed by Prolexys Pharmaceuticals. PRLX 93936 is a small-molecule anti-cancer treatment that targets the RAS protein.
So far, 14 patients who have received a median of five prior lines of therapy have been enrolled in the trial. Among the 13 patients evaluated for response, the best response observed was a minor response, which was seen in 18 percent of the patients;
Jakafi
Also on the agenda for the ASH meeting will be a presentation about Jakafi (ruxolitinib). In particular, researchers will present results of a preclinical study of the drug in combination with Revlimid and dexamethasone (abstract).
Jakafi belongs to a class of drugs known as JAK inhibitors. They work by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), which are commonly mutated and overactive in inflammatory diseases, myeloproliferative disorders, and various cancers. Jakafi is already approved by the FDA for the treatment of myelofibrosis, a disorder in which the bone marrow is scarred.
The results of the preclinical study show that the combination of Jakafi, Revlimid, and dexamethasone leads to a marked reduction of myeloma cell concentration and delays in disease proliferation in human and animal cell lines.
New Results For Potential Treatments Further Along In Development
Monoclonal Antibodies
Myeloma researchers have been particularly excited in recent years about the class of potential new myeloma therapies known as CD38 monoclonal antibodies. These drugs work by targeting a protein known as CD38 that is frequently found on the surface of myeloma cells.
SAR650984
The first clinical trial results for one of the drugs in this class of therapies, SAR650984, were presented at last year’s ASH (see related Beacon news). At the time, Dr. Joseph Mikhael of the Mayo Clinic told The Beacon, “This drug was hands down the most promising new agent at ASH for myeloma.”
During this year’s ASH meeting, updated results of a Phase 1b trial of SAR650984 in combination with Revlimid and dexamethasone in relapsed and refractory multiple myeloma will be presented (abstract). The most recent results of the trial were presented at the American Society of Clinical Oncology (ASCO) annual meeting this summer (see related Beacon news).
The study so far includes 31 myeloma patients who had received a median of six prior therapies.
The trial explored three different dose levels (3 mg/kg, 5 mg/kg, and 10 mg/kg) of SAR650984.
Overall, 65 percent of patients have responded to the treatment. The median progression-free survival was 6.2 months.
Daratumumab
The first CD38 monoclonal antibody to attract the attention of myeloma researchers was daratumumab. It is being developed by the Danish biotechnology company Genmab together with Janssen Biotech, a Johnson & Johnson subsidiary.
Results of two ongoing clinical trials involving daratumumab will be presented at this year’s ASH meeting.
The first is a Phase 1/2 trial of daratumumab in combination with Revlimid (lenalidomide), and dexamethasone (Decadron) in relapsed myeloma patients (abstract). Results were presented earlier this year at the ASCO annual meeting (see related Beacon news).
Of the 20 patients evaluable for response, 75 percent have so far responded to the three-drug treatment, with 15 percent achieving a complete response, 45 percent a very good partial response or complete response, and 15 percent a partial response.
The second study is a Phase 1b trial in which daratumumab was added to current backbone treatments (abstract). In particular, daratumumab was added to Velcade-dexamethasone (VD), Velcade-thalidomide-dexamethasone (VTD), Velcade-melphalan-prednisone (VMP), and Pomalyst-dexamethasone (POM-D).
Newly diagnosed patients were included in the VD and VTD arms of the trial, irrespective of transplant eligibility. Patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed and refractory to two or more lines of prior therapy, including at least two consecutive cycles of Revlimid and Velcade.
So far, 17 newly diagnosed patients have been treated in the VD, VTD, and VMP arms of the trial. All patients received 16 mg/kg of daratumumab. The median duration of treatment was 44 days.
According to the investigators, daratumumab was well tolerated in all evaluable patients and did not result in significant additional toxicity.
Elotuzumab
Elotuzumab, which is being developed by Bristol-Myers Squibb and AbbVie (NYSE:ABBV), is the monoclonal antibody that is furthest along in clinical development and has shown very promising results so far. It received breakthrough designation earlier this year (see related Beacon news).
Unlike SAR650984 and daratumumab, however, elotuzumab does not target the CD38 protein. Instead, it targets a different protein known as CS1.
During this year’s ASH meeting, final results from a Phase 2 study of elotuzumab in combination with Revlimid and dexamethasone will be presented (abstract).
The study included 73 myeloma patients treated with a median of two prior lines of therapy. The median patient age was 63 years.
Half of the study participants received 10 mg/kg of elotuzumab, while the other half received 20 mg/kg of the drug.
The results showed that the outcomes of patients treated with 10 mg/kg of elotuzumab were better than the outcomes of those treated with 20 mg/kg.
In particular, 92 percent of the patients in the 10 mg/kg group responded to treatment, as compared to 76 percent in the 20 mg/kg group. Median progression-free survival is 32 months for the 10 mg/kg group and 25 months for the 20 mg/kg group.
Pneumonia was the most common severe or life-threatening side effect; it occurred in 12 percent of the patients.
Initial results of another elotuzumab study, a Phase 1b/2 study in which the drug is given in combination with Revlimid, Velcade, and dexamethasone to newly diagnosed, high-risk patients, will also be presented at the meeting (abstract).
So far, eight patients with a median age of 67 years have been enrolled in the study.
Efficacy results are not yet available, but the four-drug regimen seems to be well tolerated. The most common severe side effects included peripheral neuropathy (33 percent), low white blood cell counts (17 percent), and low platelet counts (17 percent).
Next-Generation Proteasome Inhibitors
Several studies will be presented at this year’s ASH meeting about two next-generation proteasome inhibitors. This class of drugs includes Velcade and Kyprolis, and drugs in the class work work by preventing the breakdown of protein in cancer cells, triggering their death.
Unlike Kyprolis and Velcade, both of the next generation proteasome inhibitors can be taken orally.
Ixazomib
One of the newer proteasome inhibitors is ixazomib (MLN9708), which is being developed by Millennium Pharmaceuticals, the same company that developed Velcade. Results of several trials investigating ixazomib as a potential myeloma therapy have been presented a number of times at previous conferences such as ASH.
At this year’s ASH meeting, results from a Phase 2 study of ixazomib in combination with Revlimid and dexamethasone followed by ixazomib maintenance in newly diagnosed myeloma patients will be presented (abstract). The focus of the presentation will be on the maintenance part of the study.
Of the 50 patients who received induction therapy with ixazomib plus Revlimid and dexamethasone, 42 percent received ixazomib maintenance therapy.
The results show that ixazomib maintenance improved responses following ixazomib-Revlimid-dexamethasone induction therapy; 33 percent of patients improved their response during maintenance therapy.
Oprozomib
Results from two clinical trials for the second next-generation proteasome inhibitor, oprozomib, will be presented at the ASH annual meeting.
Oprozomib is being developed by Onyx Pharmaceuticals (NASDAQ: ONXX), the company that markets Kyprolis.
One of the oprozomib trials is a Phase 1/2 study that investigates the efficacy and safety of opromozib in patients with hematologic malignancies (abstract).
The study includes 106 patients with hematologic malignancies (68 with multiple myeloma) who were treated with oprozomib, using one of two different dosing schedules.
Approximately a third of the myeloma patients in both dosing groups (33 percent and 37 percent, respectively) responded to treatment. Both dosing schedules are investigated in the Phase 2 part of the trial.
Another Phase 1b/2 study investigates the efficacy and safety of oprozomib in combination with dexamethasone in relapsed and refractory myeloma patients (abstract).
The study includes 29 patients who had received a median of three prior therapies. Patients received oprozomib administered at the same two dosing schedules as in the oprozomib monotherapy trial, plus 20 mg of dexamethasone.
Almost half of the patients in the one dosing group (42 percent) responded to treatment, with 8 percent achieving a very good partial response and 15 percent achieving a partial response, while none of the patients in the second dosing group responded to treatment.
Gastrointestinal tolerability in the study was improved compared to what was seen in the studies of oprozomib by itself.
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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- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Lather, Rinse, Repeat: Will It Work With BCMA-Targeted Therapies For Multiple Myeloma?
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
Thanks for the excellent preview, which included more detail than several other previews I've read today. I'm looking forward to your upcoming reports from ASH 2014.
Are there any elotuzumab trials being conducted in India?
Thanks so much Beacon Staff for this summary of the newest therapies being investigated for treating myeloma. I find it very interesting that so many are of the 'antibody' type, i.e. attacking antigens known to be on the surface of the mutated myeloma plasma cells. I have learned that the acronym 'CD' means 'cluster of differentiation'. The numbering system is from the order in which the CD was discovered. I hope that any and all of these treatments prove to be effective, and are without major side effects.
First, thank you for this coverage. It is a great service to us patients. I quote your text above:
"However, the number of early-stage myeloma treatments with such results is smaller this year than in recent years."
That does not sound good because it is not so much in the pipeline? I would appreciate if you could give us some information what's said at ASH about the high risk disease with OS under 3 years. The OS hasn't gone up in the last years.
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