ASH 2014 Multiple Myeloma Update – Day One: Poster Session

Saturday was the official first day of the 2014 American Society of Hematology (ASH) annual meeting. The day featured a wide range of interesting presentations about multiple myeloma.
Oral presentations about new treatments under development were given mid-day and were summarized in a Beacon ASH Daily Update published yesterday morning.
During Saturday evening, a poster session took place where important new research findings were summarized in posters displayed throughout two separate large conference halls.
The studies covered a variety of myeloma-related topics, ranging from new treatments being developed for myeloma, combination therapies of approved therapies, to stem cell transplantation, to minimal residual disease testing, and much more.
New Myeloma Treatments
Saturday's poster session featured a number of posters about results from clinical studies of new drugs being developed for the treatment of multiple myeloma.
One of the posters summarized initial findings from an ongoing Phase 1 trial investigating elotuzumab in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) in multiple myeloma patients with various levels of kidney function (abstract). Twelve percent of the patients were newly diagnosed, the remainder had previously received treatment, including Velcade (bortezomib) (81 percent), thalidomide (Thalomid) (42 percent), and Revlimid (35 percent). Overall, 75 percent of patients with normal kidney function, 67 percent of patients with severe kidney impairment and 56 percent of patients with end-stage kidney disease responded to treatment. According to the investigators, the combination was well tolerated in all three patient groups. They stated that patients with severe kidney impairment and with end-stage kidney disease can be treated with 10 mg of elotuzumab in combination with Revlimid and dexamethasone.
Another posters presented final results from a Phase 2a study of NOX-A12 in combination with Velcade and dexamethasone for relapsed myeloma (abstract). NOX-A12 is being developed by Noxxon Pharma. NOX-A12 binds to a small molecule called CXCL12 that is known to play a role in drug resistance. The study included 28 patients who had received a median of two prior therapies. Overall, 68 percent of the patients responded to the combination. The investigators point out that response rates were similar among patients with standard-risk and high-risk disease (70 percent versus 67 percent). Median progression-free survival was 6.5 months. According to the investigators, the combination was well tolerated and merits further investigation.
Updated results from a Phase 1/2 study of TH-302 and dexamethasone with or without Velcade in heavily pretreated myeloma patients were also presented (abstract). TH-302 is being developed by Threshold Pharmaceuticals (NASDAQ: THLD) and the German pharmaceutical company Merck KGaA for the treatment of several different types of cancer. The drug is activated under low oxygen level conditions, which are common in solid cancer tumors and in the bone marrow of people with blood cancers.
The TH-302 study in myeloma thus far has recruited 24 patients. Of those patients, seven have received TH-302, Velcade, and dexamethasone and been evaluated for response. These patients had received a median of eight prior therapies. One of the seven patients (14 percent) achieved a very good partial response and another achieved a partial response. The most common side effects of the treatment included low platelet counts, anemia, and fatigue.
Another poster summarized results from a Phase 1 study investigating PRLX93936 in relapsed and refractory myeloma patients (abstract). PRLX93936 is being developed by Prolexys Pharmaceuticals. It is a small-molecule anti-cancer treatment that targets the RAS protein. Unfortunately, the drug did not show significant activity as a single agent, although activity improved when dexamethasone was added. So far, 14 patients who have received a median of four 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; all of these patients received PRLX93936 in combination with dexamethasone.
Combinations Of Approved Therapies
A number of posters presented results from clinical studies testing combinations of already approved anti-myeloma drugs.
One poster summarized results from a Phase 1b/2 study of Kyprolis (carfilzomib) plus Pomalyst (pomalidomide; Imnovid) and dexamethasone in myeloma patients who had previously received Revlimid but not Velcade (abstract). Research presented at last year’s ASH annual meeting showed that this combination is highly effective in heavily pretreated patients (see related Beacon news). The results of the current study show this combination is also highly active in this less pretreated patient population – in this case, patients who had received a median of two prior therapies. Of the 28 patients included in the study, 71 percent responded to the treatment. According to the investigators, responses were rapid and durable. Progression-free survival was 18.9 months. The most common severe side effects were blood-related.
Updated results were also presented from a European Phase 1/2 study of Kyprolis in combination with thalidomide and low-dose dexamethasone (KTd) for newly diagnosed, transplant-eligible myeloma patients (abstract). Patients received four cycles of induction therapy with escalating doses of Kyprolis (27 mg/m2 to 56 mg/m2), thalidomide, and low-dose dexamethasone, followed by stem cell transplantation, and four cycles of KTd consolidation therapy. The share of patients who achieved at least a very good partial response increased from 68 percent after induction therapy to 76 percent after transplantation and 89 percent after consolidation therapy, respectively. The overall response did not differ significantly between the first three dose levels (27 mg/m2 to 45 mg/m2). According to the investigators, the combination was well tolerated.
One study presented at Saturday evening's poster presentation session was an "extension" study investigating the long-term efficacy and safety of Kyprolis (abstract). It included 91 myeloma patients who had previously taken part in a Phase 1 or 2 clinical trial of single-agent Kyprolis and opted to continue treatment with Kyprolis via the extension study. During the extension study, patients could continue on single-agent Kyprolis at their previous dose, change the dose or dosing schedule, or combine other drugs with the Kyprolis.
The median duration of Kyprolis treatment (initial study plus extension study) was 89 weeks (a total of 22.5 treatment cycles). Overall, 79 percent of patients opted for one or more regimen changes during the extension study; 31 of these patients continued receiving single-agent Kyprolis at a different dose/schedule, and 69 percent changed to combination therapy. When the treatment regimen changes occurred due to disease progression, many patients were able to get a response to the new Kyprolis-containing regimen. The overall response rate was 20 percent after first progression, 35 percent after second progression, and 31 percent after third progression. According to the investigators, the types and rates of side effects observed in the extension study were similar to those observed for single-agent Kyprolis.
Another poster summarized results from a restrospective analysis showing that the addition of Velcade to a commonly used salvage therapy in myeloma, dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), is effective and safe (abstract). The overall response was 40 percent for patients who received V-DCEP as a treatment to reduce the myeloma tumor burden before stem cell transplantation; these patients had received a median of one prior line of therapy. The overall response for patients who received V-DCEP as salvage therapy was 52 percent; these patients had received a median of three prior lines of therapy. The progression-free survival for the two groups was 23 months and 8 months, respectively. Median overall survival was 79 months for patients who received V-DCEP as a treatment to reduce tumor burden before stem cell transplantation and 43 months who received V-DCEP as salvage therapy.
Minimal Residual Disease Testing
Several posters in this session covered research on minimal residual disease (MRD) testing.
One poster summarized the results of an ongoing study at the University of Pennsylvania investigating an MRD test based on samples from a patient's blood, rather than the bone marrow. It is investigating the use of the assay to detect and characterize myeloma cells in patients with multiple myeloma and its precursor disease, smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS) (abstract).
Another study presented at Saturday's session compared next-generation sequencing and multicolor flow cytometry for the assessment of minimal residual disease (abstract). The results show that minimal residual disease detection by next-generation sequencing compared favorably to multicolor flow cytometry, since all patients with residual disease by multicolor flow cytometry were also MRD positive by sequencing. In addition, next-generation sequencing picked up additional patients with MRD who were MRD negative by multicolor flow cytometry. The results also showed that MRD negativity by multicolor flow cytometry and next-generation sequencing were both associated with significantly better progression-free survival.
Survival
One poster presented during the Saturday session reported results of an interim analysis of data from the "Connect MM" registry of newly diagnosed multiple myeloma patients in the United States. The registry, which is sponsored by the pharmaceutical company Celgene, has collected information since 2009 on almost 1500 multiple myeloma patients diagnosed. Patients did not have to be treated by Celgene-marketed myeloma therapies, however, to be entered into the registry (abstract).
The interim analysis found that age, disease stage, and the presence of health problems other than multiple myeloma impact overall survival irrespective of a myeloma patient's risk status. Initial treatment with three-drug regimens was associated with a significantly longer overall survival regardless of disease risk status. Patients with high-risk disease did not have significantly lower overall survival compared to patients without high-risk features, except for patients with the chromosomal abnormality del(17p), who had shorter overall survival. The survival of these patients was improved, however, with the use of triplet therapy.
Another poster summarized findings of a population-based study conducted in the Netherlands which also investigated overall survival of newly diagnosed myeloma patients (abstract). Data collection for the study began in 2005 and includes all newly diagnosed myeloma patients in a specific province of the Netherlands. The analysis of the study results shows that age, the presence of other diseases, and the number of "CRAB" symptoms – such as high calcium levels and impaired kidney function – were associated with lower overall survival. The use of novel agents, on the other hand, was associated with improved overall survival.
Donor Transplantation
In one of the posters presented Saturday, another group of Dutch researchers showed that the impact on outcome of donor (allogeneic) transplantation as part of first-line treatment depends on the type of analysis used to assess outcome (abstract). Specifically, the Dutch researchers found that the efficacy of donor transplantation was underestimated by a common method known as "donor versus no-donor" analysis. More appropriate methods show that donor transplantation has an impact on progression-free survival that is more favorable than previously thought.
Another poster summarized the results of a German single-center analysis of survival after donor transplantation. The analysis was based on data from 95 patients who received a donor transplant between 1994 and 2013. Median age at the time of donor transplantation was 51 years (abstract).
With a median follow-up of 70 months, the overall survival was 36 months, independent of the conditioning regimen (reduced-intensity conditioning or myeloablative conditioning). Median overall survival was significantly longer for patients who received the donor transplant as their first-line treatment (89 months) compared to patients who received it as part of an auto-allo transplant (47 months), at relapse after an auto transplant (20 months), or at relapse after double auto transplants (26 months). Severe acute graft-versus-host disease (GVHD), which develops within the first 100 days after transplantation, had a negative impact on overall survival, whereas chronic GVHD of all grades, which occurs more than 100 days post transplant, did not negatively affect survival.
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Myeloma presentations from Day 2 and Day 3 of the ASH 2014 meeting 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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- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- ASCO 2018 Update – Expert Perspectives On The Key Multiple Myeloma-Related Oral Presentations
Hello Beacon Staff. Thanks for these excellent updates from ASH. I read the abstract of the Celgene-sponsored survival study and it raised an analytical issue that has often puzzled me. The median follow-up for the study was 29 months, the median OS was 44.4 months, and the 3-year OS probability was 62.6%. Naively, it has always seemed to me that the median follow-up would have to be equal or close to the median OS and to the time for which OS probability is calculated. I suppose that early mortality could account for the discrepancy seen between follow-up and survival seen in this and other studies, but I can't quite wrap my head around it especially since the upper limit for follow-up was only 49.4 months. Could you provide a citation to the kind of statistics that are used to calculate survival in this and other similar studies? Thanks much.
Thanks for your feedback and question, Holt
Although we don't always say it in our articles, the survival numbers we report are usually estimates. They are not the final, "true" numbers that can be calculated precisely once the trial has been ongoing for a very long time.
Before all patients have been followed for a long enough time for survival times to be known with certainty, researchers usually estimate median survival times using what is known as Kaplan-Meier estimation.
Basically, this statistical tool leverages the information available for the patients who have been been on the trial the longest to estimate median survival times. As more and more patients have been on the trial for longer periods of time, the estimate gets more precise.
Does that clarify things a bit?
Thanks Beacon Staff. That's very helpful.
Thanks for the great coverage and summaries of the new studies presented at ASH meeting. You are providing a great service to MM patients! Since my doctors are currently at the meeting, I have been able to get heads up information that will facilitate discussion on my next appointment. Please keep the good work!
You're welcome, Holt. And thanks for your feedback, Rafael. We're glad you are finding the updates helpful.
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