Multiple Myeloma And The ASH 2012 Meeting: Taking Stock And Tagging The Highlights
This year’s meeting of the American Society of Hematology (ASH) was held December 8 through 11 in Atlanta.
During the meeting, The Beacon published daily updates that provided overviews of the important multiple myeloma findings presented during the meeting. After the meeting concluded, The Beacon began publishing in-depth articles about the key research findings.
This article, however, shifts the focus to the bigger picture: What were the key findings of the meeting? Were there results with immediate implications for the treatment of multiple myeloma? Did the research at the meeting represent a major step forward for myeloma patients, or was it more incremental in nature?
To address these questions, the Beacon Staff conducted its own in-depth review of the meeting's research, and it also consulted with a number of myeloma specialists.
In particular, The Beacon received feedback about the meeting from two of its Medical Advisors – Dr. Adam Cohen from the Fox Chase Cancer Center and Dr. Peter Voorhees from the University of North Carolina at Chapel Hill – as well as myeloma specialists Dr. Leif Bergsagel from the Mayo Clinic and Dr. Frederic Reu from the Cleveland Clinic.
The Bottom Line: A Decent (But Not Huge) Step In The Right Direction
Overall, this year's ASH meeting was good news for myeloma patients and caregivers.
Not great news. Not earth-shattering, write-all-your-friends-about-it news. But certainly good news.
There was encouraging research about potential myeloma treatments – such as ARRY-520, circularly permuted TRAIL, and dinaciclib – that have not received much attention in the past, and which work differently than existing myeloma therapies such as Revlimid (lenalidomide) and Velcade (bortezomib).
There also were updates about potential treatments that have been discussed at previous meetings, and which continue to show promise. Treatments in this category include daratumumab, elotuzumab, and MLN9708 (ixazomib).
Finally, there continued to be good news about Kyprolis (carfilzomib), which recently was approved as a new myeloma therapy by the U.S. Food and Drug Administration (FDA), and about pomalidomide (Pomalyst), which appears likely to be approved by the FDA in the near future.
These developments mean that the menu of treatment options available to myeloma specialists can be expected to grow in the coming years.
That, in turn, is likely to result in continued improvement in the survival of myeloma patients. And that is definitely good news.
Yet, from the perspective of a myeloma patient, it seems difficult to argue that the results presented at the ASH meeting rise to a level beyond "good."
As promising as the many new myeloma treatments are, there was no convincing evidence that any of them will be real game changers. Furthermore, most of the new treatments are a number of years away from being readily available to most myeloma patients.
There is also the issue that the ASH meeting did not provide answers to some of the key controversies related to the treatment of multiple myeloma. As Dr. Reu explained in his feedback to The Beacon, "For the most part, hidden behind the strong opinions [expressed at ASH] was our lack of knowledge."
Myeloma specialists still are debating the optimal timing of stem cell transplantation. There are several different schools of thought when it comes to maintenance therapy. And the growing number of treatment options is increasing uncertainty about how many treatments (and which treatments) to use for newly diagnosed patients.
New Agents Being Tested For Myeloma
Research results for a number of new myeloma therapies deserve to be described as key highlights of the ASH meeting.
All four of the myeloma specialists The Beacon consulted for this article said that the highlights of the meeting included research related to potential new anti-myeloma agents.
Results presented at the meeting ranged from promising initial clinical results for several drugs to updated results from late stage clinical trials for several drugs that have been talked about at numerous previous medical meetings.
The drugs that were particularly promising are described below.
Several of the myeloma specialists were excited about the efficacy of ARRY-520 (filanesib) alone or in combination with dexamethasone (Decadron) in heavily relapsed and refractory (treatment-resistant) myeloma patients. Results from a Phase 2 study showed that up to 22 percent of very heavily pretreated patients responded to ARRY-520 treatment.
ARRY-520 showed “single-agent activity that improved with [the addition of] dexamethasone, all in patients [resistant to both prior Revlimid and Velcade therapy],” said Dr. Cohen. He also mentioned a second study that identified alpha-1-acid glycoprotein as a biomarker that may predict response to ARRY-520 therapy.
Results from a Phase 1/2 study of dinaciclib also showed potential in relapsed myeloma patients, with a response rate of up to 33 percent among the different doses tested.
Dr. Cohen said that, along with ARRY-520, “Dinaciclib will further broaden therapeutic options in the future based on single-agent activity in patients with relapsed and refractory disease.”
Circularly Permuted TRAIL
Several studies of circularly permuted TRAIL (known as CPT for short) were presented at the meeting, including two that tested CPT alone as well as one that tested CPT in combination with thalidomide (Thalomid).
“CPT is another attractive new treatment concept,” said Dr. Reu. However, he cautioned that the single-agent data for CPT may be less convincing than the data for some of the other new myeloma drugs since the CPT study apparently used substantial amounts of dexamethasone as pre-infusion medication.
Among the newest drugs the myeloma specialists mentioned as particularly promising, daratumumab was the only one mentioned by almost all of the myeloma specialists The Beacon consulted about the ASH meeting.
“In my view, daratumumab had the most impressive data with activity in the majority of very heavily pretreated patients,” said Dr. Reu. “Many feel this could become the ‘rituximab [Rituxan] for myeloma,’’’ he further explained.
Rituxan, like daratumumab, belongs to the class of drugs known as monoclonal antibodies. Rituxan is viewed by many physicians as having revolutionized the treatment of certain kinds of lymphoma and leukemia.
Dr. Voorhees also spoke positively about daratumumab, saying that it “demonstrated significant clinical activity in patients with relapsed or refractory myeloma." He added that it "is the first monoclonal antibody that has shown considerable single-agent activity in patients with myeloma.”
The rest of the new myeloma treatments in this article are ones that have been discussed at several previous medical meetings. The updated results presented at this year’s ASH meeting demonstrate that these drugs continue to show promise as myeloma treatments.
“Impressively, the overall response rate was 84 percent [and 92 percent for the most effective dose tested], which is significantly higher than one would expect with lenalidomide [Revlimid] and dexamethasone alone,” said Dr. Voorhees. “What is interesting about this is the fact that elotuzumab did not have significant activity as a single agent in earlier studies, suggesting that there may be true synergistic activity between these drugs.”
MLN9708 (ixazomib) in combination with Revlimid and dexamethasone also continued to demonstrate high response rates and progression-free survival rates. This combination was tested in newly diagnosed myeloma patients.
Pomalidomide And Kyprolis
A number of studies involving Kyprolis (carfilzomib) and pomalidomide (Pomalyst) were discussed at this year’s ASH meeting. Kyprolis is the latest drug to be approved by the FDA for the treatment of myeloma, and the FDA is expected to decide by mid February whether to approve pomalidomide.
The latest data on these two drugs continue to support their effectiveness and safety for patients with multiple myeloma.
“Numerous abstracts highlighted growing evidence supporting the use of pomalidomide and low-dose dexamethasone for patients with relapsed/refractory myeloma,” said Dr. Reu. “Updated data from two Phase 2 studies confirmed the efficacy of the pomalidomide and dexamethasone combination in patients that have not been well served by existing therapy,” he added
In particular, results from a Phase 3 study showed that pomalidomide plus dexamethasone provides a progression-free and overall survival benefit compared to high-dose dexamethasone.
“This result was expected and not surprising, but still this is the first Phase 3 data for pomalidomide, and was required by European regulatory authorities for approval,” explained Dr. Cohen.
Similar to the other myeloma specialists, Dr. Bergsagel said, “Pomalidomide is very active in [relapsed and refractory myeloma patients].” He also added that the results emphasize that “high-dose dexamethasone is still a bad idea.”
“These Phase 3 data and updated results from Phase 2 studies should help pave the way for FDA approval of this combination for this group of patients,” said Dr. Reu.
Pomalidomide Plus Kyprolis
One study tested the combination of pomalidomide, Kyprolis, and dexamethasone. Results from the study showed that half of the relapsed and refractory myeloma patients responded to the combination.
Dr. Cohen stated that this study “shows these drugs can be safely combined, with a promising overall response rate in a small number of patients [refractory to both Revlimid and Velcade].”
“The efficacy of carfilzomib [Kyprolis]-based therapy in newly-diagnosed myeloma patients was demonstrated in several abstracts,” said Dr. Voorhees.
These studies included Kyprolis plus Revlimid and dexamethasone; Kyprolis plus cyclophosphamide (Cytoxan), thalidomide and dexamethasone; and Kyprolis plus thalidomide and dexamethasone. The latter two of these studies will be of more interest to physicians and patients outside of theUnited States, where thalidomide is more commonly used.
In particular, Dr. Voorhees indicated that Kyprolis, Revlimid, and dexamethasone “produced impressive rates of high quality responses.”
Dr. Cohen was impressed that Kyprolis plus cyclophosphamide and dexamethasone was “very well-tolerated in an older population, with response rates (100 percent overall and 53 percent complete or near complete response) similar to Kyprolis-Revlimid-dexamethasone.” He indicated that the advantages of this combination are the high response rates without the high cost of Revlimid and with minimal neuropathy as compared to Velcade (bortezomib)-Revlimid-dexamethasone.
Several of the myeloma specialists The Beacon spoke with for this article mentioned the importance of two studies comparing Velcade-thalidomide maintenance therapy to other options. They are important, however, because they show that further study is still necessary.
The first study compared initial therapy with Velcade-melphalan (Alkeran)-prednisone therapy to initial therapy with Velcade-melphalan-prednisone-thalidomide followed by Velcade-thalidomide maintenance therapy for elderly myeloma patients.
Dr. Bergsagel concluded that the addition of thalidomide did not significantly improve initial treatment with Velcade-melphalan-prednisone but that Velcade-thalidomide maintenance therapy improved outcomes.
Dr. Cohen agreed that the results suggest maintenance therapy prolongs progression-free and overall survival for elderly patients. However, he said that the patients who received maintenance therapy were also treated with a more intensive therapy initially. In addition, treatments available at relapse differ in the U.S.and Europe, where the study was conducted, which he said may limit the ability to generalize the survival data to patients in the U.S.
The other study compared maintenance therapy with Velcade-thalidomide versus thalidomide versus interferon-alpha after stem cell transplantation. Results from this study showed that Velcade-thalidomide maintenance therapy provided a progression-free survival benefit, but not an overall survival benefit.
Although there were a number of differences in the patient population and dosing schedules between these two studies, Dr. Cohen said, “This study demonstrates that a benefit of maintenance on overall survival has not been uniformly seen, with contradictory results in different studies.”
The Hidden Gem
A year ago, in The Beacon's initial review of results from the 2011 ASH meeting, myeloma specialists identified research related to the protein cereblon as the meeting's "hidden gem" -- that is, important research that did not get as much attention as it might deserve (see related Beacon news article).
Several physicians with whom The Beacon consulted for this year's review of ASH results once again identified research concerning cereblon as the meeting's hidden gem.
A study presented at this year’s meeting showed that the amount of cereblon a patient has in their blood can be used to predict response, progression-free, and overall survival of patients treated with pomalidomide plus dexamethasone.
Dr. Cohen said this study “offers promise of a potential biomarker to predict who may respond to [pomalidomide], and possibly immunomodulatory drugs in general.”
The immunodulatory drugs used to treat myeloma include Revlimid, thalidomide, and pomalidomide.
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All of The Beacon's coverage related to the ASH 2012 meeting can be found here. The coverage will continue next week and into the New Year with additional in-depth articles about research presented at the meeting.
- ASCO 2013 And Multiple Myeloma: What Were The Highlights?
- ASH 2013 Multiple Myeloma Update - Day One
- ASH 2011 – Initial Thoughts On The Meeting's Key Myeloma-Related Findings
- ASH 2012 Multiple Myeloma Update – Day Two: Early Afternoon Oral Session
- ASH 2012 Multiple Myeloma Update – Day Three: Late Morning Oral Session