The year 2013 is likely to be remembered as a very good year when it comes to research related to multiple myeloma.
Previous years have witnessed research shedding new light on existing myeloma therapies, as well as additional research about potential new therapies.
But, in the past, most of the important new therapies that were being researched were from existing classes of therapy, making them less likely to offer dramatic improvements in the treatment of the disease.
In 2013, not only was there more research about existing therapies, and more research about new therapies from existing classes of therapies.
There was, in addition, exciting new research about entirely new classes of therapies for the potential treatment of myeloma.
There also continued to be enlightening research about how existing anti-myeloma therapies combat the disease. This research could improve treatment in the future and lead to additional new myeloma therapies.
Finally, there were concrete results to the year’s research, as some of it played a key role in the approval of a new drug (Pomalyst) to treat myeloma.
Overall, The Myeloma Beacon published close to 100 articles in 2013 on important myeloma-related studies.
Each year as a service to the multiple myeloma community, The Beacon surveys myeloma experts from around the world to identify the most significant research studies of the previous year.
Over the course of the past month, The Beacon once again conducted such a survey. Participants in the survey were asked to name the three peer-reviewed journal articles published in 2013, and the three conference presentations from 2013, that have the most important findings or implications relating to multiple myeloma.
Their selections for the most important journal articles and conference presentations are presented below.
The first place winner for most important journal article was extremely clear this year; it was nominated by three-quarters of the respondents. Additionally, the first place winner for the most important conference abstract, and the second place winners in both categories, were quite clear, with nominations from about two-thirds of the respondents.
There are three readily apparent themes among the winning articles and presentations. The most common theme, by far, is the efficacy and safety of new, or potential new, myeloma treatments. The other two important topics are the benefits and risks of maintenance therapy, and research that significantly expands our understanding of how anti-myeloma therapies work and how myeloma cells develop drug resistance.
A closer look at the results, however, also reveals another thread that connects most of the articles and presentations: a specific class of myeloma therapies.
Six of the eight articles and presentations involve – in one way or another – a drug from the immunomodulatory class of anti-myeloma therapies, which includes thalidomide, Revlimid, and Pomalyst. Indeed, five of those six articles or presentations involve one specific immunomodulatory drug: Revlimid.
Journal Articles
Several of the top journal articles from 2013 are ones that could have an immediate impact on the treatment of myeloma patients.
1: Revlimid Plus Dexamethasone For High-Risk Smoldering Myeloma
According to the experts surveyed, the most important myeloma-related research article published in 2013 was a Spanish study that focused on smoldering myeloma.
The study showed that treatment of high-risk smoldering myeloma with Revlimid (lenalidomide) plus dexamethasone (Decadron) significantly delayed progression and improved overall survival compared to delaying treatment until progression to symptomatic myeloma.
As already noted, there was widespread recognition of the Spanish study’s significance among the myeloma experts included in The Beacon’s survey.
“It is an important trial in that it brings weight to the paradigm that there are a group of higher-risk patients with early stage myeloma who could benefit from early intervention,” said Dr. Amrita Krishnan from City of Hope National Medical Center.
“This is paradigm shifting,” said Dr. Ola Landgren from the National Cancer Institute and National Institutes of Health. “In the past we always did ‘watch and wait.’ Now these findings suggest early therapy may be beneficial.”
The notion of the study being a paradigm shift was further echoed by Dr. S. Vincent Rajkumar from the Mayo Clinic. “This study challenges the existing paradigm,” he said. “It provides the first evidence that early therapy of high-risk smoldering multiple myeloma may prolong survival.”
Most of the experts, however, also said they believe it is too early to change accepted practice based on the study’s results. Not only is this the first and only study demonstrating such a survival benefit to early treatment, they note, but there also are concerns about how, exactly, to identify “high-risk” smoldering patients.
As Dr. Landgren explained, “We need more data to confirm and expand these findings.” Added Dr. Rajkumar, “The way to identify patients with high-risk [disease] who may benefit is still evolving, and the testing used in this trial is not available at present in most countries, including the United States.”
Dr. Ravi Vij of Washington University, although recognizing the study’s importance, also noted that there are concerns about whether the study’s results can be reproduced in the future. For this and other reasons, he believes most myeloma experts feel the study “should not be guiding standard of care for smoldering myeloma.”
For more information, see the New England Journal of Medicine (abstract), the related Beacon news, and all Beacon articles about smoldering myeloma.
2: Pomalyst Plus Dexamethasone For Relapsed And Refractory Myeloma
For second place, the surveyed myeloma specialists selected an international Phase 3 study that showed that Pomalyst (pomalidomide, Imnovid) in combination with low-dose dexamethasone improved overall survival compared to high-dose dexamethasone alone.
Based on the results of this study, the European Commission approved pomalidomide, which is marketed in Europe under the brand name Imnovid, for the treatment of multiple myeloma patients who have received at least two prior therapies, including Revlimid and Velcade (bortezomib), and have demonstrated disease progression on their last therapy (see related Beacon news).
“This finding supported the approval of Pomalyst-dexamethasone for relapsed and refractory multiple myeloma and this is a very important option for patients,” said Dr. Jatin Shah from MD Anderson.
“This study shows that the combination of Pomalyst and dexamethasone results in superior outcomes compared to dexamethasone alone,” explained Dr. David Vesole from the John Theurer Cancer Center. “What is also of major importance is that patients who no longer respond to Revlimid respond to Pomalyst. Thus, patients can be treated sequentially with the same class of drugs and still benefit.”
Dr. Philip McCarthy of the Roswell Park Cancer Institute said, “This is the most practice-changing study, as Pomalyst will become a new standard therapy after Velcade and Revlimid failure.”
For more information, see the journal The Lancet (abstract), the related Beacon news, and all Beacon articles about Pomalyst.
3: Revlimid Mechanism Of Action
In third place is a study that was conducted by scientists at several Boston-area research hospitals and institutes. The study sheds further light on how Revlimid works to kill myeloma cells and how myeloma cells can become resistant to Revlimid therapy.
Dr. Faith Davies from the Institute of Cancer Research and The Royal Marsden said, “To date, the mechanism of action of immunomodulatory drugs has been a bit of a mystery. This study provides valuable insight into a novel mechanism.”
“This study gives us a much better understanding of the mechanism of action of immunomodulatory drugs and could in the future allow us to better understand resistance to immunomodulatory drugs or ways to overcome resistance,” said Dr. Krishnan.
Dr. McCarthy further explained, “It identifies potential targets for the treatment of multiple myeloma patients by targeting zinc finger proteins in multiple myeloma cells.”
For more information, see the journal Science (abstract).
Runner-Up: Kyprolis Plus Revlimid And Dexamethasone For Relapsed Myeloma
The runner-up journal article summarizes the results of a U.S. and Canadian Phase 2 study that indicates the combination of Kyprolis (carfilzomib), Revlimid, and dexamethasone is effective in relapsed multiple myeloma patients.
“This article demonstrates the successful utilization of triplet therapy in the treatment of relapsed multiple myeloma,” said Dr. Ken Shain from the H. Lee Moffitt Cancer Center & Research Institute. “The introduction of Kyprolis in the relapsed setting can provide a powerful adjunct to Revlimid and dexamethasone in relapsed/refractory myeloma patients. [This combination] demonstrated rapid, deep, and protracted responses with minimal toxicities.”
“This important combination directly impacts patients with yet another option in the relapsed and refractory multiple myeloma setting,” said Dr. Shah. “The combination has also demonstrated impressive activity, with the highest complete response and minimal residual disease rates, in newly diagnosed myeloma.”
Dr. Vesole explained, “Kyprolis is approved as a single agent for patients who have received two or more prior therapies. This study shows that when Kyprolis is combined with Revlimid and dexamethasone, the response rates and duration of responses are much higher, and that combination therapy is much more effective.”
“A trial comparing Kyprolis-Revlimid-dexamethasone to Revlimid-dexamethasone for patients with one or more prior therapies has been completed. We are waiting for the results,” added Dr. Vesole. “If the triple therapy regimen shows superior results, this indication will be submitted to the U.S. Food and Drug Administration, so Kyprolis can be used earlier in the disease course and in combination therapy.”
For more information, see the journal Blood (pdf), the related Beacon news, and all Beacon articles about Kyprolis.
Conference Abstracts
The conference abstracts voted among the most important from 2013 were ones presented at the American Society of Clinical Oncology (ASCO) meeting in June and the American Society of Hematology (ASH) meeting in December.
1: Daratumumab For Relapsed And Refractory Myeloma
According to the experts surveyed by The Beacon, the most important study presented at a 2013 conference is an international Phase 1/2 study that indicates daratumumab is safe and effective in heavily pretreated myeloma patients.
Conference presentations about daratumumab have now been voted the most important for two years in a row.
“The ASCO 2013 daratumumab abstract was the most impressive single-agent data seen in multiple myeloma in several years,” said Dr. Saad Usmani from the Levine Cancer Institute. “It will likely be competing with elotuzumab for the ‘Rituxan’-equivalent title in the treatment of newly diagnosed multiple myeloma as an additional drug to established doublets and triplets.”
Dr. Adam Cohen from the Abramson Cancer Center of the University of Pennsylvania said, “These findings are important because they are the first to demonstrate significant single-agent activity for a monoclonal antibody in multiple myeloma, particularly for a heavily-pretreated population.”
“This study demonstrates the high anti-multiple myeloma efficacy of an anti-CD38 antibody,” said Dr. Hermann Einsele from the University of Würzburg in Germany.
“This is a novel target for anti-myeloma therapy with strong preliminary results. We need to follow this closely,” said Dr. Landgren.
For more information, see ASCO abstract 8512, the related Beacon news article, the slides from Dr. Lokhorst’s presentation (pdf), and all Beacon daratumumab articles.
2: Revlimid Plus Dexamethasone As Upfront Therapy For Transplant-Ineligible Patients
In second place is an international study known as the “FIRST,” or MM-020, trial, which showed that continuous administration of Revlimid and dexamethasone improves response rates as well as progression-free and overall survival in newly diagnosed multiple myeloma patients who are older or not eligible for stem cell transplantation.
“This abstract was presented at the plenary session at ASH,” said Dr. Shain. “This study provides an important scientific rationale for the continued treatment of patients with Revlimid (and/or other agents) in the newly diagnosed setting.”
Dr. Rajkumar said, “This study established long-term Revlimid-dexamethasone therapy as standard of care for elderly myeloma patients. It validates the Revlimid-dexamethasone backbone used in most Phase 3 trials.”
“This is the new standard of care for elderly patients,” said Dr. Einsele.
For more information, see ASH abstract 2, the related Beacon news, the slides from Dr. Facon’s presentation (pdf), and all Beacon articles about older myeloma patients.
3: SAR650984 For Relapsed And Refractory Myeloma
In third place is a Phase 1 study that shows SAR650984 is a promising treatment option for heavily pretreated myeloma patients.
“This is the first data presentation for this promising CD38 antibody, which, together with daratumumab, represents a new class of drugs (monoclonal antibodies) with promising potential for the treatment of myeloma,” said Dr. Vij.
“This abstract highlights the growth and success of antibody-based immunotherapy in multiple myeloma,” said Dr. Shain. “These results are in line with the successes of other antibody therapies, including a second anti-CD38 antibody, daratumumab, and the anti-CS1 antibody elotuzumab.”
Dr. Davies said, “We have spent many years looking for an effective monoclonal antibody for the treatment of multiple myeloma. The results of the early studies looking at targeting CD38 look very promising.”
For more information, see ASH abstract 284, the related Beacon news, the slides from Dr. Mikhael’s presentation (pdf), and all Beacon SAR650984 articles.
Runner-Up: Revlimid Maintenance Therapy After Stem Cell Transplantation
The runner-up abstract reported updated results from a Phase 3 study known as the “IFM 2005-02” trial — one of three recent studies that have investigated the efficacy of Revlimid maintenance therapy.
All three studies have shown that Revlimid maintenance therapy significantly improved progression-free survival, but only one study, the CALGB 100104 study, showed an overall survival benefit. The latest results from the IFM study that were presented at ASH continue to show that, although Revlimid maintenance therapy doubled progression-free survival, it did not improve overall survival in this study.
The reaction to the study among the myeloma experts surveyed by The Beacon reflects, in many ways, the differences of opinion that continue to exist about Revlimid maintenance therapy for myeloma.
Many of the perspectives shared with The Beacon were similar to those voiced by Dr. Vij, who said, “This study provides a note of caution against assuming that maintenance therapy post autologous transplant is proven beyond doubt.” For this reason, Dr. Vesole explained, “The decision to incorporate maintenance strategies in myeloma remains controversial.”
But there were other perspectives. Dr. Leif Bergsagel of the Mayo Clinic, for example, said, “This study pretty convincingly shows no overall survival benefit to Revlimid maintenance.”
Dr. McCarthy, who leads the CALGB 100104 study, suggested that the IFM results need to be interpreted mainly for what they say about how long patients should stay on Revlimid maintenance therapy, rather than if they should go on maintenance therapy.
He and other experts noted that a key difference between the IFM and CALGB trial is that, in the IFM trial, most patients stopped Revlimid maintenance therapy after two years. In the CALGB trial, in contrast, patients continued on the maintenance regimen until progression.
Thus, in Dr. McCarthy’s opinion, the IFM study “means that two years of Revlimid maintenance is not adequate for improving overall survival, especially when compared to the CALGB 100104 study, which examined Revlimid maintenance until progression.”
For more information, see ASH abstract 406, the related Beacon news, and all Beacon articles about maintenance therapy.
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The Myeloma Beacon would like to thank the physicians who participated in the survey for their assistance and expertise:
James Berenson, M.D.
Berenson Oncology, West Hollywood, CA
Leif Bergsagel, M.D.
Mayo Clinic, Scottsdale, AZ
Adam Cohen, M.D.
Abramson Cancer Center
University of Pennsylvania, Philadelphia, PA
Faith Davies, M.D.
Institute of Cancer Research
The Royal Marsden, London, United Kingdom
Hermann Einsele, M.D.
University of Würzburg, Germany
Rashid Khan, M.D.
Myeloma Institute for Research and Therapy
University of Arkansas for Medical Sciences, Little Rock, AR
Amrita Krishnan, M.D., FACP
City of Hope, Duarte, CA
C. Ola Landgren, M.D., Ph.D.
National Cancer Institute
National Institutes of Health, Bethesda, MD
María-Victoria Mateos, M.D., Ph.D.
University Hospital of Salamanca, Spain
Philip McCarthy Jr., M.D.
Roswell Park Cancer Institute, Buffalo, NY
Ruben Niesvizky, M.D.
New York-Presbyterian Hospital
Weill Cornell Medical College, New York, NY
S. Vincent Rajkumar, M.D.
Mayo Clinic, Rochester, MN
Paul G. Richardson, M.D.
Dana-Farber Cancer Institute
Harvard Medical School, Boston, MA
Jatin Shah, M.D.
MD Anderson
The University of Texas, Houston, TX
Ken Shain, M.D., Ph.D.
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Saad Zafar Usmani, M.D., FACP
Levine Cancer Institute, Charlotte, NC
University of North Carolina, Chapel Hill, NC
David Vesole, M.D., Ph.D., FACP
John Theurer Cancer Center
Hackensack University Medical Center, Hackensack, NJ
Ravi Vij, M.D.
Washington University in Saint Louis, MO