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The Top Myeloma Research Of 2012

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Published: Mar 22, 2013 2:52 pm

Looking back at all that has happened in the world of multiple myeloma since January of 2012, it is hard not to be impressed by the many im­por­tant devel­op­ments that took place.

There is the obvious fact that, during that time, not one, but two new drugs to treat myeloma were approved by the U.S. Food and Drug Adminis­tra­tion (FDA).  Prior to 2012, the FDA had not approved a novel anti-myeloma therapy in over six years.

Yet 2012 was meaningful to the myeloma community for reasons beyond the activity at the FDA’s offices.

The year was, once again, another one marked by significant new myeloma-related research.  In fact, during the year, The Myeloma Beacon published nearly 100 articles on important myeloma-related studies.

Each year as a service to the multiple myeloma community, The Beacon surveys myeloma specialists 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 2012, and the three conference presentations from 2012, 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 winners in both categories were quite clear this year, with each being nominated by three-quarters of the respondents.

There were three themes among all of the winning articles and presentations.  The most common theme, by far, included studies investigating the efficacy and safety of potential new myeloma treatments.  The other two themes were studies that demonstrate the benefits and risks of maintenance therapy, and research that significantly expands our understanding of the basic science of multiple myeloma and how to treat the disease.

Dr. Adam Cohen from Fox Chase Cancer Center explained that the top journal articles this year are the ones that have “the most impact on current practice,” while several of the top conference abstracts “identify new drugs with anti-myeloma activity with completely different mechanisms of action than any currently available agents.”

Journal Articles

The top three journal articles from 2012 are all ones that can have an immediate impact on the treatment of myeloma patients.

1: Kyprolis For The Treatment Of Myeloma

According to the physicians surveyed, the most important studies published in 2012 were ones that studied Kyprolis (carfilzomib) for the treatment of multiple myeloma.  Almost all physicians mentioned one of two Kyprolis studies.  Those two studies included a Phase 1/2 study of Kyprolis in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) for newly diagnosed myeloma patients and the Phase 2 study of single-agent Kyprolis that led to the U.S. Food and Drug Administration (FDA) approving the drug.

Dr. Vincent Rajkumar from the Mayo Clinic said that the Phase 1/2 study of Kyprolis plus Revlimid and dexamethasone is a “promising study with a highly active regimen. The regimen will enter Phase 3 testing in the United States soon.”

Regarding the Phase 2 study of single-agent Kyprolis, Dr. María-Victoria Mateos from the University Hospital in Salamanca, Spain, said, “This study confirms the efficacy of [this] second generation proteasome inhibitor in myeloma, maintaining the efficacy as compared with its predecessor [Velcade (bortezomib)] and im­prov­ing the safety because it doesn't induce peripheral neuropathy [pain, tingling, or loss of sensation in the extremities].”

Dr. David Vesole from the John Theurer Cancer Center further explained, “This trial led to the FDA-approval of this agent, an important addition to the treatment options for patients with relapsed myeloma. Further, Kyprolis has less neurotoxicity than [Velcade], providing an option for patients who either no longer respond to or are intolerant of Velcade due to peripheral neuropathy.”

For more information, see the Kyprolis-Revlimid-dexamethasone article in the journal Blood and the related Beacon news as well as the single-agent Kyprolis article in the journal Blood, the related Beacon news, and all Beacon Kyprolis articles.

2: Revlimid Maintenance After Stem Cell Transplantation

For second place, the surveyed physicians chose two Phase 3 studies that show Revlimid maintenance therapy following stem cell transplantation doubles progression-free survival.  There was some dis­agree­ment among the physicians, though, about whether the results demonstrate that Revlimid main­te­nance has a significant overall survival benefit.

“These two papers show that low-dose Revlimid maintenance can double the length of disease response after autologous [stem cell] transplant,” said Dr. William Bensinger from the Fred Hutchinson Cancer Re­search Center. “They also show that [Revlimid maintenance is associated with] more episodes of neu­tro­penia [low white blood cell counts] and infection and also increases the risk of second primary cancers.”

Dr. Edward Libby also from the Fred Hutchinson Cancer Research Center added, “These two articles confirm the significant improvement seen in progression-free survival after transplant but were unable to show improvements in overall survival.”

“Both trials confirm that single-agent Revlimid after autologous stem cell transplant doubles the progression-free survival as compared with placebo. This finding is very important,” said Dr. Mateos.  “Although no significant benefit has been observed in overall survival in the French trial, the advantage in progression-free survival is of great value.”

Dr. Heinz Ludwig from Wilhelminenspital in Vienna, Austria, on the other hand, believes Revlimid main­te­nance therapy will provide an overall survival benefit to certain myeloma patients in both studies. “Doubling progression-free survival is unprecedented, and overall survival is already superior in the CALGB study. With further follow-up a survival advantage should also become evident in the good-risk patients of the other study.”

For more information, see the CALGB and French studies in the New England Journal of Medicine, the related Beacon news, and all Beacon articles about maintenance therapy.

3: Pomalyst For Relapsed And Refractory Myeloma

In third place is the Phase 1 clinical trial that established the FDA-approved dosing schedule for Pomalyst (pomalidomide).  It is the clinical trial that supported further study of Pomalyst, which led to FDA-approval of the drug.

“This was the Phase 1 study that allowed the subsequent trial for approval of Pomalyst-dexamethasone in relapsed myeloma,” said Dr. Sagar Lonial from the Emory Winship Cancer Institute. “This study nicely documents the safety and efficacy of this very active agent, and provides context for why 4 mg is the recom­mended dose for many relapsed and refractory multiple myeloma patients.”

Dr. Vesole said that this paper “reports on the early result of a new immunomodulatory agent, Pomalyst, which is in the same class of drugs as thalidomide (Thalomid) and Revlimid. The successor Phase 2 randomized trial has subsequently led to the FDA-approval in February of Pomalyst.”

Dr. Vesole added, “Pomalyst is effective in approximately one-third of patients who no longer respond to Revlimid.”

In reference to this study as well as the one voted most important, Dr. Hermann Einsele from the University of Würzburg in Germany said, “The new agents Kyprolis and Pomalyst will be novel treatment options for our patients failing Velcade and Revlimid.”

For more information, see the journal Blood, the related Beacon news, and all Beacon Pomalyst articles.

Runner-Up Journal Articles

Whole Genome Sequencing Increases Understanding Of Myeloma

The first runner-up is a study in which myeloma researchers sequenced the genome of myeloma cells from a patient at four different time points over the course of their disease.

The results show that there can be several sets of myeloma cells, each set having different genetic make-up, present at diagnosis (each of these sets of cells is known as a clone).  The results also show that the dominant clone changes over the course of the disease, with the presence of a given clone rising and falling over time (known as clonal tides).

Dr. Jatin Shah from MD Anderson explained, “This is an important paper as it furthers the understanding of the natural history and biology of myeloma and defines for the first time in a very elegant fashion the concept of clonal tides.”

“Myeloma is unique in that it is one of very few cancers where we can re-treat patients with previous thera­pies. This has been based on clinical experience; however, this [study] provides the biology under­pin­ning for why we can re-treat and how to re-treat patients,” added Dr. Shah.

Dr. Ludwig further summarized the study’s findings. “Myeloma is genetically more complex than previously thought and is a role model for Darwin’s theory favoring survival of the fittest,” he said. “The clonal evolution results in more aggressive and more resistant clones leading to a disease at late stage that is significantly different compared to the disease at diagnosis.”

For more information, see the journal Blood and all Beacon articles about sequencing the myeloma genome.

Elotuzumab Plus Revlimid And Dexamethasone For Relapsed And Refractory Myeloma

The second runner-up is a Phase 1 clinical trial that established the optimal dosing of elotuzumab in com­bination with Revlimid and dexamethasone.  This trial supported further study of the combination.

Dr. Philip McCarthy from Roswell Park Cancer Institute said, “This may be the breakthrough antibody that in combination with Revlimid and dexamethasone generates excellent responses in relapsed and refractory multiple myeloma.  The Phase 3 trials [of this combination] are ongoing for upfront and relapsed and refractory myeloma patients.”

“This is the first demonstration that monoclonal antibodies can have an important clinical effect in multiple myeloma,” said Dr. Bensinger.  “Antibodies rely on specific targets unique to cancer cells and can have synergistic activity with chemotherapeutic agents.”

“When approved, [elotuzumab] will offer a new class of drugs for the treatment of myeloma,” added Dr. Bensinger.

For more information, see the Journal of Clinical Oncology, the related Beacon news, and all Beacon elotuzumab articles.

Conference Abstracts

All of the conference abstracts voted among the most important from 2012 were ones presented at the American Society of Hematology (ASH) meeting in December (see related Beacon coverage of the ASH meeting).

1: Daratumumab For Relapsed And Refractory Myeloma

According to the physicians surveyed, the most important study presented at a 2012 conference is a Phase 1/2 study that indicates daratumumab is safe and effective in heavily pretreated myeloma patients.

Dr. Amrita Krishnan from City of Hope said that daratumumab is “important as a single-agent monoclonal antibody showing responses in advanced multiple myeloma. Also the favorable toxicity profile naturally raises the question of combinations with other novel agents as well as many other future applications.”

“Daratumumab is a monoclonal antibody, an antibody directed against a protein on the surface of myeloma cells,” Dr. Vesole explained. “For many years, researchers have been investigating antibody treatment directed specifically against myeloma cells. A number of prior antibodies have been evaluated, but none have had significant anti-myeloma activity as a single agent.”

Dr. Vesole added, “Daratumumab, in this pilot trial, has single-agent activity against myeloma. Unlike chemotherapy agents, monoclonal antibodies are safe with few side effects. This may be a very exciting new approach to the treatment of myeloma.”

For more information, see ASH abstract 73, the related Beacon news, the slides from Dr. Plesner’s presentation (pdf), and all Beacon daratumumab articles.

2: Cereblon And The Efficacy Of Pomalyst

In second place is a retrospective study demonstrating that a protein named cereblon is necessary for the immunomodulatory drugs, Pomalyst in particular, to be effective against multiple myeloma.

Dr. Ravi Vij from Washington University in Saint Louis said that cereblon “may turn out to be the first bio­marker to predict response to immunomodulatory drugs if it is validated in additional trials.”

“Cereblon plays a central role in the activity of the immunomodulatory agents (thalidomide, Revlimid and Pomalyst),” explained Dr. Libby.  “We are still striving to understand how these drugs work, and by doing so, we may be able to advance the development of new agents.

“This abstract points out the strong relationship between [levels of] cereblon and outcomes for myeloma patients on immunomodulatory therapy,” added Dr. Libby.

Dr. Krishnan explained that physicians now have “the potential to further target therapy; i.e., a method of predicting who will respond to immunomodulatory therapy. [It is] another step in the direction of personalized medicine.”

Dr. Einsele agreed that “cereblon and other biomarkers will help to personalize treatment.”

Last year, a related preclinical study was voted as one of the most important journal articles published in 2011.

For more information, see ASH abstract 194, the related Beacon news, and all Beacon cereblon articles.

3: ARRY-520 For Myeloma Refractory To Velcade

In third place is a Phase 2 study that indicates ARRY-520 (filanesib), particularly in combination with dexamethasone, may be a reasonable treatment option for heavily pretreated myeloma patients.

“This trial is the first large experience with the new target [known as KSP] in multiple myeloma,” said Dr. Lonial.  “This agent has activity in the setting of refractory multiple myeloma and is different from the other classes of agents that we see activity in.  It potentially offers our patients yet another option when protea­some inhibitors and immunomodulatory drugs no longer work.”

Dr. Shah, who was lead investigator of the study, said, “This is an important abstract, as this new compound is the first new drug in development outside of proteasome inhibitors and immunomodulatory drugs with single-agent activity.”

“Importantly, there was clear activity in patients with unmet medical need who were refractory to Velcade and Revlimid.  It is also a very well-tolerated drug. The future is bright with new options,” he added.

For more information, see ASH abstract 449, the related Beacon news, the slides from Dr. Shah’s presentation (pdf), and all Beacon ARRY-520 articles.

Runner-Up Conference Abstracts

Kyprolis, Pomalyst, And Dexamethasone For Relapsed And Refractory Myeloma

The first runner-up abstract is a Phase 1/2 study of a regimen that combines both of the newly-approved myeloma treatments, Kyprolis and Pomalyst, plus dexamethasone.  The results show that the combination is effective and safe in heavily pretreated myeloma patients.

Dr. Leif Bergsagel from the Mayo Clinic said that this regimen produces “high response rates and is well tolerated. [It combines] the two drugs recently approved for relapsed multiple myeloma, and is a good option for patients in the relapsed setting.”

“This is an important abstract with immediate impact for physicians and patients,” said Dr. Shah, lead investigator of the study. “The abstract showed very high response rates with a clinical benefit rate (at least a minor response) of 67 percent in patients who were refractory to both Velcade and Revlimid.”

“The response rates compare favorably to those with Pomalyst-dexamethasone, and this abstract demon­strates that the combination can be safely administered with significant activity,” he added.

For more information, see ASH abstract 74, the related Beacon news, and the slides from Dr. Shah’s presentation (pdf).

Maintenance Therapy For Myeloma Patients Not Undergoing Stem Cell Transplantation

The second runner-up is a Phase 3 study comparing initial therapy consisting of Velcade, mel­phalan (Alkeran), and prednisone (known as VMP) to initial therapy consisting of Velcade, melphalan, prednisone, and thalidomide followed by maintenance therapy with Velcade and thalidomide (known as VMPT-VT).

The results show that, among these myeloma patients who did not undergo stem cell transplantation, overall survival was greater for those who received VMPT-VT.

“The use of maintenance therapy among post-transplant patients is something that is being done more commonly now, but this trial represents the first effort to apply this concept to non-transplant patients,” explained Dr. Lonial.  “The fact that they demonstrate a survival benefit is the first trial of its kind to do this and suggests that the use of post-induction maintenance may offer a significant benefit for patients.”

Dr. Bergsagel cautioned that although “the four drug regimen prolonged survival in patients 65 to 75 [years of age], it was not well-tolerated by patients over 75.”

For more information, see ASH abstract 200, the related Beacon news, and the slides from Dr. Palumbo’s presentation (pdf).

───────────────── ♦ ─────────────────

The Myeloma Beacon would like to thank the physicians who participated in the survey for their assistance and expertise:

William Bensinger, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA

Leif Bergsagel, M.D.
Mayo Clinic, Scottsdale, AZ

Adam Cohen, M.D.
Fox Chase Cancer Center, Philadelphia, PA

Hermann Einsele, M.D.
University of Würzburg, Germany

Amrita Krishnan, M.D., FACP
City of Hope, Duarte, CA

Edward Libby, M.D.
Fred Hutchinson Cancer Research Center
University of Washington, Seattle, WA

Sagar Lonial, M.D.
Winship Cancer Institute
Emory University School of Medicine, Atlanta, GA

Heinz Ludwig, M.D.
Wilhelminenspital, Vienna, Austria

María-Victoria Mateos, M.D., Ph.D.
University Hospital of Salamanca, Spain

Philip McCarthy Jr., M.D.
Roswell Park Cancer Institute, Buffalo, 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

Saad Zafar Usmani, M.D., FACP
Myeloma Institute for Research and Therapy
University of Arkansas for Medical Sciences, Little Rock, AR

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

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  • Jan Stafl MD said:

    Thank you Julie for another annual excellent summary of the top clinically relevant research of the previous year. This column is one of the most useful, especially with the links to the articles, with many accompanied by slides. I find myself in the position of resistance to Revlimid (within the BiRD protocol) a little over a year from my ASCT. As I research the options with my hematologist, the top 5 journal articles and abstracts are quite relevant. I wish it was possible to have a Cerebron level tested, since that would indicate the likelihood of responding to Pomalyst. Daratumumab appears to be an effective single agent monoclonal antibody, unlike elotuzumab which has to be used with other novel agents to be effective. Any idea how close the FDA is on approval of the first monoclonal Ab for myeloma? Thank you again, Jan

  • marty melley said:

    after reading all of the articales about the new medicines and research on the various tratments for myeoloma i was amazed that some of the new methods being used in clinical trials were not mentioned.
    today is my tenth anniversity of my first transplant at the greenebaum cancer center at the ummc. my onc. and i have been through the whole gament of treatments but i have trusted him and he has brought me thru it all. i am at present in a clinical trial using a "a genetically engineered tee cell" that hunts myoloma cells
    and destroys them. i have been in this trial for about 13 months and the only problem i have had is low platlet count. so i have to be careful a bleeding problems which i don't have now. i have not taken any maint. drugs since i started this trial in january of 2012 with my second transplant. this trial is being held in conjunction with university of pa,and university of md. at my last meeting with dr.rapoport he said my protien count was down and my "new tee-cells" were replicating themselves and all systems are going gangbusters now. i am not kidding my self this is just the beginng for this research and myeoloma is always lurking around, but people who are just about ready to take this "ride", know there are good researchers
    looking for the "cure" and clinical trials are our best hope so check with your onc. and check out some clinical trials and join the fight.

    marty melley

  • Julie Shilane (author) said:

    Hi Jan,

    Glad to hear you found this article very helpful.

    Elotuzumab is likely to be the first monoclonal antibody to receive FDA approval for treating myeloma. Dr. Vesole said that if the elotuzumab results continue to be positive, that it could be approved in 2014.

  • Julie Shilane (author) said:

    Hi Marty,

    Thanks for sharing your experiences participating in this gene therapy study.

    If you haven't read them already, you may be interested in the Beacon's news articles about gene therapy. They were among the most popular Myeloma Beacon news articles in both 2011 and 2012:

    Top Myeloma Beacon News Articles of 2012

    Top Myeloma Beacon News Articles of 2011