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