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).

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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