Many new and promising re­search devel­op­ments oc­curred in the field of mul­ti­ple myeloma during 2011. Over the course of the year, The Myeloma Beacon pub­lished nearly 100 articles on im­por­tant myeloma-related stud­ies ^[1].

To identify the most im­por­tant of these stud­ies from 2011, The Myeloma Beacon surveyed lead­ing physicians and re­searchers in the field.  They were asked to name the three peer-reviewed journal articles pub­lished in 2011 and the three conference pre­sen­ta­tions from 2011 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 winners were quite clear this year, with the top journal article being nominated almost unanimously.  There are two main themes among the winning articles and pre­sen­ta­tions: re­search that sig­nif­i­cantly ex­pands our under­stand­ing of the basic science of mul­ti­ple myeloma, and stud­ies investigating the ef­fi­cacy and safety of po­ten­tial new myeloma treat­ments.

Journal Articles

1: Genome Sequencing And The Underlying Causes Of Multiple Myeloma

According to the physicians surveyed, the most im­por­tant study pub­lished in 2011 was a study in which re­searchers sequenced the genomes of 38 mul­ti­ple myeloma patients and identified a num­ber of ge­netic mutations that may con­trib­ute to the onset of mul­ti­ple myeloma.

Dr. Edward Libby from the Fred Hutchinson Cancer Re­search Center and who was not in­volved with the study said, “This is the first ‘deep’ look at the ge­netics of myeloma.”

“Hopefully, as addi­tional myeloma genomes are sequenced, one will be able to unravel the key ge­netic changes that underlie this dis­ease and identify addi­tional targets for drug devel­op­ment,” said Dr. Ravi Vij from Washington Uni­ver­sity in St. Louis and one of the study in­ves­ti­ga­tors, “truly lead­ing us into an era of personalized med­i­cine for treat­ment.”

For more in­­for­ma­tion, see the journal Nature ^[2] and the re­lated Beacon ^[3] news.

2: Cereblon And The Efficacy Of Revlimid And Poma­lido­mide

For sec­ond place, the surveyed physicians chose a study demonstrating that a pro­tein named cereblon is nec­es­sary for the immuno­modu­la­tory drugs, Revlimid ^[4] (lena­lido­mide) and pomalidomide ^[5] in par­tic­u­lar, to be ef­fec­tive against mul­ti­ple myeloma.

“This basic science article is one of the first that truly ex­plains why myeloma cells be­come resistant to chemo­ther­apy,” ex­plained Dr. David Vesole from the John Theurer Cancer Center and who was not in­volved with the study. “Cereblon, a common cel­lu­lar pro­tein, is nec­es­sary for immuno­modu­la­tory drugs (Revlimid and poma­lido­mide) to destroy myeloma cells. As the myeloma cells mutate, they lose their ability to gen­er­ate cereblon and, thus, the myeloma cells be­come resistant to these agents.”

“If we can de­vel­op treat­ments that prevent cereblon loss or that can reconstitute cereblon pro­duc­tion, then we may be able to treat patients for much longer periods of time with immuno­modu­la­tory agents,” added Dr. Vesole.

Dr. Saad Zafar Usmani from the Uni­ver­sity of Arkansas for Medical Sciences addi­tionally ex­plained, “These findings are being pro­spec­tively eval­u­ated by the mul­ti­ple myeloma com­munity to assess prog­nos­tic/therapeutic implications at large.”

For more in­­for­ma­tion, see the journal Blood ^[6] (abstract) and the re­lated Beacon ^[7] news.

3: Subcutaneous Velcade

In third place is a study demonstrating that sub­cu­tane­ous admin­istra­tion of Velcade ^[8] (bor­tez­o­mib) is as ef­fec­tive as in­tra­venous admin­istra­tion, but also causes fewer side effects.  In par­tic­u­lar, the rate of severe periph­eral neu­rop­athy (pain and tingling in the extremities) was sub­stan­tially lower in patients re­ceiv­ing sub­cu­tane­ous in­jec­tions than in those re­ceiv­ing in­tra­venous Velcade (6 per­cent versus 16 per­cent, re­spec­tively).

Based in part on the re­­sults of this study, sub­cu­tane­ous admin­istra­tion of Velcade is now approved ^[9] by the U.S. Food and Drug Admin­istra­tion (FDA) along with the originally-approved in­tra­venous admin­istra­tion.

“With regard to having the most im­medi­ate im­pact on myeloma ther­apy, I’d vote for the [subcutaneous Velcade] paper, since it has largely changed the way we give Velcade,” said Dr. Adam Cohen from the Fox Chase Cancer Center.

“The sub­cu­tane­ous dosing of Velcade is a major finding for patient care,” said Dr. Vincent Rajkumar from the Mayo Clinic.  “Combining this finding with the once weekly schedule from last year, we can limit greatly the prob­lems of Velcade-induced neu­rop­athy.”

For more in­­for­ma­tion, see The Lancet Oncology ^[10] (abstract), the re­lated Beacon ^[11] news, and the Beacon's recent Q&A article ^[12] about the FDA ap­prov­al of sub­cu­tane­ous Velcade.

4: Poma­lido­mide Plus Dexa­meth­a­sone In Revlimid- And Velcade-Resistant Multiple Myeloma Patients

In fourth place is a journal article com­par­ing re­­sults from two stud­ies of poma­lido­mide plus low-dose dexamethasone ^[13] (Decadron) in myeloma patients resistant to both Revlimid and Velcade.  Both stud­ies showed that the poma­lido­mide-dexamethasone com­bi­na­tion is ef­fec­tive.

Pomalidomide was admin­istered at dif­fer­en­t doses in the two trials – 2 mg in one trial and 4 mg in the other.  Results from the two stud­ies showed that the two doses had similar ef­fi­cacy.

“Pomalidomide is a highly promising novel immuno­modu­la­tory drug,” said Dr. Peter Voorhees of the Uni­ver­sity of North Carolina, Chapel Hill.  “This study dem­onstrates ac­­tiv­ity in patients with Revlimid- and Velcade-resistant dis­ease, thus providing a treat­ment op­tion for patients who had no good op­tions pre­vi­ously.”

Dr. Sagar Lonial from the Emory Winship Cancer In­sti­tute had similar sentiments. “Pomalidomide rep­re­sents a crit­i­cal new agent for re­lapsed mul­ti­ple myeloma,” he said.

For more in­­for­ma­tion, see the journal Blood ^[14], the re­lated Beacon ^[15] news, and all Beacon pomalidomide ^[16] news articles.

Conference Abstracts

1: Carfilzomib Com­bi­na­tion For Newly Diagnosed Myeloma

According to the physicians surveyed, the most im­por­tant study pre­sented at a 2011 conference is one that showed carfilzomib ^[17] (Kyprolis ^[18]) in com­bi­na­tion with Revlimid and dexa­meth­a­sone is ef­fec­tive for newly diag­nosed myeloma.  Presented at the American Society of He­ma­tol­ogy (ASH) meeting, the re­­sults of this Phase 1/2 study showed that 94 per­cent of the par­tic­i­pants achieved at least a partial re­sponse, with 53 per­cent achieving a com­plete or stringent com­plete re­sponse.

“The re­­sults of this front-line regi­men are quite impressive, with over­all re­sponse rates ap­proach­ing 100 per­cent and high quality re­sponses,” said Dr. Voorhees. “It would be in­ter­est­ing to see how this compares with Revlimid, Velcade, plus dexa­meth­a­sone in a head to head comparison.”

“Carfilzomib is asso­ci­ated with less periph­eral neu­rop­athy.  Thus, this will be a very in­ter­est­ing drug for triple drug induction, which is becoming the standard of care for mul­ti­ple myeloma,” said Dr. Philip McCarthy of Roswell Park Cancer In­sti­tute.

For more in­­for­ma­tion, see ASH abstract 631 ^[19], the re­lated Beacon ^[20] news, and all Beacon carfilzomib ^[21] news articles.

2: Elotuzumab Com­bi­na­tion For Re­lapsed And Re­frac­tory Multiple Myeloma

In sec­ond place is a Phase 2 study that showed elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone is safe and ef­fec­tive for re­lapsed and re­frac­tory myeloma patients.  At the time the re­­sults were pre­sented at ASH, 82 per­cent of patients had achieved at least a partial re­sponse to the treat­ment regi­men, with 12 per­cent of patients achieving a com­plete re­sponse and 32 per­cent a very good partial re­sponse.

“Elotuzumab is probably the most promising mono­clonal anti­body under study at present with dramatic re­­sults seen in com­bi­na­tion with Revlimid and dexa­meth­a­sone,” said Dr. Paul Richardson of the Dana-Farber Cancer In­sti­tute.

“It has shown an ex­cel­lent safety profile as well, making it a prime can­di­date for up­front/maintenance in­ves­ti­ga­tions,” added Dr. Usmani.

For more in­­for­ma­tion, see ASH abstract 303 ^[22], the re­lated Beacon ^[23] news, the slides ^[24] from Dr. Lonial’s pre­sen­ta­tion (pdf), and all Beacon elotuzumab ^[25] news articles.

3: Oral MLN9708 Com­bi­na­tion For Newly Diagnosed Multiple Myeloma

For third place, the surveyed physicians chose interim re­­sults from an on­go­ing Phase 1/2 study of MLN9708 ^[26] (ixazomib ^[27]) in com­bi­na­tion with Revlimid and dexa­meth­a­sone in newly diag­nosed myeloma patients.  All patients en­rolled in the study at the time it was pre­sented at ASH had achieved at least a partial re­sponse to the MLN9708 com­bi­na­tion, with 27 per­cent achieving a com­plete re­sponse and 33 per­cent achieving a very good partial re­sponse.

“In the future, MLN9708 could be com­bined with Revlimid and dexa­meth­a­sone to de­vel­op an all oral triple drug regi­men as up­front ther­apy for mul­ti­ple myeloma,” said Dr. McCarthy.

“There is really en­cour­ag­ing data for this all oral regi­men with an over­all re­sponse rate of 100 per­cent and no sig­nif­i­cant periph­eral neu­rop­athy,” said Dr. Richardson.  “Some skin rash was seen, although this proved man­ageable.”

For more in­­for­ma­tion, see ASH abstract 479 ^[28] and the re­lated Beacon ^[29] news.

4: Poma­lido­mide For Re­lapsed And Re­frac­tory Multiple Myeloma

In fourth place is a Phase 2 study com­par­ing poma­lido­mide alone to poma­lido­mide plus low-dose dexa­meth­a­sone in heavily pre­treated re­lapsed and re­frac­tory myeloma patients.  Results of the study, which were pre­sented at ASH, showed that 34 per­cent of patients in the poma­lido­mide plus dexa­meth­a­sone group achieved at least a partial re­sponse to treat­ment, com­pared to 13 per­cent of patients in the poma­lido­mide only group.

During the pre­sen­ta­tion, Dr. Richardson, who was lead in­ves­ti­ga­tor of the study, said the re­­sults in­di­cate that both regi­mens are active and generally well tol­er­ated in patients with ad­vanced mul­ti­ple myeloma. He also noted that poma­lido­mide plus dexa­meth­a­sone appears to be more active with no in­crease in side effects com­pared to poma­lido­mide alone.

“Of great importance, approx­i­mately 35 per­cent of patients who no longer responded to Revlimid did respond to poma­lido­mide,” ex­plained Dr. Vesole.  “This provides another treat­ment op­tion for patients who no longer respond to Revlimid and Velcade. The toxicity profile was similar to Revlimid and quite man­ageable.”

For more in­­for­ma­tion, see ASH abstract 634 ^[30], the re­lated Beacon ^[20] news, the slides ^[31] from Dr. Richardson’s pre­sen­ta­tion (pdf), and all Beacon pomalidomide ^[16] news articles.

5: Progression Of Smoldering Multiple Myeloma And Revlimid-Dexamethasone Therapy

For fifth place, the surveyed physicians voted for a Phase 3 study pre­sented at ASH that showed Revlimid plus dexa­meth­a­sone delayed dis­ease pro­gres­sion and extended over­all sur­vival in mul­ti­ple myeloma patients who were at high risk of pro­gress­ing to mul­ti­ple myeloma.

“Although the study was small and the re­­sults should be rep­li­cated, this is the first study to dem­onstrate that early intervention in high-risk smol­der­ing (asymptomatic) myeloma not only im­proves time to pro­gres­sion to symp­tomatic dis­ease, but also leads to an over­all sur­vival ad­van­tage,” said Dr. Voorhees.  “Based on these re­­sults, all patients with high-risk smol­der­ing myeloma should be ap­proached and at the very least con­sidered for earlier intervention.”

“Although I will not change to­day how I treat smol­der­ing mul­ti­ple myeloma patients based on these stud­ies,” said Dr. Ken Shain from the Moffitt Cancer Center, “these data strongly sug­gest we should con­sider a par­a­digm shift in how we man­age higher risk smol­der­ing mul­ti­ple myeloma patients.”

For more in­­for­ma­tion, see ASH abstract 303 ^[32], the re­lated Beacon ^[33] news, and a dis­cus­sion with Dr. Ola Landgren ^[34] about the re­­sults.

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

James Berenson, M.D. ^[35]
Berenson Oncology, West Hollywood, CA

Adam D. Cohen, M.D. ^[36]
Fox Chase Cancer Center, Philadelphia, PA

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

Edward N. Libby, M.D. ^[37]
Fred Hutchinson Cancer Re­search Center
University of Washington, Seattle, WA

Sagar Lonial, M.D. ^[38]
Winship Cancer In­sti­tute
Emory Uni­ver­sity School of Medicine, Atlanta, GA

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

Philip McCarthy Jr., M.D. ^[39]
Roswell Park Cancer In­sti­tute, Buffalo, NY

Antonio Palumbo, M.D.
University of  Torino, Italy

S. Vincent Rajkumar, M.D. ^[40]
Mayo Clinic, Rochester, MN

Paul G. Richardson, M.D. ^[41]
Dana-Farber Cancer In­sti­tute
Harvard Medical School, Boston, MA

Ken Shain, M.D., Ph.D. ^[42]
H. Lee Moffitt Cancer Center & Re­search In­sti­tute, Tampa, FL

Saad Zafar Usmani, M.D., FACP ^[43]
Myeloma In­sti­tute for Re­search and Therapy
University of Arkansas for Medical Sciences, Little Rock, AR

David H Vesole, M.D., Ph.D., FACP ^[44]
John Theurer Cancer Center
Hackensack Uni­ver­sity Medical Center, Hackensack, NJ

Ravi Vij, M.D. ^[45]
Washington Uni­ver­sity in Saint Louis, MO

Peter Voorhees, M.D. ^[46]
Lineberger Comprehensive Cancer Center
The Uni­ver­sity of North Carolina, Chapel Hill, NC