This year’s meeting of the American Society of He­ma­tol­ogy (ASH) was held De­cem­ber 8 through 11 in Atlanta.

During the meeting, The Beacon pub­lished daily up­dates ^[1] that provided overviews of the im­por­tant mul­ti­ple myeloma findings pre­sented during the meeting.  After the meeting concluded, The Beacon began pub­lishing in-depth articles ^[2] about the key re­search findings.

This article, how­ever, shifts the focus to the bigger picture: What were the key findings of the meeting? Were there re­­sults with im­medi­ate implica­tions for the treat­ment of mul­ti­ple myeloma?  Did the re­search at the meeting rep­re­sent a major step for­ward for myeloma patients, or was it more incremental in nature?

To address these questions, the Beacon Staff con­ducted its own in-depth review of the meeting's re­search, and it also consulted with a num­ber of myeloma spe­cialists.

In par­tic­u­lar, The Beacon re­ceived feedback about the meeting from two of its Medical Advisors – Dr. Adam Cohen from the Fox Chase Cancer Center and Dr. Peter Voorhees from the Uni­ver­sity of North Carolina at Chapel Hill – as well as myeloma spe­cialists Dr. Leif Bergsagel from the Mayo Clinic and Dr. Frederic Reu from the Cleveland Clinic.

The Bottom Line: A Decent (But Not Huge) Step In The Right Direction

Overall, this year's ASH meeting was good news for myeloma patients and care­givers.

Not great news.  Not earth-shattering, write-all-your-friends-about-it news.  But cer­tainly good news.

There was en­cour­ag­ing re­search about poten­tial myeloma treat­ments – such as ARRY-520 ^[3], circularly permuted TRAIL ^[4], and dinaciclib ^[5] – that have not re­ceived much attention in the past, and which work dif­fer­en­tly than existing myeloma ther­a­pies such as Revlimid ^[6] (lena­lido­mide) and Velcade ^[7] (bor­tez­o­mib).

There also were up­dates about poten­tial treat­ments that have been discussed at pre­vi­ous meetings, and which con­tinue to show prom­ise.  Treatments in this category in­clude daratumumab ^[8], elotuzumab ^[9], and MLN9708 ^[10] (ixazomib ^[11]).

Finally, there con­tinued to be good news about Kyprolis ^[12] (car­filz­o­mib), which recently was approved as a new myeloma ther­apy by the U.S. Food and Drug Admin­istra­tion (FDA), and about pomalidomide ^[13] (Pomalyst ^[14]), which appears likely to be approved by the FDA in the near future.

These devel­op­ments mean that the menu of treat­ment op­tions avail­able to myeloma spe­cialists can be ex­pec­ted to grow in the com­ing years.

That, in turn, is likely to re­­sult in con­tinued im­prove­ment in the sur­vival of myeloma patients.  And that is definitely good news.

Yet, from the perspective of a myeloma patient, it seems dif­fi­cult to argue that the re­­sults pre­sented at the ASH meeting rise to a level beyond "good."

As promising as the many new myeloma treat­ments are, there was no convincing evi­dence that any of them will be real game changers.  Furthermore, most of the new treat­ments are a num­ber of years away from being readily avail­able to most myeloma patients.

There is also the issue that the ASH meeting did not provide answers to some of the key controversies re­lated to the treat­ment of mul­ti­ple myeloma.  As Dr. Reu ex­plained in his feedback to The Beacon, "For the most part, hidden behind the strong opinions [expressed at ASH] was our lack of knowledge."

Myeloma spe­cialists still are debating the optimal timing of stem cell trans­plan­ta­tion.  There are sev­er­al dif­fer­en­t schools of thought when it comes to main­te­nance ther­apy.  And the grow­ing num­ber of treat­ment op­tions is in­creas­ing un­cer­tainty about how many treat­ments (and which treat­ments) to use for newly diag­nosed patients.

New Agents Being Tested For Myeloma

Research re­­sults for a num­ber of new myeloma ther­a­pies deserve to be described as key highlights of the ASH meeting.

All four of the myeloma spe­cialists The Beacon consulted for this article said that the highlights of the meeting in­cluded re­search re­lated to poten­tial new anti-myeloma agents.

Results pre­sented at the meeting ranged from promising initial clin­i­cal re­­sults for sev­er­al drugs to up­dated re­­sults from late stage clin­i­cal trials for sev­er­al drugs that have been talked about at nu­mer­ous pre­vi­ous med­i­cal meetings.

The drugs that were par­tic­u­larly promising are described below.

ARRY-520

Several of the myeloma spe­cialists were ex­cited about the ef­fi­cacy of ARRY-520 ^[3] (filanesib ^[15]) alone or in com­bi­na­tion with dexamethasone ^[16] (Decadron) in heavily re­lapsed and re­frac­tory (treatment-resistant) myeloma patients.  Results from a Phase 2 study showed that up to 22 per­cent of very heavily pre­treated patients responded to ARRY-520 treat­ment.

ARRY-520 showed “single-agent ac­­tiv­ity that im­proved with [the addi­tion of] dexa­meth­a­sone, all in patients [resistant to both prior Revlimid and Velcade ther­apy],” said Dr. Cohen.  He also mentioned a sec­ond study that identified alpha-1-acid glycoprotein as a bio­­marker that may predict re­sponse to ARRY-520 ther­apy.

Dinaciclib 

Results from a Phase 1/2 study of dinaciclib ^[5] also showed poten­tial in re­lapsed myeloma patients, with a re­sponse rate of up to 33 per­cent among the dif­fer­en­t doses tested.

Dr. Cohen said that, along with ARRY-520, “Dinaciclib will fur­ther broaden therapeutic op­tions in the future based on single-agent ac­­tiv­ity in patients with re­lapsed and re­frac­tory dis­ease.”

Circularly Permuted TRAIL

Several stud­ies of circularly permuted TRAIL ^[4] (known as CPT for short) were pre­sented at the meeting, in­clud­ing two that tested CPT alone as well as one that tested CPT in com­bi­na­tion with thalidomide ^[17] (Thalomid).

“CPT is another attractive new treat­ment concept,” said Dr. Reu.  However, he cautioned that the single-agent data for CPT may be less convincing than the data for some of the other new myeloma drugs since the CPT study apparently used sub­stan­tial amounts of dexa­meth­a­sone as pre-infusion med­i­ca­tion.

Daratumumab

Among the newest drugs the myeloma spe­cialists mentioned as par­tic­u­larly promising, daratumumab ^[8] was the only one mentioned by almost all of the myeloma spe­cialists The Beacon consulted about the ASH meeting.

“In my view, dara­tu­mu­mab had the most impressive data with ac­­tiv­ity in the majority of very heavily pre­treated patients,” said Dr. Reu. “Many feel this could be­come the ‘rituximab [Rituxan] for myeloma,’’’ he fur­ther ex­plained.

Rituxan, like dara­tu­mu­mab, belongs to the class of drugs known as mono­clonal anti­bodies.  Rituxan is viewed by many physicians as having revolutionized the treat­ment of cer­tain kinds of lym­phoma and leukemia.

Dr. Voorhees also spoke pos­i­tively about dara­tu­mu­mab, saying that it “demonstrated sig­nif­i­cant clin­i­cal ac­­tiv­ity in patients with re­lapsed or re­frac­tory myeloma."  He added that it "is the first mono­clonal anti­body that has shown con­siderable single-agent ac­­tiv­ity in patients with myeloma.”

Elotuzumab

The rest of the new myeloma treat­ments in this article are ones that have been discussed at sev­er­al pre­vi­ous med­i­cal meetings.  The up­dated re­­sults pre­sented at this year’s ASH meeting dem­onstrate that these drugs con­tinue to show prom­ise as myeloma treat­ments.

Elotuzumab ^[9] in com­bi­na­tion with Revlimid ^[6] (lena­lido­mide) and low-dose dexa­meth­a­sone con­tinued to dem­onstrate high re­sponse rates in pre­vi­ously-treated patients.

“Impressively, the over­all re­sponse rate was 84 per­cent [and 92 per­cent for the most ef­fec­tive dose tested], which is sig­nif­i­cantly higher than one would ex­pec­t with lena­lido­mide [Revlimid] and dexa­meth­a­sone alone,” said Dr. Voorhees.  “What is in­ter­est­ing about this is the fact that elotuzumab did not have sig­nif­i­cant ac­­tiv­ity as a single agent in earlier stud­ies, sug­gesting that there may be true syn­­er­gis­tic ac­­tiv­ity be­tween these drugs.”

MLN9708

MLN9708 ^[18] (ixazomib ^[11]) in com­bi­na­tion with Revlimid and dexa­meth­a­sone also con­tinued to dem­onstrate high re­sponse rates and pro­gres­sion-free sur­vival rates.  This com­bi­na­tion was tested in newly diag­nosed myeloma patients.

Pomalidomide And Kyprolis

A num­ber of stud­ies involving Kyprolis ^[12] (car­filz­o­mib) and pomalidomide ^[13] (Pomalyst ^[14]) were discussed at this year’s ASH meeting.  Kyprolis is the latest drug to be approved by the FDA for the treat­ment of myeloma, and the FDA is ex­pec­ted to decide by mid Feb­ru­ary whether to approve poma­lido­mide.

The latest data on these two drugs con­tinue to sup­port their ef­fec­tiveness and safety for patients with mul­ti­ple myeloma.

Pomalidomide

“Numerous abstracts highlighted grow­ing evi­dence sup­porting the use of poma­lido­mide and low-dose dexa­meth­a­sone for patients with re­lapsed/refractory myeloma,” said Dr. Reu.  “Updated data from two Phase 2 stud­ies confirmed the efficacy of the poma­lido­mide and dexa­meth­a­sone com­bi­na­tion in patients that have not been well served by existing ther­apy,” he added

In par­tic­u­lar, re­­sults from a Phase 3 study showed that poma­lido­mide plus dexa­meth­a­sone provides a pro­gres­sion-free and over­all sur­vival ben­e­fit com­pared to high-dose dexa­meth­a­sone.

“This re­­sult was ex­pec­ted and not surprising, but still this is the first Phase 3 data for poma­lido­mide, and was re­quired by Euro­pean regu­la­tory author­i­ties for ap­prov­al,” ex­plained Dr. Cohen.

Similar to the other myeloma spe­cialists, Dr. Bergsagel said, “Pomalidomide is very active in [relapsed and re­frac­tory myeloma patients].” He also added that the re­­sults emphasize that “high-dose dexa­meth­a­sone is still a bad idea.”

“These Phase 3 data and up­dated re­­sults from Phase 2 stud­ies should help pave the way for FDA ap­prov­al of this com­bi­na­tion for this group of patients,” said Dr. Reu.

Pomalidomide Plus Kyprolis

One study tested the com­bi­na­tion of poma­lido­mide, Kyprolis, and dexa­meth­a­sone.  Results from the study showed that half of the re­lapsed and re­frac­tory myeloma patients responded to the com­bi­na­tion.

Dr. Cohen stated that this study “shows these drugs can be safely com­bined, with a promising over­all re­sponse rate in a small num­ber of patients [refractory to both Revlimid and Velcade].”

Kyprolis

“The ef­fi­cacy of car­filz­o­mib [Kyprolis]-based ther­apy in newly-diagnosed myeloma patients was dem­onstrated in sev­er­al abstracts,” said Dr. Voorhees.

These stud­ies in­cluded Kyprolis plus Revlimid and dexa­meth­a­sone; Kyprolis plus cyclophosphamide ^[19] (Cytoxan), thalido­mide and dexa­meth­a­sone; and Kyprolis plus thalido­mide and dexa­meth­a­sone.  The latter two of these stud­ies will be of more interest to physicians and patients outside of theUnited States, where thalido­mide is more commonly used.

In par­tic­u­lar, Dr. Voorhees in­di­cated that Kyprolis, Revlimid, and dexa­meth­a­sone “produced impressive rates of high quality re­sponses.”

Dr. Cohen was impressed that Kyprolis plus cyclo­phos­pha­mide and dexa­meth­a­sone was “very well-tolerated in an older pop­u­la­tion, with re­sponse rates (100 per­cent over­all and 53 per­cent com­plete or near com­plete re­sponse) similar to Kyprolis-Revlimid-dexamethasone.”  He in­di­cated that the ad­van­tages of this com­bi­na­tion are the high re­sponse rates without the high cost of Revlimid and with minimal neu­rop­athy as com­pared to Velcade ^[7] (bor­tez­o­mib)-Revlimid-dexamethasone.

Maintenance Therapy

Several of the myeloma spe­cialists The Beacon spoke with for this article mentioned the importance of two stud­ies com­par­ing Velcade-thalidomide main­te­nance ther­apy to other op­tions.  They are im­por­tant, how­ever, because they show that fur­ther study is still nec­es­sary.

The first study com­pared initial ther­apy with Velcade-melphalan ^[20] (Alkeran)-prednisone ^[21] ther­apy to initial ther­apy with Velcade-melphalan-prednisone-thalidomide followed by Velcade-thalidomide main­te­nance ther­apy for elderly myeloma patients.

Dr. Bergsagel concluded that the addi­tion of thalido­mide did not sig­nif­i­cantly im­prove initial treat­ment with Velcade-melphalan-prednisone but that Velcade-thalidomide main­te­nance ther­apy im­proved out­comes.

Dr. Cohen agreed that the re­­sults sug­gest main­te­nance ther­apy pro­longs pro­gres­sion-free and over­all sur­vival for elderly patients.  However, he said that the patients who re­ceived main­te­nance ther­apy were also treated with a more intensive ther­apy initially.  In addi­tion, treat­ments avail­able at relapse differ in the U.S.and Europe, where the study was con­ducted, which he said may limit the ability to generalize the sur­vival data to patients in the U.S.

The other study com­pared main­te­nance ther­apy with Velcade-thalidomide versus thalido­mide versus interferon-alpha after stem cell trans­plan­ta­tion.  Results from this study showed that Velcade-thalidomide main­te­nance ther­apy provided a pro­gres­sion-free sur­vival ben­e­fit, but not an over­all sur­vival ben­e­fit.

Although there were a num­ber of dif­fer­ences in the patient pop­u­la­tion and dosing schedules be­tween these two stud­ies, Dr. Cohen said, “This study dem­onstrates that a ben­e­fit of main­te­nance on over­all sur­vival has not been uni­formly seen, with contradictory re­­sults in dif­fer­en­t stud­ies.”

The Hidden Gem

A year ago, in The Beacon's initial review of re­­sults from the 2011 ASH meeting, myeloma spe­cialists identified re­search re­lated to the pro­tein cereblon as the meeting's "hidden gem" -- that is, im­por­tant re­search that did not get as much attention as it might deserve (see re­lated Beacon ^[22] news article).

Several physicians with whom The Beacon consulted for this year's review of ASH re­­sults once again identified re­search con­cern­ing cereblon as the meeting's hidden gem.

A study pre­sented at this year’s meeting showed that the amount of cereblon a patient has in their blood can be used to predict re­sponse, pro­gres­sion-free, and over­all sur­vival of patients treated with poma­lido­mide plus dexa­meth­a­sone.

Dr. Cohen said this study “offers prom­ise of a poten­tial bio­­marker to predict who may respond to [pomalidomide], and possibly immuno­modu­la­tory drugs in general.”

The immunodulatory drugs used to treat myeloma in­clude Revlimid, thalido­mide, and poma­lido­mide.

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All of The Beacon's coverage re­lated to the ASH 2012 meeting can be found here ^[23]. The coverage will con­tinue next week and into the New Year with addi­tional in-depth articles about re­search pre­sented at the meeting.