Yesterday was the first day of the American Society of He­ma­tol­ogy (ASH) 2011 annual meeting, which is being held in San Diego.

Although the day featured no oral pre­sen­ta­tions of new myeloma-related re­search, it started with an in­ter­est­ing educational session focused on mul­ti­ple myeloma.

There also were a num­ber of poster pre­sen­ta­tions during the day summarizing im­por­tant new re­search findings.

The educational session in the morn­ing featured three pre­sen­ta­tions by lead­ing myeloma spe­cialists.

Induction Therapy And Maintenance Treatment

The first pre­sen­ta­tion was by Dr. Donna Reece of the Princess Margaret Hospital in Toronto.  Her pre­sen­ta­tion focused on two key stages in the treat­ment of newly diag­nosed myeloma patients.

The first is induction ther­apy, which is the treat­ment regi­men patients re­ceive right after diag­nosis.  It is usually rel­a­tively brief and rel­a­tively intensive.

The sec­ond is main­te­nance ther­apy, which is longer-term ther­apy that patients often re­ceive after induction ther­apy and (usually) a stem cell trans­plant.

Dr. Reece ex­plained that a large num­ber of clin­i­cal trials have shown that the most ef­fec­tive induction treat­ment for newly diag­nosed myeloma patients is ther­apy involving at least one of the novel myeloma treat­ments – thalidomide ^[1] (Thalomid), Velcade ^[2] (bor­tez­o­mib), or Revlimid ^[3] (lena­lido­mide) – com­bined with one or more older myeloma treat­ments such as dexamethasone ^[4] (Decadron).

Indeed, Dr. Reece feels there is evi­dence that the most ef­fec­tive induction regi­mens may be those involving at least two of the novel agents com­bined with one or more of the older myeloma treat­ments.  A prime example of such a regi­men would be the “RVD” (Revlimid + Velcade + dexa­meth­a­sone) regi­men that has dem­onstrated a very high re­sponse rate.

Dr. Reece personally uses with her patients the so-called CyBorD regi­men, which is a com­bi­na­tion of cyclophosphamide ^[5] (Cytoxan), Velcade, and dexa­meth­a­sone.  This com­bi­na­tion has shown very high and very deep re­sponse rates, and it also is less costly than a regi­men such as RVD that in­volves two newer drugs (see re­lated Beacon ^[6] news).

On the topic of main­te­nance ther­apy, Dr. Reece noted that after thalido­mide became a common myeloma treat­ment there was interest in using it as a main­te­nance treat­ment.  However, many patients could not tolerate the drug over extended periods of time, and the evi­dence was mixed as to whether there is an over­all sur­vival ben­e­fit from thalido­mide main­te­nance.

For this reason, physicians started exploring the use of Revlimid as main­te­nance ther­apy.  Dr. Reece be­lieves the data are suf­fi­ciently pos­i­tive in regard to this treat­ment op­tion that she uses it with most of her patients.

However, she admits that the risk of secondary cancer ^[7] asso­ci­ated with Revlimid main­te­nance is some­thing that needs to be in­ves­ti­gated fur­ther, and she noted that not all major trials looking at Revlimid main­te­nance ther­apy have shown that it has a ben­e­fit in terms of over­all sur­vival.

Stem Cell Transplantation And New Myeloma Treatments

The next pre­sen­ta­tion during the educational session was by Dr. Sergio Giralt of Memorial Sloan-Kettering Cancer Center in New York City.  He spoke on the role of stem cell trans­plan­ta­tion in the treat­ment of mul­ti­ple myeloma.

Dr. Giralt’s pre­sen­ta­tion made it clear that there are many unanswered questions when it comes to the role of stem cell trans­plants in the treat­ment of myeloma.

For example, although a large share of  U.S. myeloma spe­cialists be­lieves it makes sense to carry out an au­tol­o­gous (own) stem cell trans­plant soon after diag­nosis in younger, other­wise healthy myeloma patients, this view is not held by all.

There are well-respected myeloma spe­cialists who point to the very high re­sponse rates of the newer induction treat­ments for myeloma, and they ask whether it might not be best to reserve stem cell trans­plants for fur­ther into a patient’s treat­ment, per­haps at relapse.

This question is suf­fi­ciently im­por­tant that it is being in­ves­ti­gated in a large U.S.-French clin­i­cal trial.

Dr. Giralt also pointed out that the re­search so far is not as rich as it should be in regard to the value of so-called tandem trans­plants – two trans­plants carried out within a short period of time.

Similarly, although some analyses have shown that donor (allogeneic) stem cell trans­plants are very risky and do not provide a sizable sur­vival ben­e­fit, newer methods are being used for such trans­plants that may make them less risky and more ef­fec­tive.

The final pre­sen­ta­tion during the educational session was by Dr. Kenneth Anderson of the Dana-Farber Cancer Center in Boston.  During his pre­sen­ta­tion, Dr. Anderson reviewed the large variety of drugs cur­rently being in­ves­ti­gated as future myeloma treat­ments.

And there truly are a large num­ber of po­ten­tial new myeloma treat­ments.  A conservative esti­mate would be that Dr. Anderson mentioned at least 20 possible new myeloma treat­ments cur­rently being in­ves­ti­gated.

These in­clude possible new treat­ments that are chemically similar to Velcade, in­clud­ing carfilzomib ^[8], MLN2238/9708, and NPI-0052 ^[9].

Likewise, the po­ten­tial new treat­ment pomalidomide ^[10] is chemically similar to Revlimid and thalido­mide.

There also are a wide range of treat­ments under devel­op­ment that have very dif­fer­en­t ap­proaches to the treat­ment of myeloma than existing ther­a­pies.

These in­clude possible new treat­ments with names and codenames such as elotuzumab ^[11], BT062 ^[12], BHQ880, LY2127399, perifosine ^[13], panobinostat ^[14], Zolinza ^[15] (vorinostat), BMS833923, and selumetinib – to name just a few that Dr. Anderson described during his pre­sen­ta­tion.

Overall, Dr. Anderson be­lieves re­searchers are continuing to make progress to­ward trans­forming myeloma from an incurable cancer into a chronic, man­ageable con­di­tion.

Data On Potential New Myeloma Therapies: GSK2110183, ARRY-520 ... And Carfilzomib

Dr. Anderson’s pre­sen­ta­tion is a good start­ing point for a dis­cus­sion of the poster summaries of re­search re­­sults that were on dis­play during yes­ter­day's session.

Two of those posters dealt with po­ten­tial new myeloma treat­ments in the very early stages of devel­op­ment.

One poster looked at a drug being devel­oped by GlaxoSmithKline, codenamed GSK2110183 (afuresertib ^[16]) (abstract ^[17]). It is a so-called "Akt in­hib­i­tor", which means it is in the same class of drugs as perifosine ^[18], another po­ten­tial myeloma drug that is fur­ther along in devel­op­ment.

Both GSK2110183 and perifosine are drugs that can be taken as pills or capsules.

The other rel­a­tively new drug covered in a poster pre­sen­ta­tion was ARRY-520 ^[19] (filanesib ^[20]), which is being devel­oped by Array BioPharma (abstract ^[21]). ARRY-520 is in a new class of po­ten­tial anti-myeloma agents known as kinesin spindle pro­tein in­hib­i­tors. It is admin­istered by in­fusion.

Both GSK2110183 and ARRY-520 were tested as single treat­ments for myeloma patients who have failed a num­ber of pre­vi­ous ther­a­pies.

In the GSK2110183 trial, 8.8 per­cent of the patients achieved a partial re­sponse and another 8.8 per­cent had a minimal re­sponse.

In the ARRY-520 trial, 10 per­cent achieved a partial re­sponse, 3.3 per­cent achieved a minor re­sponse, and 27 per­cent achieved stable dis­ease lasting more than six months.

These re­­sults in­di­cate that the drugs have some po­ten­tial as future myeloma treat­ments.  And, in fact, the de­vel­opers of ARRY-520 in­tend to test it fur­ther in a larger Phase 2 trial.

The re­searchers investigating GSK2110183, in contrast, seem less clear about whether the drug will go for­ward as a single treat­ment for myeloma patients, or if it may work better in com­bi­na­tion with other myeloma treat­ments, or for cer­tain myeloma patients with spe­cif­ic char­ac­ter­istics.

Another po­ten­tial new treat­ment discussed in a poster yes­ter­day was car­filz­o­mib.

Carfilzomib is one of the best known po­ten­tial new myeloma treat­ments.  A poster during yes­ter­day's session looked at car­filz­o­mib as a treat­ment for re­lapsed myeloma patients (abstract ^[22]).  In par­tic­u­lar, it reviewed data that sheds light on whether the drug has similar ef­fi­cacy in re­lapsed patients with or without ge­netic char­ac­ter­istics asso­ci­ated with “high risk” dis­ease.

On the surface, the re­­sults summarized in the poster in­di­cate that car­filz­o­mib may be equally ef­fec­tive in re­lapsed patients re­gard­less of whether they have high-risk ge­netic char­ac­ter­istics.

For example, car­filz­o­mib’s over­all re­sponse rate in a group of patients viewed as having high-risk ge­netic markers was actually higher than it was for patients without such markers.

The authors of the poster emphasize these re­­sults.  However, other re­­sults in the poster sug­gest that the similarity in re­sponse rates may mask dif­fer­ences in how the two groups are actually responding to the treat­ment.

There are trends in both the duration of re­sponse and pro­gres­sion-free sur­vival re­­sults in­di­cating that patients with high-risk ge­netic markers do not respond as well to the car­filz­o­mib, and there appears to be a statistically sig­nif­i­cant dif­fer­ence in over­all sur­vival be­tween the high-risk patients (11.9 months sur­vival) and those without high-risk char­ac­ter­istics (19.2 months).

Thus, although car­filz­o­mib seems to per­form better than ex­pected in re­lapsed patients with high-risk char­ac­ter­istics, it seems premature to say that the char­ac­ter­istics do not affect the out­come of the treat­ment.

New Approaches To Stem Cell Transplantation

There also was in­ter­est­ing news during yes­ter­day’s poster sessions re­lated to stem cell trans­plan­ta­tion.

In par­tic­u­lar, re­searchers from Duke Uni­ver­sity in Durham, North Carolina reported on the re­­sults of a retro­spec­tive study com­par­ing two dif­fer­en­t “conditioning” regi­mens prior to au­tol­o­gous stem cell trans­plan­ta­tion (abstract ^[23]).

Currently, the standard con­di­tioning regi­men (high-dose chemo­ther­apy) used before au­tol­o­gous stem cell trans­plants is high-dose melphalan ^[24] (Alkeran). This is also one of the con­di­tioning regi­mens examined by the Duke re­searchers.

The alter­na­tive regi­ment that the Duke re­searchers examine is high dose mel­phalan plus BCNU (carmustine).

As chance would have it, myeloma patients at Duke who re­ceived stem cell trans­plants in the late 1990s and the early 2000s – before the in­tro­duc­tion of novel myeloma treat­ments – were given mel­phalan and BCNU as a con­di­tioning regi­men.

After the in­tro­duc­tion of the novel agents, stem cell trans­plant patients at Duke started re­ceiv­ing only mel­phalan as a con­di­tioning agent.

So the re­searchers collected relapse and sur­vival data on all the myeloma patients who re­ceived stem cell trans­plants at Duke from the late 1990s until 2008, and they com­pared dif­fer­en­t measures of sur­vival for the two patient groups: those who re­ceived mel­phalan plus BCNU as a con­di­tioning regi­men, and those who re­ceived only mel­phalan.

All out­comes in­di­cated a ben­e­fit to using the com­bi­na­tion regi­men of mel­phalan plus BCNU. For a measure called “event free sur­vival”, which is similar to pro­gres­sion free sur­vival, the com­bi­na­tion regi­men was clearly and statistically better than mel­phalan alone. There also is a very noticeable trend in the over­all sur­vival data in favor of the com­bi­na­tion regi­men.

The Duke re­searchers there­fore argue that more re­search should be done into the ef­fi­cacy and safety of the com­bi­na­tion con­di­tioning regi­men.

Researchers on Saturday also pre­sented data from a Phase 1 for another com­bi­na­tion con­di­tioning regi­men – involving Treanda ^[25] (bendamustine) com­bined with mel­phalan – that also yielded promising re­­sults (abstract ^[26]). The re­searchers are studying the com­bi­na­tion fur­ther in a larger Phase 2 clin­i­cal trial that is on­go­ing.

A final trans­plant-related poster yes­ter­day looked at a type of trans­plant that is not carried out very often: allo­geneic (donor) stem cell trans­plants (abstract ^[27]).

The poster summarized re­­sults of a very small trial – involving 13 patients – carried out by re­searchers at Memorial Sloan-Kettering Cancer Center.

The pur­pose of the trial was to see if an ad­vanced ap­proach to allo­geneic stem cell trans­plants can offer a viable treat­ment op­tion for myeloma patients who have re­lapsed quickly after an au­tol­o­gous stem cell trans­plant, and who also have high-risk ge­netic char­ac­ter­istics.

The patients in the trial re­ceived a so-called “t-cell depleted” donor stem cell trans­plant. Modifying the donor stem cell trans­plant in this way is thought to lower the risk asso­ci­ated with the pro­ce­dure without sig­nif­i­cantly reducing its ef­fi­cacy.

Patients in the trial also were given what is known as donor lym­pho­cyte in­fusions (DLIs) after they started recovering from their trans­plants. These are white blood cell in­fusions from the original stem cell donor that can in­crease the re­sponse to the original stem cell trans­plant.

Of the original 13 patients in the Sloan-Kettering study, nine are still alive after a follow-up time of be­tween 19 and 45 months post trans­plant. Estimated one-year sur­vival based on the trial re­­sults is 69 per­cent, which is also the esti­mated two-year sur­vival.

The re­searchers be­lieve the re­­sults of this trial point to an ef­fec­tive way of dealing with dis­ease relapse in patients with high risk ge­netic markers, and they have started a larger trial to fur­ther test the treat­ment ap­proach.

Two Posters About "Hot Topics"

We will close this “ASH 2011 Multiple Myeloma Daily Update” with a short mention of two other posters, each of which dealt with a topic that has re­ceived sig­nif­i­cant attention during the past year.

One poster reported re­­sults looking into how often sec­ond­ary cancers have been oc­curring in U.S. myeloma patients over the past 35 years (abstract ^[28]).  Secondary cancers are addi­tional cancers – beyond a patient’s myeloma – that some­times oc­cur in myeloma patients. There is evi­dence that treat­ment with Revlimid can in­crease a patient’s risk of devel­op­ing addi­tional cancers.

The re­search summarized in yes­ter­day’s poster shows that, after the in­tro­duc­tion of the three novel myeloma agents about ten years ago, the rate of sec­ond­ary cancers among U.S. myeloma patients started to rise. By the later periods covered by the poster re­search, myeloma patients in the U.S. were experiencing sec­ond­ary cancers at a rate 53 per­cent to 63 per­cent higher than what it was in the years before the in­tro­duc­tion of novel myeloma ther­a­pies.

The re­searchers be­lieve this is addi­tional evi­dence that some -- or per­haps even all -- the novel agents in­crease the risk of sec­ond­ary cancer.

Finally, one of the posters pre­sented yes­ter­day provided addi­tional in­­for­ma­tion re­lated to Velcade admin­istered by sub­cu­tane­ous in­jec­tion instead of by in­tra­venous in­fusion (abstract ^[29])

There is grow­ing interest in the op­tion of giving Velcade sub­cu­tane­ously, similar to the way insulin is given to patients with diabetes. Previously pub­lished data have shown that sub­cu­tane­ous Velcade may be just as ef­fec­tive as in­tra­venous Velcade, and sub­cu­tane­ous in­jec­tions also may reduce how fre­quently patients experiencing neg­a­tive side effects due to treat­ment (see re­lated Beacon ^[30] news).

Yesterday’s poster provided evi­dence as to why the two ways of admin­istering Velcade might re­­sult in similar ef­fi­cacy but im­proved side effects for the sub­cu­tane­ous op­tion.

The poster reported an analysis of patients who par­tic­i­pated in trials involving both sub­cu­tane­ous and in­tra­venous Velcade. The patients allowed their blood to be tested during reg­u­lar in­ter­vals after Velcade admin­istering, and re­searchers then measured the con­cen­tra­tion of Velcade in the patients' blood samples.

The re­searchers found that the over­all con­cen­tra­tion of Velcade over time was similar be­tween the two ways of admin­istering the drug. This most likely accounts for the similar ef­fi­cacy of the two ways of giving the drug.

However, the con­cen­tra­tion of Velcade in the blood did not spike nearly as much when the drug is admin­istered sub­cu­tane­ously, and the drug also persisted somewhat longer in the blood after sub­cu­tane­ous admin­istra­tion.

This dif­fer­ence be­tween the two ways of giving the drug could ex­plain the dif­fer­en­t side effects asso­ci­ated with the two ap­proaches to giving the drug if it is the case that high peak con­cen­tra­tions of the drug play an im­por­tant role in the devel­op­ment of side effects such as periph­eral neu­rop­athy (numbness or pain in the hands and feet).

For more detailed coverage of yes­ter­day's myeloma-related pre­sen­ta­tions and re­search at the ASH meeting, see the ASH 2011 Day On ^[31]e thread in The Myeloma Beacon dis­cus­sion forum.

The Beacon will be pub­lishing reg­u­lar ”as it hap­pens” up­dates from the sec­ond full day of ASH in this thread ^[32] in the Beacon’s myeloma forums ^[33].   Similar “as it hap­pens” up­dates also will be provided for Day Three ^[34] and Day Four ^[35].  As always, the news from each day also will be summarized in daily up­dates like this one.