This past Sunday was the second day of the American Society of Hema­tology’s (ASH) annual meeting, which was held in San Francisco.

As on the first day of the meeting, myeloma-related pre­sen­ta­tions once again took place during several sessions through­out the day.

A myeloma-related education session held the first day of the conference was repeated once again on Sunday morning.

While the education session was being held, a separate “scientific sym­po­sium” with two oral pre­sen­ta­tions took place in parallel.  The session focused on a novel immuno­therapeutic ap­proach to treating cancer known as CAR-T ther­apy.  One of the pre­sen­ta­tions during the session in­cluded a brief update on a pilot study testing CAR-T ther­apy in myeloma patients.

At midday, an oral session took place focused on recently approved and poten­tial new myeloma ther­a­pies, in­clud­ing dara­tu­mu­mab, ixazomib (MLN9708), and SAR650984.

The education session, scientific symposium, and the midday oral session will be summarized in this article.

In the late afternoon, there were two oral pre­sen­ta­tion sessions focused solely on myeloma, and an addi­tion­al oral session about stem cell trans­plan­ta­tion, which in­cluded a few myeloma-related pre­sen­ta­tions.  A poster session in the evening in­cluded results from a number of myeloma-related re­search studies.

Research pre­sented in Sunday’s afternoon and evening sessions will be summarized in a separate Beacon ASH Daily Update.

Education Sessions

Three myeloma experts gave pre­sen­ta­tions during Sunday morning's education session.

The initial two pre­sen­ta­tions formed a debate on the role of au­tol­o­gous stem cell trans­plan­ta­tion for newly diag­nosed multiple myeloma.  The third pre­sen­ta­tion discussed treat­ment options for re­lapsed myeloma.

Early Stem Cell Transplantation For All

In the first pre­sen­ta­tion, Dr. Philippe Moreau of the University Hospital in Nantes, France, took the position that all trans­plant-eligible newly diag­nosed myeloma patients should undergo trans­plan­ta­tion as part of their initial treat­ment; trans­plan­ta­tion should not be delayed until first relapse or later (abstract).

Dr. Moreau noted that the sur­vival of multiple myeloma patients has in­creased markedly since stem cell trans­plan­ta­tion became a common part of initial ther­apy for newly diag­nosed patients.  In addi­tion, of the seven clin­i­cal trials in the last 20 years that have directly com­pared early versus delayed trans­plan­ta­tion for multiple myeloma, six have dem­onstrated that early trans­plan­ta­tion yields a pro­gres­sion-free sur­vival benefit, and three have shown an over­all sur­vival benefit for early trans­plan­ta­tion.

These trials, Dr. Moreau admitted, were carried out prior to reg­u­lar use of novel agents in the treat­ment of multiple myeloma. Thus, two new trials examining the issue – the IFM/DFCI 2009 and HOVON/EMN H095 studies – will provide im­por­tant new insights on the subject. Initial results of the IFM/DFCI 2009 trial, he said, will most likely be pre­sented late next year.

Dr. Moreau noted, as well, that au­tol­o­gous stem cell trans­plan­ta­tion is safe, with a treat­ment related mortality of less than two per­cent. In addi­tion, delaying trans­plan­ta­tion creates the risk that a patient will be­come in­eli­gible for trans­plan­ta­tion when their dis­ease relapses, due to the devel­op­ment of treat­ment- or dis­ease-related health issues.

Early Stem Cell Transplantation For Some

The second pre­sen­ta­tion during the education session was by Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston.  He took issue with Dr. Moreau’s perspective on trans­plan­ta­tion, arguing instead that trans­plan­ta­tion as part of a myeloma patient’s initial ther­apy should be pursued in a more selective manner (abstract).

At a fundamental level, Dr. Richardson argued, a one-size-fits-all ap­proach to treating newly diag­nosed myeloma patients does not make sense given that the dis­ease itself varies so much among patients.

Furthermore, myeloma patients are now living much longer than they did five, ten, and fifteen years ago. When patients today undergo stem cell trans­plan­ta­tion early in the treat­ment of their dis­ease, Dr. Richardson noted, many of them will have to live for a long time with the side effects that often can occur as a result of trans­plan­ta­tion.

More im­por­tantly, he ex­plained, there are now several retro­spec­tive­ studies using data from the era of novel ther­a­pies for myeloma that in­di­cate early stem cell trans­plan­ta­tion does not provide a clear benefit versus delayed trans­plan­ta­tion.  These results can be ex­plained, Dr. Richardson said, by the fact that novel thera­pies today reg­u­larly achieve the kind of deep treat­ment re­sponse­s that, in the past, required the use of trans­plan­ta­tion.

The occurrence of such deep treat­ment re­sponse­s without the use of trans­plan­ta­tion is likely to be­come even more common in the future, Dr. Richardson ex­plained, as addi­tional novel myeloma ther­a­pies be­come avail­able. Among the new myeloma ther­a­pies cur­rently under devel­op­ment, he feels the mono­clonal anti­bodies, such as elotuzumab, dara­tu­mu­mab, and SAR650984 represent sig­nif­i­cant “game changers.”

These new ther­a­pies are likely to extend the strong in­creases in sur­vival myeloma patients have experi­enced in recent years as existing novel ther­a­pies – more so than trans­plan­ta­tion – have im­proved the treat­ment of the dis­ease, Dr. Richardson concluded.

How To Treat Re­lapsed Myeloma

The final pre­sen­ta­tion during Sunday’s education session was given by Dr. Joseph Mikhael from the Mayo Clinic, who described a "practical ap­proach to re­lapsed multiple myeloma" (abstract, pre­sen­ta­tion slides [PDF] courtesy of Dr. Mikhael).

Dr. Mikhael began his pre­sen­ta­tion by reviewing recent findings related to intra-clonal heterogeneity in multiple myeloma (see the related Beacon physician column by Dr. Gareth Morgan of the University of Arkansas for Medical Sciences).

There are several key takeaways of this re­search, Dr. Mikhael ex­plained.  One is that, even at the time of diag­nosis, a single patient’s dis­ease is com­prised of several genetically dif­fer­en­t myeloma sub-types, each of which is likely to respond dif­fer­en­tly to dif­fer­en­t myeloma ther­a­pies.  As a result, treating multiple myeloma effectively often requires com­bi­na­tion ther­apy with treat­ments from dif­fer­en­t drug classes.

Just as im­por­tantly, multiple myeloma as a dis­ease evolves over time in every patient, and this process is complex. While pro­gres­sion of the dis­ease nor­mally means that it be­comes resistant to ther­a­pies already used to treat it, this is not universally the case.  Sub-types of the dis­ease that initially diminish in importance due to treat­ment can reappear and play a sig­nif­i­cant role, making retreatment with prior ther­a­pies a viable option.

Dr. Mikhael next went on to say that, when deciding how to treat a re­lapsed patient, physicians should ask themselves five key questions:

1. Do I really need to treat the patient now – that is, am I certain the patient is truly relapsing?
2. Should I retreat with a previous therapy?
3. Have I employed the “Big Five” myeloma therapies – thalidomide (Thalomid), Velcade (bortezomib), Revlimid (lenalidomide), Kyprolis (carfilzomib), and Pomalyst (pomalidomide, Imnovid)?
4. Have I used the key add-on therapies – corticosteroids, including dexamethasone (Decadron) and prednisone; alkylating agents, including melphalan (Alkeran) and cyclophosphamide (Cytoxan); and Doxil (doxorubicin liposomal)?
5. Have I considered an individualized approach to treatment, taking into account the patient’s characteristics, the characteristics of the patient’s disease, and available treatments and their characteristics?

CAR-T Therapy For Multiple Myeloma

Also on the ASH meeting agenda on Sunday morning was a scientific symposium con­sist­ing of two extended oral pre­sen­ta­tions.  Both pre­sen­ta­tions focused on a novel immuno­therapeutic ap­proach to treating cancer known as chi­meric an­ti­gen re­cep­tor T-cell (CAR-T) ther­apy.

The first step in CAR-T treat­ment in­volve­s harvesting immune sys­tem cells known as T-cells from the patient.  The T-cells are then treated in a way that genetically alters them so that, when the cells are re-infused into the patient, they attack and kill the patient’s cancer cells.

Initial results of the CAR-T ap­proach to treating cancer caused a great deal of excitement in the on­col­ogy com­munity when they were announced three years ago (see related Beacon news, a follow-up article from a year later, and a review of novel immuno­therapeutic ther­a­pies for myeloma pub­lished by The Beacon prior to last year’s ASH meeting).

At the ASH meeting session on Sunday, Dr. Carl June of the University of Pennsylvania discussed work that he and his colleagues are doing on a CAR-T ther­apy known as CTL019 (abstract). The treat­ment has been used primarily to treat both the chronic and acute forms of lym­pho­cytic leukemia.  However, Dr. June briefly discussed during his pre­sen­ta­tion the initial results of a pilot trial testing the ther­apy in multiple myeloma.

A total of four late-stage patients have thus far been treated with CTL019, with the first patient re­ceiv­ing treat­ment prior to the start of the current trial.  All patients achieved at least a very good partial re­sponse­ to CTL019, and at least two patients have achieved a stringent com­plete re­sponse­ (slide from Dr. June’s pre­sen­ta­tion with results of CTL019 treat­ment of myeloma thus far; addi­tional insights into the study results were provided to The Beacon by a patient participating in the trial, who reported that, to his knowledge, all three patients in the trial have achieved a stringent com­plete re­sponse­.)

Oral Presentations About New Myeloma Therapies

A midday oral session at ASH on Sunday focused on results from clin­i­cal trials involving recently approved and poten­tial new myeloma ther­a­pies.

Kyprolis-Revlimid-Dexamethasone

The first talk was given by Dr. Keith Stewart from the Mayo Clinic. Dr. Stewart pre­sented results from the "ASPIRE" trial, which compares the efficacy of Kyprolis, Revlimid, and dexa­meth­a­sone to Revlimid and dexa­meth­a­sone in re­lapsed myeloma patients (abstract, presentation slides [PDF] courtesy of Dr. Stewart).

Initial results of the trial, which were released this summer, showed that patients in the trial who re­ceived the Kyprolis-Revlimid-dexamethasone com­bi­na­tion (KRd) had sig­nif­i­cantly longer pro­gres­sion-free sur­vival than patients who re­ceived only Revlimid and dexa­meth­a­sone (Rd) (see related Beacon news).

The ASPIRE trial in­cluded 792 patients who had re­ceived a median of two prior ther­a­pies.

Dr. Stewart reported that 87 per­cent of patients re­ceiv­ing KRd responded to treat­ment, com­pared to 67 per­cent of patients re­ceiv­ing Rd. Responses were deeper in the KRd treat­ment group, with 32 per­cent of patients achieving a stringent com­plete re­sponse­ or com­plete re­sponse­, com­pared to 9 per­cent in the Rd treat­ment group.

Progression-free sur­vival was 26.3 months for patients in the KRd treat­ment group, com­pared to 17.6 months in the Rd treat­ment group. The median over­all sur­vival has not been reached yet in both treat­ment groups. However, there is a trend in over­all sur­vival favoring the KRd treat­ment group.

The rate of severe, treat­ment-emergent side effects was similar be­tween the two treat­ment groups (84 per­cent for patients re­ceiv­ing KRd versus 80 per­cent for patients re­ceiv­ing Rd).

Dr. Stewart also noted that KRd im­proved health-related quality of life com­pared to Rd alone.

Reaction to Dr. Stewart’s pre­sen­ta­tion has been very fa­vor­able, with experts commenting on the sig­nif­i­cant efficacy dem­onstrated by the KRd regi­men and the lack of any unexpected safety con­cerns asso­ci­ated with the regi­men.

Long-Term Ixazomib Maintenance

Dr. Shaji Kumar pre­sented results from a Phase 2 study of ixazomib (MLN9708) in com­bi­na­tion with Revlimid and dexa­meth­a­sone followed by ixazomib main­te­nance in newly diag­nosed myeloma patients (abstract, pre­sen­ta­tion slides courtesy of Dr. Kumar).

Ixazomib belongs to the same class of drugs as Velcade and Kyprolis, called pro­te­a­some in­hib­i­tors. It is being devel­oped by Millennium Pharma­ceu­ticals, the same com­pany that devel­oped Velcade. Unlike Velcade and Kyprolis, which are given by in­fusion or in­jec­tion, ixazomib is admin­istered orally.

Results pre­sented at last year’s ASH annual meeting showed that ixazomib-Revlimid-dexamethasone induction ther­apy generated a high re­sponse­ rate in newly diag­nosed myeloma patients (see related Beacon news).

Dr. Kumar’s pre­sen­ta­tion focused on the main­te­nance part of the study.

Of the 49 evaluable patients who re­ceived induction ther­apy with ixazomib plus Revlimid and dexa­meth­a­sone, 90 per­cent responded; 43 per­cent of patients went on to re­ceive ixazomib main­te­nance ther­apy.

Dr. Kumar reported that 48 per­cent of patients im­proved their re­sponse­ during ixazomib main­te­nance ther­apy. The rate of com­plete and near com­plete re­sponse­s im­proved from 24 per­cent after induction ther­apy to 62 per­cent after main­te­nance ther­apy.

According to Dr. Kumar, ixazomib main­te­nance was well tolerated. The onset of new side effects was limited, and only 10 per­cent of patients required dose re­duc­tions during main­te­nance ther­apy.

The results Dr. Kumar pre­sented were re­ceived pos­i­tively by the audience at Sunday’s session. The possibility of a highly active, all-oral three-drug regi­men for myeloma was seen as very desirable.

SAR650984 Plus Revlimid And Dexa­meth­a­sone

Dr. Thomas Martin from the University of California San Francisco pre­sented updated results of a Phase 1b trial of SAR650984 in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed and re­frac­tory multiple myeloma (abstract, pre­sen­ta­tion slides [PDF] courtesy of Dr. Martin). Early results of the trial were pre­vi­ous­ly pre­sented at the American Society of Clinical Oncology (ASCO) annual meeting this summer (see related Beacon news).

SAR650984 is being devel­oped by the pharma­ceu­tical com­pany Sanofi (NYSE:SNY).  It belongs to a class of drugs called mono­clonal anti­bodies. It targets cancer cells that have a protein called CD38 on their surface.

The study so far in­cludes 31 myeloma patients who have re­ceived a median of seven prior ther­a­pies. The majority of patients (84 per­cent) were re­lapsed and re­frac­tory to immuno­modu­la­tory agents, such as Revlimid and Pomalyst.

The trial explored three dif­fer­en­t dose levels (3 mg/kg, 5 mg/kg, and 10 mg/kg) of SAR650984.

Overall, 58 per­cent of patients responded, with 6 per­cent achieving a com­plete re­sponse­, 29 per­cent a very good partial re­sponse­, and 23 per­cent a partial re­sponse­. Patients who re­ceived the highest tested dose of SAR650984 had an over­all re­sponse­ rate of 63 per­cent, patient who were re­lapsed or re­frac­tory to prior Revlimid ther­apy had an over­all re­sponse­ rate of 50 per­cent.

The median pro­gres­sion-free sur­vival was 6.2 months across all patients.

According to Dr. Martin, the com­bi­na­tion has a man­ageable side effect profile.  Indeed, in re­sponse­ to a question re­gard­ing the dosing of SAR650984, Dr. Martin commented that the drug was suf­fi­ciently safe at the doses tested during the trial that he, personally, would be inclined to admin­ister it at con­siderably higher doses.

The results Dr. Martin pre­sented appear to have reinforced the opinion among many myeloma experts that SAR650984 con­tinues to be one of the most promising poten­tial new myeloma ther­a­pies in the middle stages of devel­op­ment.

Daratumumab In Com­bi­na­tion With Revlimid And Dexa­meth­a­sone

The last talk of the Sunday midday session was given by Dr. Torben Plesner from Velje Hospital in Denmark. Dr. Plesner pre­sented results from a Phase 1/2 trial of dara­tu­mu­mab with Revlimid and dexa­metha­sone in re­lapsed myeloma patients (abstract, pre­sen­ta­tion slides [PDF] courtesy of Dr. Plesner). Initial results of the trial were pre­sented earlier this year at the ASCO annual meeting (see related Beacon news).

Daratumumab is another mono­clonal anti­body that targets the CD38 protein found in myeloma cells. It is being devel­oped by the Danish bio­technology com­pany Genmab together with Janssen Biotech, a Johnson & Johnson (NYSE:JNJ) sub­sid­i­ary.

The trial thus far in­cludes 45 patients with a median age of 61 years and a median of two prior myeloma ther­a­pies.

Patients re­ceived dara­tu­mu­mab doses ranging from 2 mg/kg to 16 mg/kg in the Phase 1 part of the trial. Since the maximum tolerated dose was not reached, 16 mg/kg is being explored in the Phase 2 part of the trial.

All 13 patients in the Phase 1 part of the trial responded to the three-drug regi­men. Of the 30 patients evaluable for re­sponse­ in the Phase 2 part of trial, 87 per­cent have thus far responded to the three-drug treat­ment, with 7 per­cent achieving a com­plete re­sponse­, 43 per­cent a very good partial re­sponse , and 37 per­cent a partial re­sponse­.

The depth of re­sponse­s during the Phase 2 portion of the study are likely to in­crease further, Dr. Plesner noted, as many patients in that part of the trial have just started treat­ment with the three-drug com­bi­na­tion.

In addi­tion, Dr. Plesner ex­plained that it is likely that the number of deep re­sponse­s in the trial is being underestimated.  Recent re­search, he elaborated, in­di­cates that mono­clonal anti­bodies such as dara­tu­mu­mab often interfere with the serum immuno­fix­a­tion electrophoresis (IFE) test that must be done to de­ter­mine a myeloma patient’s re­sponse­ to treat­ment.  Patients who have responded very well to treat­ment with a mono­clonal anti­body can have IFE test results in­di­cating the presence of a mono­clonal protein when, in fact, no such protein is present.

A modified IFE test is under devel­op­ment that will take into account this phenomenon.

The most common side effects of the dara­tu­mu­mab-Revlimid-dexamethasone com­bi­na­tion in­cluded low white blood cell counts (64 per­cent), muscle spasms (44 per­cent), and diarrhea (31 per­cent).

Dr. Plesner said that a Phase 3 trial of the three-drug com­bi­na­tion in re­lapsed and re­frac­tory patients has been ini­ti­ated and that a Phase 3 trial of the same com­bi­na­tion in newly-diagnosed patients is ex­pec­ted to start in 2015.

The audience at the session responded well to Dr. Plesner’s pre­sen­ta­tion. The results he pre­sented appeared to be further evi­dence that dara­tu­mu­mab is highly active and safe as a myeloma ther­apy.

Pomalyst Plus Low-Dose Dexa­meth­a­sone

There were two pre­sen­ta­tions during Sunday’s session focused on drugs in the immunodulatory class of ther­a­pies.

Dr. Meletios Dimopoulos from Athens University in Greece reported results from a single-arm, European Phase 3 trial – the "STRATUS" trial – of Pomalyst in com­bi­na­tion with low-dose dexa­meth­a­sone (abstract).

The study in­cluded 604 patients who had re­ceived a median of five prior ther­a­pies. All patients had pre­vi­ous­ly re­ceived Revlimid and Velcade, and 78 per­cent were re­frac­tory to both Revlimid and Velcade.

Overall, 35 per­cent of patients responded, with 1 per­cent achieving a com­plete re­sponse­, 5 per­cent a very good partial re­sponse­, and 29 per­cent a partial re­sponse­.

The median pro­gres­sion-free sur­vival was 4.2 months, and the median over­all sur­vival was 11.9 months.

Dr. Dimopoulos pointed out that patients who were re­frac­tory to Revlimid and Velcade reached similar over­all re­sponse­, pro­gres­sion-free and over­all sur­vival as the over­all study pop­u­la­tion.

According to Dr. Dimopoulos, the com­bi­na­tion was well tolerated. The most common severe side effects in­cluded low white blood cell counts (42 per­cent), in­fec­tions (30 per­cent), and anemia (29 per­cent).

Continuous Revlimid Plus Low-Dose Dexa­meth­a­sone In Older Patients

The second pre­sen­ta­tion related to the immodulatory class of ther­a­pies was by Dr. Cyrille Hulin from the University Hospital in Nantes, France. He pre­sented results of a sub-analysis that in­ves­ti­gated the effect of age on out­comes in the "FIRST" trial (abstract).

Patients in the FIRST trial had newly diag­nosed multiple myeloma and were either at least 65 years of age or not eli­gible for stem cell trans­plan­ta­tion. Trial par­tic­i­pants were ran­domly assigned to re­ceive one of three dif­fer­en­t myeloma treat­ment regi­mens: Revlimid plus dexa­meth­a­sone (Rd) until dis­ease pro­gres­sion (“continous Rd”), Rd for a fixed duration of 72 weeks, or mel­phalan plus pred­ni­sone and thalido­mide (MPT) for a fixed duration of 72 weeks.

Initial results of the FIRST trial were pre­sented at last year’s ASH annual meeting. They showed that patients treated with con­tin­uous Revlimid and dexa­meth­a­sone had the highest over­all re­sponse­ rate and exper­i­enced the longest pro­gres­sion-free sur­vival (see related Beacon news).

In his pre­sen­ta­tion on Sunday, Dr. Hulin showed that these key out­comes of the FIRST trial also were found when he and his colleagues split the study par­tic­i­pants into two age groups: patients 75 years of age or younger, and patients older than 75.  In both these groups, con­tin­uous Revlimid and dexa­meth­a­sone pro­vided the highest over­all re­sponse­ rate and the longest pro­gres­sion-free sur­vival.

For example, in patients over the age of 75, more patients responded to con­tin­uous Rd ther­apy (71 per­cent) than to fixed-duration Rd (66 per­cent) or to fixed duration MPT (55 per­cent).  Likewise, the median pro­gres­sion-free sur­vival also was longer for those who re­ceived con­tin­uous Rd (21 months) than for those who re­ceived fixed duration Rd (19 months) or fixed duration MPT (19 months).

Dr. Hulin also noted that the pattern and frequency of side effects ex­peri­enced by patients on con­tin­uous Rd were similar in the two age groups. He attributed this result to dose ad­just­ments that were made dur­ing the trial based on patient age, kidney function, and bone mar­row function.

According to Dr. Hulin, these new results from the FIRST trial sup­port the use of con­tin­uous Revlimid and dexa­meth­a­sone as a new standard of care in newly diag­nosed, trans­plant-ineligible multiple myeloma pa­tients, re­gard­less of age.

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Additional myeloma pre­sen­ta­tions from the rest of Day 2 of the ASH 2014 meeting, as well as pre­sen­ta­tions on Day 3, will be summarized in addi­tional ASH daily updates to be pub­lished at The Beacon the next several days.  Further coverage of key re­search results from the meeting will con­tinue after the meeting in in­di­vid­ual, topic-specific news articles.

Unless other­wise noted, all pre­sen­ta­tion and poster summaries in the Beacon's ASH-related articles report results pre­sented at this year's meeting. These data are often more recent or extensive than what is con­tained in the pre­sen­ta­tion and poster abstracts.  In addi­tion, Beacon ASH-related articles will be updated on an ongoing basis in the coming weeks with links to the actual slides and posters pre­sented at the meeting (when avail­able and subject to permission of the lead author).

For more in­­for­ma­tion on ASH’s 56^th Annual Meeting, in­clud­ing the final pre­sen­ta­tion schedule and all meeting abstracts, please see the ASH annual meeting website.