This year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago came to an end yesterday.

The fourth day of the meeting, which was Monday, was the busiest day in regard to myeloma-related re­search. It started with an oral pre­sen­ta­tion session that in­cluded seven talks about im­por­tant new myeloma-related re­search. A poster session in the afternoon in­cluded several posters about myeloma-related re­search.

This article summarizes the most im­por­tant findings from Monday’s oral pre­sen­ta­tion session. A later article will cover the findings from the after­noon poster session.

The morning session started off with a pre­sen­ta­tion about a key trial involving the inves­ti­ga­tional drug pano­bino­stat (LBH589). The results of the trial show that adding pano­bino­stat to Velcade (bor­tez­o­mib) and dexa­meth­a­sone (Decadron) im­proves pro­gres­sion free sur­vival in re­lapsed myeloma patients by four months versus Velcade and dexa­meth­a­sone alone.

Based on these results, the Swiss pharma­ceu­tical com­pany Novartis recently sub­mitted a new drug ap­pli­ca­tion on behalf of pano­bino­stat with the U.S. Food and Drug Admin­istra­tion. In addi­tion, Novartis an­nounced on Monday that the FDA in May granted “priority review” to panibinostat.  This means that the FDA ex­pec­ts to make a de­ci­sion in regard to pano­bino­stat's new drug appli­ca­tion by this fall (see related Beacon news).

Also during yesterday’s oral morning session, trial results for the inves­ti­ga­tional mono­clonal anti­bodies dara­tu­mu­mab and SAR650984 were pre­sented. Both sets of results show that the drugs con­tin­ue to show sub­stan­tial anti-myeloma ther­apy.

Another study shed light on the rel­a­tive­ efficacy and safety of Revlimid (lena­lido­mide) and thalido­mide (Thalomid) when they are used in com­bi­na­tion with other drugs to treat newly diag­nosed multiple myeloma. Revlimid and thalido­mide are chemically related to one another.  Until recently, how­ever, there has been only limited in­for­ma­tion avail­able to make reliable comparisons be­tween the two drugs. The study results in­di­cate that thalido­mide and Revlimid have similar efficacy. Revlimid, how­ever, seemed to be the more tolerable of the two drugs.

The treat­ment of newly diag­nosed myeloma also was the focus of an analysis conducted by Italian re­search­ers using data from three large clin­i­cal trials .  The analysis examined whether con­tin­uous ther­apy, involving a fixed duration of intensive initial ther­apy followed by main­te­nance ther­apy until dis­ease pro­gres­sion, is superior to a fixed duration of intensive initial ther­apy alone.

The analysis by the Italian re­search­ers found that the com­bi­na­tion of intensive initial ther­apy plus main­te­nance ther­apy yielded superior pro­gres­sion-free sur­vival and over­all sur­vival versus intensive initial ther­apy alone.

The content in the Beacon's daily updates is based on the actual pre­sen­ta­tions and posters pre­sented at the meeting, which often differ in terms of their content com­pared to what is avail­able prior to the meeting in abstracts sub­mitted for the meeting.

The Beacon’s ASCO updates also in­clude links to pre­sen­ta­tions and posters that the ASCO presenters have made avail­able to the Beacon’s readers for review. The Beacon’s meeting-related articles are oc­ca­sion­al­ly up­dated as more presenters make their slide decks and posters avail­able to The Beacon. The “updated” time at the top of updated articles allows readers to see if new files or other content have been added.

Panobinostat Plus Velcade And Dexa­meth­a­sone

The morning’s oral pre­sen­ta­tion session started off with pre­sen­ta­tion by Dr. Paul Richardson from the Dana-Farber Cancer Center in Boston about the initial results from the so-called PANORAMA 1-study. The PANORAMA 1-study is a Phase 3 trial that eval­u­ates the safety and efficacy of pano­bino­stat (LBH589) plus Velcade and dexa­meth­a­sone versus Velcade and dexa­meth­a­sone alone in re­lapsed or re­lapsed and re­frac­tory multiple myeloma (abstract 8510; presentation [pdf] courtesy of Dr. Richardson).

The study in­cluded 768 re­lapsed and re­frac­tory patients with a median age of 63 years. The patients had been treated with a median of one prior regi­men, in­clud­ing Velcade (43 per­cent), Revlimid (19 per­cent), thalido­mide (51 per­cent), and Kyprolis (car­filz­o­mib) (15 per­cent).

The results show that 61 per­cent of patients re­ceiv­ing pano­bino­stat plus Velcade and dexa­meth­a­sone responded to the treat­ment, com­pared to 55 per­cent of patients re­ceiv­ing Velcade and dexa­meth­a­sone. The com­plete/near com­plete re­sponse­ rate was sig­nif­i­cantly higher among patients re­ceiv­ing the pano­bino­stat-Velcade-dexa­meth­a­sone com­bi­na­tion (28 per­cent) than among patients re­ceiv­ing Velcade-dexa­meth­a­sone (16 per­cent).

The addi­tion of pano­bino­stat to Velcade and dexa­meth­a­sone im­proved pro­gres­sion-free sur­vival by four months (12 months) versus Velcade and dexa­meth­a­sone alone (8.1 months).

An interim analysis of over­all sur­vival data shows that median over­all sur­vival is slightly longer in patients re­ceiv­ing pano­bino­stat-Velcade-dexa­meth­a­sone (34 months) than in patients re­ceiv­ing Velcade-dexa­meth­a­sone (30 months).

The rate of severe side effects was noticeably higher when pano­bino­stat was added. The most common severe side effects in­cluded low platelet counts (67 per­cent of patients re­ceiv­ing pano­bino­stat-Velcade-dexa­meth­a­sone versus 31 per­cent of patients re­ceiv­ing Velcade-dexa­meth­a­sone), low lym­pho­cyte counts (53 per­cent versus 41 per­cent), low neu­tro­phil counts (35 per­cent versus 11 per­cent), and diarrhea (26 per­cent versus 8 per­cent).

Twice as many patients re­ceiv­ing pano­bino­stat-Velcade-dexa­meth­a­sone (34 per­cent) discontinued treat­ment due to side effects, com­pared to patients re­ceiv­ing Velcade-dexa­meth­a­sone  (17 per­cent).

Daratumumab

Dr. Henk Lokhorst from UMC Utrecht in the Netherlands reported results from the ongoing Phase 2, or ex­pan­sion part, of a Phase 1/2 study of dara­tu­mu­mab in re­lapsed and re­frac­tory multiple myeloma patients (abstract 8513; presentation [pdf]).

Dr. Lokhorst had pre­sented results from the Phase 1 part of the trial at last year’s ASH annual meeting (see related Beacon news).

Daratumumab is being devel­oped by the Danish bio­technology com­pany Genmab together with Janssen Biotech, a Johnson & Johnson (NYSE: JNJ) sub­sid­i­ary. It is a mono­clonal anti­body, like elotuzumab and SAR650984. It works by targeting a protein known as CD38 that is fre­quently found on the surface of myeloma cells.

During Phase 1 of the study, patients re­ceived varying doses of dara­tu­mu­mab, ranging from 0.005 mg/kg up to 24 mg/kg.

In the Phase 2 part of the study, the re­search­ers eval­u­ated the safety and efficacy of two specific dara­tu­mu­mab doses: 8 mg/kg, at three dif­fer­en­t in­fusion times, or 16 mg/kg once a week for 8 weeks, followed by 8 doses twice monthly and monthly dosing up to 24 months.

The Phase 2 part of the trial has recruited 50 patients so far; 30 patients re­ceived the 8 mg/kg dosing and 20 the 16 mg/kg dosing.

The patients in the 8 mg/kg dosing groups were somewhat younger than patients in the patients in the 16 mg/kg dosing group, but they had re­ceived more prior treat­ments (median of five) than the patients in the 16 mg/kg dosing group (median of four).

Of the 30 patients in 8 mg/kg dosing groups, 10 per­cent responded, and all these re­sponse­s were partial re­sponse­s. The over­all re­sponse­ rate was much higher in the 16 mg/kg dosing group. Of the 20 patients in that group, 35 per­cent responded, with 10 per­cent achieving a com­plete re­sponse­, 5 per­cent a very good partial re­sponse­, and 20 per­cent a partial re­sponse­.

The median pro­gres­sion-free sur­vival was 15 months in the 8 mg/kg dosing groups, com­pared to 23 months in the 16 mg/kg dosing group. However, Dr. Lokhorst pointed out that the pro­gres­sion-free sur­vival result for the higher dosing group is based on limited data.

According to Dr. Lokhorst, dara­tu­mu­mab was well tolerated.

The most common severe side effects in the 8 mg/kg dosing groups were low platelet counts (13 per­cent), pneu­monia (10 per­cent), and high blood sugar levels (7 per­cent); in the 16 mg/kg dosing group, they were low lym­pho­cyte counts (10 per­cent), low blood sugar levels (5 per­cent), and low potassium levels (5 per­cent). The re­search­ers did not observe any severe in­fusion-related reac­tions.

The re­search­ers also did not observe any dose-related in­creases in side effects.

SAR650984

Dr. Thomas Martin from the University of San Francisco pre­sented initial results from a Phase 1b study of SAR650984 in com­bi­na­tion with Revlimid and dexa­meth­a­sone in re­lapsed myeloma (abstract 8512, pre­sentation [pdf] courtesy of Dr. Martin).

SAR650984, which is being devel­oped by the French pharma­ceu­tical com­pany Sanofi, is also a mono­clonal anti­body and targets the same protein as dara­tu­mu­mab.

The study thus far in­cludes 31 heavily pre­treated myeloma patients with a median age of 59 years who had re­ceived a median of six prior ther­a­pies; 94 per­cent had pre­vi­ously re­ceived Revlimid, 94 per­cent Velcade, 48 per­cent Kyprolis, and 29 per­cent Pomalyst (poma­lido­mide; Imnovid).

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 23 per­cent achieving a very good partial re­sponse­ and 35 per­cent a partial re­sponse­. The median time on treat­ment was 20 weeks.

At the highest SAR650984 dose level (10 mg/kg), the over­all re­sponse­ rate was 63 per­cent, with 25 per­cent achieving a very good partial re­sponse­ and 38 per­cent a partial re­sponse­.

Of the patients who were resistant (refractory) to Revlimid, 48 per­cent responded; 20 per­cent achieved a very good partial re­sponse­ and 28 per­cent a partial re­sponse­.

According to Dr. Martin, SAR650984 in com­bi­na­tion with Revlimid and dexa­meth­a­sone was well tolerated. The most common severe effects in­cluded fever (13 per­cent), low white blood cell counts (12 per­cent), and pneu­monia (6 per­cent).  The maximum tolerated dose of SAR650984 in the com­bi­na­tion regi­men has not yet been reached.

MPT-T Versus MPR-R in Newly Diagnosed, Transplant-Ineligible Multiple Myeloma Patients

Dr. Keith Stewart from the Mayo Clinic pre­sented results of a Phase 3 clin­i­cal study, known as the E1A06 trial, that com­pared  melphalan (Alkeran), prednisone, and thalidomide, followed by thalido­mide main­te­nance (MPT-T), with mel­phalan, prednisone, and Revlimid, followed by Revlimid main­te­nance (MPR-R) (abstract 8511; presentation [pdf] courtesy of Dr. Stewart).

The E1A06 trial in­cluded 306 newly diag­nosed myeloma patients with a median age of 76 who were not can­di­dates for stem cell trans­plan­ta­tion.

The results show that re­sponse­ rates, pro­gres­sion-free sur­vival rates, and three-year over­all sur­vival rates for the two regi­mens were similar, which may come as a surprise to some, given that Revlimid is often con­sidered to be a more effective drug than thalido­mide.

Specifically, 75 per­cent of patients responded to MPT-T treat­ment, com­pared to 70 per­cent who re­ceived MPR-R.  The share of patients achieving a very good or com­plete re­sponse­ was higher for the Revlimid-based regi­men (32 per­cent) than for the thalido­mide-based regi­men (25 per­cent).

The median pro­gres­sion-free sur­vival was 21 months for patients who re­ceived MPT-T, com­pared to 18.7 months for patients who re­ceived MPR-R. Dr. Stewart pointed out the sur­vival out­come for the MPT-T regi­men is similar to what has been seen in pre­vi­ous studies involving the regi­men.  The result for the MPR-R regi­men, on the other hand, is not as good as has been pre­vi­ously seen.

In his discussion of the study results later in the session, Dr. Robert Orlowski of the MD Anderson Cancer Center said the lower-than ex­pec­ted pro­gres­sion-free sur­vival for the MPR-R regi­men may be due to the fact that the patients in the E1A06 trial were older than in pre­vi­ous trials testing the regi­men.

The median over­all sur­vival was also longer for patients who re­ceived MPT-T (52.6 months), com­pared to that for patients who re­ceived MPR-R (47.7 months).

The MPT-T regi­men appeared to be less tolerable than MPR-R among the pa­tients in the E1A06 trial.  The rate of severe side effects was sig­nif­i­cantly higher in  patients on the MPT-T regi­men (73 per­cent) than in patients on the MPR-R regi­men (58 per­cent). Measures of patient quality of life were also lower in the patients who re­ceived the thalido­mide-containing regi­men.

Continuous Therapy Versus Fixed Duration Of Therapy

Dr. Antonio Palumbo of the University of Torino in Italy pre­sented results of a study that in­ves­ti­gated the poten­tial benefit in newly diag­nosed myeloma patients of adding main­te­nance ther­apy until dis­ease pro­gres­sion to initial intensive ther­apy (abstract 8515).

The com­bi­na­tion of intensive initial ther­apy with main­te­nance ther­apy until dis­ease pro­gres­sion is an example of con­tin­uous ther­apy.  It stands in contrast to treat­ment that is given for a set amount of time (or cycles), which is known as fixed duration ther­apy.

Continuous ther­apy has been the subject of interest since initial results of the so-called FIRST trial were pre­sented at last De­cem­ber’s American Society of Hematology annual meeting. The FIRST trial is com­par­ing three treat­ment regi­mens for newly diag­nosed multiple myeloma: con­tin­uous treat­ment with Revlimid and dexa­meth­a­sone (Rd) until pro­gres­sion; treat­ment with Rd for a fixed period of time; and treat­ment with mel­phalan, pred­ni­sone, and thalido­mide for a fixed period of time.

The results pre­sented in De­cem­ber showed that con­tin­uous Rd ther­apy im­proved re­sponse­ rates and measures of sur­vival versus the alter­na­tive fixed-duration-of-therapy regi­mens (see related Beacon news).

The study that Dr. Palumbo pre­sented yesterday is based on data from three Italian trials involving a total of 1,218 newly diag­nosed multiple myeloma patients. In all three of the trials, there were two groups of patients.  The first group re­ceived con­tin­uous ther­apy con­sist­ing of a fixed duration of intensive initial ther­apy followed by main­te­nance ther­apy until pro­gres­sion.  The second group re­ceived just the fixed duration of initial intensive ther­apy.

One of the three trials in­volve­d Velcade-based treat­ment regi­mens, and the other two in­volve­d Revlimid-based regi­mens.

All three trials differed from the FIRST trial in that, in the FIRST trial, the patients who re­ceived con­tin­uous ther­apy re­ceived the same treat­ment regi­men the entire length of time they were treated.

In the three trials analyzed by Dr. Palumbo and his colleagues, the patients who re­ceived con­tin­uous ther­apy initially re­ceived a more intensive initial ther­apy, involving three or four anti-myeloma drugs and sometimes trans­plan­ta­tion, followed by a less intensive main­te­nance ther­apy involving one or two drugs.

Based on their analyses of the results of the three trials in­cluded in their study, Dr. Palumbo and his col­leagues conclude that, as was the case in the results for the FIRST trial, con­tin­uous ther­apy is more ad­van­tageous than treat­ment for a fixed duration of time.

Specifically, the re­search­ers found that pro­gres­sion-free sur­vival was twice as long for patients re­ceiv­ing con­tin­uous ther­apy (32 months) than for patients re­ceiv­ing treat­ment for a fixed duration of time (16 months).

Dr. Palumbo and his colleagues also looked at a measure of pro­gres­sion-free sur­vival known as “PFS2,” which measures the time from the start of treat­ment to when the patient ex­peri­ences a second pro­gres­sion. They found that PFS2, as well, was sig­nif­i­cantly longer in patients re­ceiv­ing con­tin­uous ther­apy (55 months) than patients re­ceiv­ing treat­ment for a fixed duration of time (40 months).

The four-year over­all sur­vival rate was also higher in patients re­ceiv­ing patients re­ceiv­ing con­tin­uous ther­apy (69 per­cent) than for patients re­ceiv­ing treat­ment for a fixed duration of time (60 months).

Quality Of Life In Transplant-Ineligible, New Diagnosed Myeloma Patients

Later in the session, Dr. Michel Delforge from the University Hospital in Leuven, Belgium, pre­sented health-related quality of life data from the FIRST trial (abstract 8516).

Dr. Delforge reported that con­tin­uous treat­ment with Revlimid and dexa­meth­a­sone (Rd) until pro­gres­sion im­proved health-related quality of life mea­sure­ments, such as physical functioning, pain, fatigue, and dis­ease symp­toms over the course of treat­ment, as long as patients did not progress. Progressive dis­ease, on the other hand, was asso­ci­ated with a worsening across all health-related quality of life mea­sure­ments. Continuous treat­ment with Revlimid and dexa­meth­a­sone was also perceived as having better treat­ment side effects than MPT.

Benefits Of Stem Cell Transplantation In Older Myeloma Patients

Dr. Gunjan Shah from the Tufts Medical Center in Boston pre­sented results from a study that in­ves­ti­gated the sur­vival benefit and cost of au­tol­o­gous stem cell trans­plan­ta­tion in elderly myeloma patients (abstract 8517; presentation [pdf] courtesy of Dr. Shah).

The study was based on data from the SEER-Medicare database, which was created by linking patient records from the Surveillance, Epidemiology, and End Results (SEER) database – a key source of U.S. cancer sur­vival statistics – with beneficiary claims records from the U.S. Medicare pro­gram, which is the federally funded health insurance sys­tem for U.S. citizens 65 years of age and older.

Dr. Shah and his colleagues identified 12,803 patients who were diag­nosed with multiple myeloma be­tween Jan­u­ary­ 2000 and Jan­u­ary­ 2008; 270 of these patients re­ceived a stem cell trans­plant. The median patient age was 69 years; the oldest patient who re­ceived a trans­plant was 92 years old.

When they com­pared out­comes be­tween these patients and patients with similar char­ac­ter­istics who did not re­ceive a trans­plant, they found that the patients who re­ceived the trans­plant sur­vived sig­nif­i­cantly longer (58 months) than those who did not re­ceive a trans­plant (37 months).

However, the cost of treat­ment after diag­nosis was sig­nif­i­cantly higher for patients who re­ceived a trans­plant ($301,000), com­pared to those who did not re­ceive a trans­plant ($124,000).

Dr. Shah pointed out, though, that the incremental cost that was asso­ci­ated with trans­plan­ta­tion was below commonly ac­cepted thresholds for such costs, taking into account the added benefit of the pro­ce­dure.

Discussions Of Results Presented During The Session

There were two review pre­sen­ta­tions of the myeloma-related studies pre­sented during Monday's oral pre­sentation session at ASCO.   One that already has been mentioned earlier in this article – by Dr. Robert Orlowski -- reviewed the pre­sen­ta­tions by Dr. Richardson and Dr. Stewart (presentation [pdf] courtesy of Dr. Orlowski).  The other, by Dr. Luciano Costa of the Medical University of South Carolina, reviewed the pre­sen­ta­tions by Dr. Palumbo, Dr. Delforge, and Dr. Shah (presentation [pdf] courtesy of Dr. Costa).

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Additional coverage of key re­search results from the meeting will con­tinue after the meeting is over with in­di­vid­ual, topic-specific news articles.  For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2014 coverage.