This Monday was the third day of the 2013 American Society of Hema­tol­o­gy (ASH) annual meeting, which was held in New Orleans.

More than any other day of the conference, Monday was packed with im­por­tant myeloma pre­sen­ta­tions, from 7:00 in the morning until almost 8:00 in the eve­ning.

This ASH update will summarize the oral pre­sen­ta­tion sessions about treat­ment-related myeloma studies that were held Monday morning. An ASH update that was pub­lished on Wednesday focused on the sessions that were held Monday afternoon and evening.

Monday morning started with three simultaneous oral pre­sen­ta­tion ses­sions devoted solely to multiple myeloma.  During these sessions, myeloma experts discussed the biology of myeloma (abstracts), pre-clinical studies about drug resistance (abstracts), and treat­ment options for patients with re­lapsed and re­frac­tory multiple myeloma (abstracts).  This last session in­cluded pre­senta­tions about three new multiple myeloma treat­ments under devel­op­ment: afuresertib (GSK2110183), SAR650984, and filanesib (ARRY-520).

Mid-morning, there also were two oral pre­sen­ta­tion sessions that ran simultaneously that were focused solely on myeloma, and another session that had two myeloma-related oral pre­sen­ta­tions (abstracts).  During the two sessions focused on myeloma, experts again discussed the biology of myeloma (abstracts) as well as treat­ment options for myeloma patients, particularly those who are newly diag­nosed (abstracts).  In this session, there was one pre­sen­ta­tion that com­pared sequential treat­ment with two regi­mens to a novel ap­proach of alternating be­tween those two regi­mens.  There were also several pre­sen­ta­tions of up­dated results from studies investigating Revlimid (lena­lido­mide) main­te­nance ther­apy.

Treatment Options For Re­lapsed And Re­frac­tory Myeloma

Afuresertib Plus Velcade And Dexa­meth­a­sone

Dr. Peter Voorhees from the University of North Carolina - Chapel Hill gave the first talk of the morning.  He pre­sented results of a Phase 1b study of afuresertib (GSK2110183) in com­bi­na­tion with Velcade (bortezo­mib) and dex­a­meth­a­sone (Decadron) for the treat­ment of re­lapsed and re­frac­tory myeloma (abstract).

Overall, a total 81 myeloma patients were in­cluded in the three parts of this study.  The patients had a median of three pre­vi­ous ther­a­pies.

The first part of the study tested dif­fer­en­t dose levels for afuresertib, Velcade, and dex­a­meth­a­sone, to de­ter­mine the maximum tolerated dosing regi­men.  In the second and third parts of the study, patients were treated with the maximum tolerated regi­men.

Across all 81 patients, 56 per­cent responded, with 3 per­cent of the patients achieving a com­plete re­sponse­ or stringent com­plete re­sponse­, 15 per­cent a very good partial re­sponse­, and 37 per­cent a partial re­sponse­.

Among the 47 patients in the two parts of the trial who re­ceived afuresertib at its maximum tolerated dose, 60 per­cent of patients responded, with 4 per­cent achieving a stringent com­plete re­sponse­, 19 per­cent a very good partial re­sponse­, and 36 per­cent a partial re­sponse­.

SAR650984

The second talk was given by Dr. Joseph Mikhael from the Mayo Clinic. Dr. Mikhael pre­sented results from a Phase 1 study of a mono­clonal anti­body called SAR650984 (abstract).

The study in­cluded 39 patients with heavily pre­treated myeloma (87 per­cent) or another blood cancer (13 per­cent).  The myeloma patients had a median of six prior ther­a­pies.

The trial explored 12 dif­fer­en­t dose and dosing-frequency com­bi­na­tions of SAR650984, ranging from 0.0001 mg/kg every two weeks to 10 mg/kg every week.   SAR650984 was admin­istered as a single agent, although patients re­ceiv­ing SR650984 doses of 3 mg/kg or higher also re­ceived 100 mg of pred­ni­sone during their SAR650984 in­fusions to prevent in­fusion-related side effects.

Among the myeloma patients in­cluded in the study, 25 per­cent of those treated with at least 1 mg/kg of SAR650984 every two weeks responded, and 31 per­cent of those treated with at least 10 mg/kg every two weeks responded.

The maximum tolerated dose of single-agent SAR650984 has not yet been reached during the study.

Filanesib With Or Without Dexa­meth­a­sone

The next pre­sen­ta­tion was given by Dr. Jonathan Kaufman from Emory University.  Dr. Kaufman pre­sented results from a Phase 2 study of filanesib (ARRY-520) with or without dex­a­meth­a­sone in patients with re­lapsed and re­frac­tory myeloma (abstract, slide deck [PDF]).

The first group of patients (37 per­cent of the study par­tic­i­pants) was treated with filanesib alone; this group had a median of three pre­vi­ous ther­a­pies.  The second group of patients (63 per­cent) had a median of five pre­vi­ous ther­a­pies, and was treated with filanesib plus dex­a­meth­a­sone.

Response rates were similar for both treat­ment groups: 16 per­cent for the first group and 15 per­cent for the second.  The median duration of re­sponse­ and over­all sur­vival were longer, though, for the first (less pre­treated) group (duration of re­sponse­: 8.6 months and 5.1 months for the two groups, re­spec­tive­ly; over­all sur­vival: 19 months and 11 months, re­spec­tive­ly).

The re­searchers also found that patients with low levels of alpha 1-acid glycoprotein (AAG), which binds to filanesib, were more likely to respond to filanesib ther­apy; none of the patients with high levels of AAG re­sponded to ther­apy.

Treanda Plus Thalidomide And Dexa­meth­a­sone

Next, Dr. Stephen Schey from King’s College in London pre­sented results from a Phase 2 study of Treanda (bendamustine) in com­bi­na­tion with thalidomide (Thalomid) and dex­a­meth­a­sone for re­lapsed or re­frac­tory myeloma (abstract).

The study in­cluded 95 patients who were treated with one of two doses of Treanda.  More than three quar­ters of the patients had three or more prior ther­a­pies, and almost all had pre­vi­ously been treated with thalido­mide, either alone or in com­bi­na­tion with another drug.

Outcomes were better at the lower dose of Treanda.  Among the patients treated at the lower dose, 56 per­cent of patients responded, and the median pro­gres­sion-free sur­vival for these patients was 8.2 months.  The higher dose was not well tolerated.

Revlimid Plus Cyclophosphamide And Prednisone

The final myeloma-related pre­sen­ta­tion of the session was given by Dr. Inger Nijhof from the University Medical Center in Utrecht, Netherlands.

Dr. Nijhof pre­sented initial results from the Phase 1, dose-finding portion of a Phase 1/2 study known as the REPEAT trial.  The trial is testing the com­bi­na­tion of Revlimid, cyclophosphamide (Cytoxan), and pred­ni­sone in patients re­frac­tory to pre­vi­ous Revlimid ther­apy (abstract).

Among the 21 patients enrolled in Phase 1 of the study, all were re­frac­tory to Revlimid, and 76 per­cent were re­frac­tory to pre­vi­ous Velcade treat­ment.

Overall, 67 per­cent of patients responded to the three-drug regi­men, with 33 per­cent achieving at least a very good partial re­sponse­.  The median pro­gres­sion-free sur­vival was 6.3 months, and the median over­all sur­vival was 15.5 months.

These results compare favorably, Dr. Nijhof said, to pre­vi­ous findings showing that re­lapsed patients who have failed ther­apy on both Revlimid and Velcade have a median over­all sur­vival of 9 months.

The Phase 2 part of the study will further test the maximum tolerated dose of the three-drug regi­men, which was de­ter­mined to be 25 mg of Revlimid on days 1 through 21 of a 28-day cycle, 50 mg of cyclo­phos­pha­mide daily, and 20 mg of pred­ni­sone daily.

Pomalyst Plus Low-Dose Dexa­meth­a­sone Versus High-Dose Dexa­meth­a­sone Alone

During the next oral session of the morning, Dr. Meletios Dimopoulos from Alexandria Hospital in Athens pre­sented a final analysis of the results from the Phase 3 study com­par­ing treat­ment with Pomalyst plus low-dose dex­a­meth­a­sone to treat­ment with high-dose dex­a­meth­a­sone alone (abstract).  This is the study that led to the ap­­prov­al of poma­lido­mide, mar­keted under the brand name Imnovid, in Europe.

Among the 455 heavily pre­treated myeloma patients in­cluded in the study, 75 per­cent were re­frac­tory to prior Revlimid and Velcade ther­apy.  This final analysis with a median follow-up time of 15.4 months con­firmed the pro­gres­sion-free and over­all sur­vival benefits for Pomalyst plus low-dose dex­a­meth­a­sone com­pared to high-dose dex­a­meth­a­sone.

The pro­gres­sion-free sur­vival results were 4.0 months and 1.9 months, re­spec­tive­ly (Pomalyst+low-dose dex­a­meth­a­sone versus high-dose dex­a­meth­a­sone alone), and the over­all sur­vival results were 13.1 months and 8.1 months, re­spec­tive­ly.

In addi­tion, the updated analysis pre­sented by Dr. Dimopoulos showed that Pomalyst plus low-dose dex­a­meth­a­sone also im­proved sur­vival versus high-dose dex­a­meth­a­sone alone in patients with the high-risk chromosomal ab­nor­mal­i­ties del(17p) and t(4;14).

In particular, Pomalyst and low-dose dex­a­meth­a­sone appeared to have almost the same efficacy in patients with the del(17p) chromosomal ab­nor­mal­ity as in patients without either the t(4:14) or del(17p) ab­nor­mal­ity.

The median over­all sur­vival of patients treated with Pomalyst and low-dose dex­a­meth­a­sone was 14.0 months for patients without either of the two high-risk ab­nor­mal­i­ties, 12.6 months for patients with the del(17p) ab­nor­mal­ity, and 7.5 months for patients with the t(4;14) ab­nor­mal­ity.

The findings in this study in regard to Pomalyst and the del(17p) ab­nor­mal­ity are similar to those reported during two Pomalyst-related pre­sen­ta­tions later in Monday's ASH sessions (see related Beacon ASH up­date).

Treatment Options For Newly Diagnosed Myeloma

Sequential Versus Alternating Use Of Velcade-Melphalan-Prednisone And Revlimid-Dexamethasone

Dr. Maria-Victoria Mateos from the  University Hospital in Salamanca, Spain, pre­sented the results of a study com­par­ing the sequential versus alternating use of Velcade-melphalan (Alkeran)-prednisone (VMP) and Revlimid-dex­a­meth­a­sone (Rd) in elderly, newly diag­nosed myeloma patients (abstract).

The patients who re­ceived the sequential treat­ment scheme re­ceived nine consecutive cycles of VMP followed by nine consecutive cycles of Rd.

Patients who re­ceived the alternating scheme either started with one cycle of VMP and alternated with one cycle of Rd for up to 18 cycles, or started with one cycle of Rd and alternated with one cycle of VMP for up to 18 cycles.

After nine months of treat­ment, more patients who re­ceived alternating treat­ment responded to treat­ment (93 per­cent) com­pared to patients who re­ceived sequential treat­ment (89 per­cent). The share of patients who achieved at least a very good partial re­sponse­ also was sig­nif­i­cantly higher in the alternating treat­ment group (78 per­cent) than in the sequential treat­ment group (56 per­cent).

In addi­tion, the pro­gres­sion-free sur­vival at 20 months was higher for patients in the alternating group (84 per­cent) than for patients in the sequential group (80 per­cent), and the 20-month over­all sur­vival rate was higher for patients in the alternating group (92 per­cent) than for patients in the sequential group (88 per­cent).

While a longer follow-up is needed, the results so far sug­gest that the alternating scheme may lead to better re­sponse­ rates and out­comes.

PAD-Velcade Versus VAD-Thalidomide

Next, Dr. Pieter Sonneveld from the Erasmus Medical Center in Rotterdam in the Netherlands pre­sented extended follow-up results from the HOVON-65/GMMG-HD4 trial (abstract). That trial com­pared the ef­fec­tive­ness of a Velcade-doxorubicin (Adriamycin)-dex­a­meth­a­sone initial ther­apy followed by Velcade main­te­nance (PAD-Velcade) with a vincristine-doxorubicin-dex­a­meth­a­sone initial ther­apy followed by tha­lid­o­mide main­te­nance (VAD-thalidomide) in newly diag­nosed multiple myeloma patients.

After a median follow-up of 67 months, pro­gres­sion-free and over­all sur­vival con­tinued to be superior for patients in the PAD-Velcade arm of the trial com­pared to patients in the VAD-thalidomide arm.

Although pro­gres­sion-free sur­vival was not sig­nif­i­cantly dif­fer­en­t from the start of main­te­nance ther­apy for the two treat­ment groups, over­all sur­vival from the start of main­te­nance ther­apy was better for patients re­ceiv­ing Velcade main­te­nance ther­apy.

Updates On Revlimid Maintenance Therapy

Two pre­sen­ta­tions during the mid-morning session on Monday provided updates from two of the three large clin­i­cal trials which have been testing the efficacy and safety of Revlimid main­te­nance ther­apy (see related Beacon news article from this spring with updates from all three trials as well as addi­tional back­ground in­for­ma­tion).

Revlimid-Melphalan-Prednisone Followed By Revlimid Maintenance Therapy

Dr. Dimopoulos, who spoke earlier in the day about Pomalyst, pre­sented an updated analysis of the Phase 3 MM-015 trial, which in­ves­ti­gated treat­ment with Revlimid, melphalan, and prednisone as initial ther­a­py followed by Revlimid main­te­nance ther­a­py for older newly diag­nosed patients (abstract).

Participants in the trial re­ceived one of three treat­ment regi­mens. The first group re­ceived initial treat­ment with mel­phalan, pred­ni­sone, and a placebo and then main­te­nance ther­a­py with another placebo (this reg­i­men is referred to as MP). The second group re­ceived initial treat­ment with mel­phalan, pred­ni­sone, and Rev­li­mid, followed by a placebo as main­te­nance ther­a­py (MPR). The final group re­ceived the same initial treat­ment as the second group, but also re­ceived Revlimid as main­te­nance ther­a­py (MPR-R).

In the current analysis, the study in­ves­ti­ga­tors looked at a measure of pro­gres­sion-free sur­vival known as “PFS2,” which measures the time from when a patient enters the trial to when the patient ex­peri­ences a second pro­gres­sion.   Results from this analysis showed that median PFS2 was sig­nif­i­cantly higher for patients treated with MPR-R (40 months) than for patients treated with MPR (28 months) and patients treated with MP (29 months).

However, the trial results did not show that Revlimid main­te­nance ther­a­py sig­nif­i­cantly im­proved over­all sur­vival. After a median follow-up time of 53 months, the median over­all sur­vival was 54 months for the MPR-R group, 52 months for the MPR group, and 55 months for the MP group.

The rate of second cancers was higher in patients re­ceiv­ing Revlimid: 11 per­cent for patients re­ceiv­ing MPR-R, 11 per­cent for patients re­ceiv­ing MPR, and 8 per­cent for patients re­ceiv­ing MP.

Stem Cell Transplantation Followed By Revlimid Maintenance Therapy

Dr. Michel Attal from the Purpan Hospital in Toulouse, France, gave the next talk.  He pre­sented an updated analysis of the IFM 2005-02 trial, which in­ves­ti­gated the efficacy of Revlimid main­te­nance ther­apy after stem cell trans­plan­ta­tion for newly diag­nosed myeloma patients (abstract).

With a median follow-up time of 67 months, the median pro­gres­sion-free sur­vival was sig­nif­i­cantly longer for patients re­ceiv­ing Revlimid main­te­nance (46 months) than for patients who re­ceived a placebo main­te­nance ther­apy (24 months).

However, patients re­ceiv­ing Revlimid main­te­nance ther­a­py had shorter second pro­gres­sion-free sur­vival – time from pro­gres­sion after first-line ther­a­py to pro­gres­sion after second-line ther­a­py or death. Specifically, the median second pro­gres­sion-free sur­vival time was 13 months for patients re­ceiv­ing Rev­li­mid main­te­nance ther­a­py, com­pared to 24 months for patients who re­ceived a placebo.

In addi­tion, sur­vival after first pro­gres­sion was also shorter for patients re­ceiv­ing Rev­li­mid main­te­nance ther­a­py (29 months), com­pared to patients who re­ceived a placebo (49 months).

This resulted in similar median over­all sur­vival times for the Revlimid main­te­nance ther­a­py group (82 months) and the placebo group (81 months).

The share of patients who ex­peri­enced second cancers was higher among patients re­ceiv­ing Rev­li­mid main­te­nance ther­a­py (13 per­cent) than in patients re­ceiv­ing a placebo (7 per­cent).

Meta-Analysis Of Revlimid Maintenance Studies

The final pre­sen­ta­tion during the morning was given by Dr. Preet Singh from the Mayo Clinic. Dr. Singh pre­sented the results of a meta-analysis of four ran­dom­ized clin­i­cal trials, involving a total of almost 2,000 multiple myeloma patients, that in­ves­ti­gated Revlimid main­te­nance for multiple myeloma (abstract).

The results of the analysis showed that Revlimid main­te­nance ther­apy is asso­ci­ated with a sig­nif­i­cant im­prove­ment in pro­gres­sion-free sur­vival and a modest im­prove­ment in over­all sur­vival.  However, Revlimid main­te­nance ther­apy is also asso­ci­ated with an in­creased risk of severe side effects, in­clud­ing second cancers.

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This article concludes The Beacon’s daily updates from ASH.  Additional coverage of key re­search results from the meeting will con­tinue the next several weeks in in­di­vid­ual, topic-specific news articles. For a list of all myeloma-related ASH abstracts, a schedule of the myeloma-related ASH sessions, and all Beacon articles related to this year’s ASH meeting, see The Beacon’s ASH 2013 Myeloma Gateway.