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ASH 2013 Multiple Myeloma Update - Day Three: Morning Oral Sessions

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Published: Dec 13, 2013 9:16 pm

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.

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3 Comments »

  • Mark said:

    Thanks for the excellent ASH coverage. I keep hearing the Celgene Consultants/Board Members say that the overall survival advantage with Revlimid maintenance will come with longer follow up. How much longer is it going to take? I do not use maintenance and the more data I see the happier I am with my decision. All the extra side effects for a few extra months of OS hardly seems worth it to me. I never hear the Celgene Consultants/Board Members discuss this:

    "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."

    I guess they view myeloma therapy as a sprint and just look at short term data.

  • Nancy Shamanna said:

    It is interesting to read of the phase 1 study for the AKT inhibitor, afuresitib, and that it shows good response on the patients. The lead investigator, Dr. Voorhees, posts frequently on the Beacon, to help patients with their questions. The study was carried out with other investigators in the US, Canada , Taiwan and Australia.

  • Lennie Bible said:

    What is the tradeoff for someone with myeloma who is a 64 male in good health, who has had initial 4 cycle treatment with Revlimid and Velcade. Then a stem cell transplant and is now on Revlimid maintenance vs not being on any maintenance. I'm having diarrhea every day with it. Can't eat good and have nausea in the morning.