ASCO 2013 Multiple Myeloma Update – Day Four: Oral Presentations
Published: Jun 5, 2013 7:43 am; Updated: Jun 12, 2013 12:30 pm
This year’s annual meeting of the American Society of Clinical Oncology (ASCO) came to an end yesterday in Chicago.
Monday was the busiest day with regard to myeloma-related research. The day started with an oral presentation session that included eight 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 content in our 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 will be updated regularly 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.
During the morning’s oral presentation session, Dr. Henk Lokhorst from UMC Utrecht in the Netherlands reported results from the Phase 1 portion of a Phase 1/2 study of daratumumab in relapsed and refractory multiple myeloma patients (abstract; presentation [pdf] courtesy of Dr. Lokhorst).
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 siltuximab, that signals the immune system to kill myeloma cells.
The Phase 1 portion of this study included 32 relapsed and refractory myeloma patients who had been treated with a median of six prior lines of therapy. The Phase 2 portion of the study has thus far enrolled seven patients.
During Phase 1 of the study, patients received varying doses of daratumumab, ranging from 0.005 mg/kg up to 24 mg/kg.
Of the 12 patients who were treated with 4 mg/kg or more of daratumumab, 42 percent responded, and all these responses were partial responses. Another 25 percent achieved a minimal response.
The median progression-free survival for this subset of patients has not yet been reached after a median follow-up of 18.4 weeks.
During Phase 1 of the study, 44 percent of patients experienced mild to severe infusion-related side effects.
Patients enrolled in Phase 2 of the study are currently being treated with the maximum tolerated dose from Phase 1 of the study: 8 mg/kg of daratumumab.
The daratumumab trial results were reviewed by Dr. Saad Usmani from the University of Arkansas for Medical Science in a presentation that also took place during the morning session (presentation [pdf] courtesy of Dr. Usmani).
Dr. Usmani described the results as encouraging, especially since the patient population was highly refractory. He described the side effects as similar to those observed with other monoclonal antibodies.
Going forward, he would like to see clinical and biological features of the patients reported because he feels that this information will be critical to identifying which patients will benefit the most from daratumumab.
Dr. Shaji Kumar from the Mayo Clinic discussed results from a Phase 1 study of single-agent ixazomib (MLN9708) in relapsed and refractory multiple myeloma patients after enrollment for the trial was completed (abstract; presentation [pdf] courtesy of Dr. Kumar).
Ixazomib is an orally administered proteasome inhibitor, in the same class of drugs as Velcade (bortezomib); it is being developed by Millennium Pharmaceuticals, the same company that developed and markets Velcade.
Previous studies have demonstrated that ixazomib may be effective in both newly diagnosed and relapsed and refractory myeloma.
The study included 60 relapsed and refractory patients with a median age of 64 years. The patients had been treated with a median of four prior regimens, including Velcade (85 percent), Revlimid (lenalidomide) (97 percent), thalidomide (Thalomid) (53 percent), and Kyprolis (carfilzomib) (15 percent).
The median time from diagnosis was 4.9 years, and 72 percent of the patients were refractory to their last regimen.
So far, patients have received a median of two cycles of treatment, and 5 percent remain on treatment.
Of the 50 patients evaluable for response, 18 percent responded, with 2 percent achieving a very good partial response and 16 percent a partial response. Rates of progression-free and overall survival are not available at this time.
According to Dr. Kumar, ixazomib is fairly well tolerated and the side effects are in line with those of other drugs in the same category.
Common severe side effects included low platelet counts (33 percent), diarrhea (17 percent), low white blood cell counts (16 percent), fatigue (8 percent), decreased appetite (7 percent), and nausea (7 percent). In addition, 18 percent of patients experienced mild to moderate drug-related peripheral neuropathy.
Overall, 32 percent of patients required dose reductions and 12 percent discontinued treatment due to side effects.
The results of the ixazomib trial also were discussed by Dr. Usmani during his review presentation.
Dr. Usmani said that ixazomib showed good single-agent activity in relapsed and refractory patients. However, he pointed out the there was only a small fraction of patients with high-risk chromosomal abnormalities included in the study.
He also was concerned about the fact that patients with existing moderate or severe peripheral neuropathy were excluded from the study. He thinks that the exclusion will call into question somewhat the applicability of the results of the Phase 2 expansion of the trial, because one third of Velcade-exposed patients have moderate or severe peripheral neuropathy.
Pomalyst Plus Low-Dose Dexamethasone Versus High-Dose Dexamethasone Alone
Dr. Katja Weisel from the University Hospital in Tübingen, Germany, presented updated results from a Phase 3 study comparing the efficacy and safety of Pomalyst (pomalidomide) in combination with low-dose dexamethasone (Decadron) versus treatment with only high-dose dexamethasone (abstract; presentation [pdf] courtesy of Dr. Weisel).
Pomalyst is an immunomodulatory agent in the same class of drugs as Revlimid and thalidomide. It works by inducing a patient's immune system to target and destroy myeloma cells.
Interim results of the Phase 3 trial had shown that Pomalyst plus low-dose dexamethasone increases progression-free survival compared to high-dose dexamethasone. Based on these findings, the independent review board recommended that patients on high-dose dexamethasone should have access to Pomalyst as well; 50 percent of patients received Pomalyst.
At ASCO, Dr. Weisel presented the results of the updated survival analysis.
The study included 455 relapsed and refractory multiple myeloma patients with a median age of 64 years. They had received a median of five prior lines of therapy, and 74 percent of the patients were refractory to both Revlimid and Velcade.
The updated survival analysis showed that after a median follow-up of 10 months, the overall response rate for patients who were treated with Pomalyst plus low-dose dexamethasone was 31 percent, with 1 percent achieving a complete response, 5 percent a very good partial response, and 26 percent a partial response. In comparison,10 percent of patients who received high-dose dexamethasone responded, with 1 percent achieving a very good partial response and 9 percent a partial response.
Patients who received Pomalyst plus low-dose dexamethasone had a median progression-free survival of 4 months, versus 1.9 months for those who received high-dose dexamethasone alone.
The median overall survival for patients given Pomalyst plus low-dose dexamethasone was 12.7 months, compared to 8.1 months for patients who were treated with high-dose dexamethasone.
Dr. Weisel pointed out the survival benefit was maintained, despite the fact that 50 percent of patients from the high-dose dexamethasone treatment group crossed over to the Pomalyst plus low-dose dexamethasone treatment group.
For patients who received Pomalyst plus low-dose dexamethasone versus high-dose dexamethasone alone, the most common severe to life-threatening side effects included low white blood cell counts (42 percent versus 15 percent), anemia (27 percent versus 29 percent), and infection (24 percent versus 23 percent).
Kyprolis Plus Melphalan And Prednisone
Later in the session, Dr. Cyrille Touzeau from the University Hospital in Nantes, France, presented results from a Phase 1/2 study of Kyprolis plus melphalan (Alkeran) and prednisone in newly diagnosed myeloma patients over the age of 65 (abstract; presentation [PDF] courtesy of Dr. Touzeau).
Kyprolis is a proteasome inhibitor in the same class of drugs as Velcade and ixazomib (MLN9708).
Phase 1 of the study included 24 newly diagnosed multiple myeloma patients over the age of 65 years.
Patients in this study received escalating doses of Kyprolis, between 20 mg/m2 and 45 mg/m2, plus melphalan and prednisone to determine the maximum tolerated dose of Kyprolis when used in this combination. The dosing of Kyprolis approved by the U.S. Food and Drug Administration is no more than 27 mg/m2 per administration.
Two patients treated with 45 mg/m2 of Kyprolis experienced dose-limiting toxicities. Thus, the maximum tolerated dose was determined to be 36 mg/m2.
In Phase 2 of the study, 44 additional newly diagnosed elderly patients were enrolled and treated with 36 mg/m2 of Kyprolis in combination with melphalan and prednisone. Overall, the patients from both phases of the study had a median age of 72 years.
The median follow-up time was 12 months.
Of the 68 patients from both phases of the study who were evaluated for response, 91 percent responded to treatment, including 6 percent who achieved a complete response, 50 percent a very good partial response, and 35 percent a partial response.
At a median follow-up of 12 months, the median progression-free survival was 22 months, and the estimated 2-year overall survival rate was 87 percent.
The most common side effects of Kyprolis plus melphalan and prednisone were low red blood cell counts (54 percent), infections (52 percent), and fatigue (40 percent). In addition, 43 percent experienced heart-related complications and 6 percent of patients experienced moderate to severe peripheral neuropathy.
Overall, 11 percent of patients discontinued treatment due to side effects.
In his review of these results, Dr. Usmani said that he was very encouraged by the high response rates of the combination. However, he added that he is concerned about the high rate of heart-related side effects observed in this trial because elderly patients frequently already have heart disease.
Nevertheless, he feels this combination is a good treatment option for transplant-ineligible, newly-diagnosed myeloma patients.
Melphalan-Prednisone-Revlimid Versus Tandem Transplantation
Dr. Antonio Palumbo from the University of Torino in Italy reported results from a study comparing a combination regimen of melphalan (Alkeran), prednisone, and Revlimid (lenalidomide) (MPR) with tandem stem cell transplantation. This study also examined the effect of Revlimid maintenance therapy following either of these treatment regimens (abstract; presentation [pdf] courtesy of Dr. Palumbo).
The study included 402 newly diagnosed multiple myeloma patients with a median age 58 years.
All patients in the study first received four 28-day cycles of Revlimid combined with low-dose dexamethasone.
Next, the patients were randomly assigned to one of four groups. Two of the groups received six cycles of MPR. One of these two groups also received Revlimid maintenance therapy after their MPR therapy ended, while the other received no further treatment.
The other two groups received tandem stem cell transplants. Once again, one of these two groups also received Revlimid maintenance therapy after the transplants, while the other received no further treatment.
Response rates after MPR or transplantation were not reported during the presentation.
However, among patients who received Revlimid maintenance therapy, the overall response rate was 78 percent, with 23 percent achieving a complete response, 25 percent a very good partial response, and 30 percent a partial response.
Similarly, the overall response rate for patients who did not receive Revlimid maintenance was 77 percent, with 19 percent achieving a complete response, 29 percent a very good partial response, and 29 percent a partial response.
After a median follow-up of 45 months, the median progression-free survival was 24 months for patients treated with MPR, compared to 38 months for patients who underwent tandem transplantation.
The median progression-free survival for patients who received Revlimid maintenance therapy was 37 months, versus 26 months for patients who did not receive maintenance therapy.
The five-year overall survival rate from the time of diagnosis was 62 percent for patients treated with MPR, 71 percent for patients who underwent tandem transplantation, 75 percent for patients who received Revlimid maintenance therapy, and 58 percent for patients who received no maintenance therapy.
The trial results were reviewed by Dr. Sagar Lonial from the Winship Cancer Institute at Emory University in another review presentation (pdf, courtesy of Dr. Lonial).
According to Dr. Lonial, the current findings show the clear benefit of high-dose chemotherapy plus stem cell transplantation as well as maintenance therapy.
Dr. Lonial also pointed out that Dr. Palumbo’s findings suggest that overall response rates as defined today cannot be used as the best way to assess the long-term benefit of a therapy, given that response rates were similar for those who did and did not receive Revlimid maintenance therapy, but progression-free and overall survival were so different between the two treatment groups. In his opinion, progression-free and overall survival are currently the two factors that best define the long-term benefit of a treatment.
Dr. Palumbo also reported results from a meta-analysis investigating the relationship between treatment with Revlimid and the likelihood of developing a secondary cancer (abstract; presentation [pdf] courtesy of Dr. Palumbo).
Previous research has shown that patients taking Revlimid maintenance therapy may be more likely to develop a secondary cancer than patients who do not receive Revlimid maintenance therapy (see related Beacon news articles).
In the current analysis, the researchers retrospectively evaluated data from 6,383 myeloma patients who participated in randomized clinical trials. Some were treated with Revlimid, while others were not. The patients had a median age of 69 years.
After a median follow-up of 30 months, 6.6 percent of patients developed secondary cancers. This included 2.9 percent who developed blood cancers and 3.6 percent who developed solid tumors.
Solid tumors were similarly common among patients treated with and without Revlimid.
However, the frequency of blood cancers was significantly higher in patients treated with Revlimid. The investigators found, though, that this increased risk was limited to patients treated with Revlimid in combination with melphalan.
In a review presentation that was also part of the morning session, Dr. Jonathan Kaufman from the Winship Cancer Institute at Emory University said that, despite the increased risk of second cancers in patients treated with Revlimid and melphalan, he still feels that Revlimid’s benefits continue to outweigh its risks in the post-transplant setting. Thus, he will continue to discuss the benefits and risks of Revlimid maintenance therapy with his relevant patients.
───────────────── ♦ ─────────────────
Myeloma presentations from the rest of Day 4 will also be summarized in a Beacon ASCO daily update to be published later today. Additional coverage of key research results from the meeting will continue after that with individual, topic-specific news articles. For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2013 coverage.
Note: Electronic copies of conference presentations and posters made available to the Beacon's readers are for personal use only. Further transmission or publication of the files is not permitted, although hyperlinks to the files are permitted with attribution to the author and to The Beacon (for example, "courtesy of Dr. Jane Doe and The Myeloma Beacon.")
- ASCO 2013 Multiple Myeloma Update – Day Four: Poster Presentations
- ASCO 2012 Multiple Myeloma Update – Day Two: Poster Session
- ASCO 2013 Multiple Myeloma Update – Day Three: Poster Presentations
- ASH 2013 Multiple Myeloma Update - Day Three: Afternoon Oral Sessions
- ASH 2012 Multiple Myeloma Update – Day Three: Late Afternoon Oral Session