In this morning's session, Dr. Gareth Morgan presented additional results from his trial comparing the bisphosphonates Zometa with Bonefos (clodronate), which was presented at ASCO (see related Beacon news) and showed that Zometa increased overall survival by 5.5 months compared to Bonefos.
The results of this new analysis showed that fewer patients had bone complications when treated with Bonefos, regardless of whether they had any bone lesions at the start of the trial, highlighting the need to treat all patients with bisphosphonate regardless of existing bone disease.
In addition to treatment with bisphosphonate for bone health, patients were treated with or without stem cell transplantation and then either thalidomide maintenance or just observed. The results from this part of the study showed that patients who did not receive a transplant and were treated with CTD (cyclophosphamide, thalidomide, dexamethasone) and Zometa had significantly better anti-myeloma responses than patients who received CTD and Bonefos. Likewise, this same group of patients had the best bone health.
The physicians in attendance asked whether recommendations regarding the use of bisphosphonates for myeloma need to be updated to include administration of Zometa at diagnosis, regardless of bone health, and for longer than the currently recommended 2 years.
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Re: ASH 2010 Multiple Myeloma Discussion - Day 3
Indeed, a lot of people are talking about lenalidomide maintenance and the number of people that are getting additional malignancies. Dr. Attal in his talk mentioned about 4 people that developed other malignancies, the control group had none.
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aliarsan - Name: Ali Arsan
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
The final talk in this morning’s session was given by Dr. Phillipe Moreau. He presented a study comparing IV administration of Velcade (the current approved mode of administration) with subcutaneous administration (which is more convenient because patients can self-administer it at home). If after 3 cycles patients hadn’t achieved at least a partial response, dexamethasone could be added.
Dr. Moreau showed that the median number of cycles of treatment, time on study, percent of patients needing dexamethasone, response, time to response, time to progression, and survival were the same for both modes of administration. The overall response rate was 42% for both arms after 4 cycles of treatment and 52% after 8 cycles. The 1 year survival was 76% for IV administration and 73% for subcutaneous administration. Time-to-progression, although similar, was slightly faster for IV Velcade.
To get into the biology of it, the results showed that IV Velcade is absorbed faster, but total exposure is the same for either mode of administration. Proteasome inhibition was also identical for both modes.
The most significant findings were that the side effects were significantly reduced with subcutaneous Velcade. Severe side effects occurred in 70% of IV patients and 57% of subcutaneous patients. Peripheral neuropathy occurred in 53% of IV patients and 38% percent of subcutaneous patients. Severe neuropathy occurred in 16% and 6% of patients, respectively. Note that pre-existing neuropathy was slightly higher in the IV group, but the difference was not significant. 6% of patients in the subcutaneous group had injection site reactions (1% severe).
Dr. Moreau concluded that subcutaneous Velcade had similar efficacy as IV Velcade but an improved safety profile, especially considering peripheral neuropathy. “In my opinion, these findings are really important for our patients,” said Dr. Moreau. A physician in the audience called the results “fabulous data.” Another physician pointed out that weekly Velcade also causes less neuropathy and asked about the possibility of weekly subcutaneous Velcade, which would be important in the maintenance setting. A clinical trial studying that combination would be very interesting.
Dr. Moreau showed that the median number of cycles of treatment, time on study, percent of patients needing dexamethasone, response, time to response, time to progression, and survival were the same for both modes of administration. The overall response rate was 42% for both arms after 4 cycles of treatment and 52% after 8 cycles. The 1 year survival was 76% for IV administration and 73% for subcutaneous administration. Time-to-progression, although similar, was slightly faster for IV Velcade.
To get into the biology of it, the results showed that IV Velcade is absorbed faster, but total exposure is the same for either mode of administration. Proteasome inhibition was also identical for both modes.
The most significant findings were that the side effects were significantly reduced with subcutaneous Velcade. Severe side effects occurred in 70% of IV patients and 57% of subcutaneous patients. Peripheral neuropathy occurred in 53% of IV patients and 38% percent of subcutaneous patients. Severe neuropathy occurred in 16% and 6% of patients, respectively. Note that pre-existing neuropathy was slightly higher in the IV group, but the difference was not significant. 6% of patients in the subcutaneous group had injection site reactions (1% severe).
Dr. Moreau concluded that subcutaneous Velcade had similar efficacy as IV Velcade but an improved safety profile, especially considering peripheral neuropathy. “In my opinion, these findings are really important for our patients,” said Dr. Moreau. A physician in the audience called the results “fabulous data.” Another physician pointed out that weekly Velcade also causes less neuropathy and asked about the possibility of weekly subcutaneous Velcade, which would be important in the maintenance setting. A clinical trial studying that combination would be very interesting.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
There were some exciting talks in the early afternoon that I wasn't able to attend. For anyone who was able to attend these talks, please feel free to share your observations and opinions of the talks. I'll try to go back and provide some information based on the abstracts.
At the tail end of the afternoon session, Dr. Murielle Roussel presented the results of a Phase 2 study in which patients received VRD (Velcade, Revlimid, dexamethasone) induction followed by stem cell transplant, VRD consolidation, and Revlimid maintenance.
CR+nCR response rates were 23% after induction, 36% after transplant, and 46% after consolidation. The overall response rate after consolidation was 94%.
Almost all patients experienced side effects from this regimen: 97% thrombocytopenia, 87% anemia,87% neutropenia, 68% peripheral neuropathy, 32% rash, as well as some infections and thromboembolism. Severe side effects included neutropenia, thrombocytopenia, and anemia. Peripheral neuropathy led to dose reduction in 23% of patients, but there was no severe neuropathy. Dr. Roussel claimed that the side effects were manageable.
All except for one patient were able to collect enough stem cells for transplantation after induction therapy.
Dr. Roussel concluded that this regimen is highly effective and that RVD is being used in a clinical trial comparing the use of transplant upfront as compared to novel agents.
At the tail end of the afternoon session, Dr. Murielle Roussel presented the results of a Phase 2 study in which patients received VRD (Velcade, Revlimid, dexamethasone) induction followed by stem cell transplant, VRD consolidation, and Revlimid maintenance.
CR+nCR response rates were 23% after induction, 36% after transplant, and 46% after consolidation. The overall response rate after consolidation was 94%.
Almost all patients experienced side effects from this regimen: 97% thrombocytopenia, 87% anemia,87% neutropenia, 68% peripheral neuropathy, 32% rash, as well as some infections and thromboembolism. Severe side effects included neutropenia, thrombocytopenia, and anemia. Peripheral neuropathy led to dose reduction in 23% of patients, but there was no severe neuropathy. Dr. Roussel claimed that the side effects were manageable.
All except for one patient were able to collect enough stem cells for transplantation after induction therapy.
Dr. Roussel concluded that this regimen is highly effective and that RVD is being used in a clinical trial comparing the use of transplant upfront as compared to novel agents.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
Tonight’s evening session and tomorrow’s morning session cover treatments under development. There has been and will be a lot of talk about carfilzomib and pomalidomide during these sessions.
The first presentation of the evening was made by Dr. Xavier Leleu. He presented a study comparing two different dosing schedules for pomalidomide in combination with low-dose dexamethasone.
Half of the patients received 4 mg pomalidomide daily 21 out of a 28 day cycle as well as low-dose dexamethasone. The other half of the patients received 4 mg pomalidomide daily 28 out of 28 days as well as low-dose dexamethasone. In both groups, treatment was continued until progression.
The study was made up of heavily pre-treated patients with a median of 4 prior lines of therapy. All patients were resistant to Revlimid and Velcade therapy, and about 50% had received thalidomide previously.
Response rates were 42% for the 21/28 day regimen and 39% for the continuous regimen, with most responses partial responses. There were no stringent CRs and very few CRs. Time to best response was 2 and 1.7 months, respectively, and the median number of cycles was 5 for both groups.
With a median follow-up of 6.5 months, time to progression was predicted to be 7 months for the first group, and 9.7 months for the second. But these were considered to be similar.
6 month overall survival was 88% for the first group and 85% for the second group, which Dr. Leleu said was “absolutely remarkable.”
Severe side effects were low, with the most common being neutropenia, which occurred in 34% of patients. No patients had worsening of peripheral neuropathy, and there were no blood clots.
49% of patients in the first group require a dose reduction, and 41% in the second group did as well. However, many of them were able to go back to higher doses. 12% and 7% of patients in the two arms discontinued therapy.
Dr. Leleu suggested that they would probably go forward with 21/28 day dosing since efficacy was the same in the two groups, but treatment 3 out of 4 weeks would cause fewer side effects and be more convenient. A physician in the audience suggested they try administering pomalidomide 14 out of 28 days to see if it was as effective.
There was a lot of interest from the audience regarding this study, with one physician commenting, “These are very positive results.”
The first presentation of the evening was made by Dr. Xavier Leleu. He presented a study comparing two different dosing schedules for pomalidomide in combination with low-dose dexamethasone.
Half of the patients received 4 mg pomalidomide daily 21 out of a 28 day cycle as well as low-dose dexamethasone. The other half of the patients received 4 mg pomalidomide daily 28 out of 28 days as well as low-dose dexamethasone. In both groups, treatment was continued until progression.
The study was made up of heavily pre-treated patients with a median of 4 prior lines of therapy. All patients were resistant to Revlimid and Velcade therapy, and about 50% had received thalidomide previously.
Response rates were 42% for the 21/28 day regimen and 39% for the continuous regimen, with most responses partial responses. There were no stringent CRs and very few CRs. Time to best response was 2 and 1.7 months, respectively, and the median number of cycles was 5 for both groups.
With a median follow-up of 6.5 months, time to progression was predicted to be 7 months for the first group, and 9.7 months for the second. But these were considered to be similar.
6 month overall survival was 88% for the first group and 85% for the second group, which Dr. Leleu said was “absolutely remarkable.”
Severe side effects were low, with the most common being neutropenia, which occurred in 34% of patients. No patients had worsening of peripheral neuropathy, and there were no blood clots.
49% of patients in the first group require a dose reduction, and 41% in the second group did as well. However, many of them were able to go back to higher doses. 12% and 7% of patients in the two arms discontinued therapy.
Dr. Leleu suggested that they would probably go forward with 21/28 day dosing since efficacy was the same in the two groups, but treatment 3 out of 4 weeks would cause fewer side effects and be more convenient. A physician in the audience suggested they try administering pomalidomide 14 out of 28 days to see if it was as effective.
There was a lot of interest from the audience regarding this study, with one physician commenting, “These are very positive results.”
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
Dr. Niesvizky gave the next talk about a new treatment under development called PD 0332991 (or just PD for short). PD is a selective, reversible, oral inhibitor of cyclin-dependent kinases 4 and 6.
In this Phase 1 dose escalation study, PD was given in combination with Velcade and dexamethasone. Half of the patients received PD daily for 21 out of 28 days; the other half received PD daily for 12 out of 28 days.
2 patients, one in each dosing schedule group achieved a VGPR.
Side effects were mainly myelosuppression (low blood cell counts), which is a known side effect of PD and Velcade.
A Phase 2 trial is underway using the dose limiting toxicity from this study: 100 mg PD, 1.0 mg/m2 Velcade, 20 mg dexamethasone. 10 patients have been enrolled, and 2 have achieved PR.
A physician in the audience asked whether the group was going to try testing PD for single-agent activity. Dr. Niesvizky said they decided to go with the combination therapy because in mice it showed the combination was much more efficacious. The physician replied that presumably the path to approval for PD would be really difficult if they can’t show single-agent activity.
In this Phase 1 dose escalation study, PD was given in combination with Velcade and dexamethasone. Half of the patients received PD daily for 21 out of 28 days; the other half received PD daily for 12 out of 28 days.
2 patients, one in each dosing schedule group achieved a VGPR.
Side effects were mainly myelosuppression (low blood cell counts), which is a known side effect of PD and Velcade.
A Phase 2 trial is underway using the dose limiting toxicity from this study: 100 mg PD, 1.0 mg/m2 Velcade, 20 mg dexamethasone. 10 patients have been enrolled, and 2 have achieved PR.
A physician in the audience asked whether the group was going to try testing PD for single-agent activity. Dr. Niesvizky said they decided to go with the combination therapy because in mice it showed the combination was much more efficacious. The physician replied that presumably the path to approval for PD would be really difficult if they can’t show single-agent activity.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
Dr. Carolina Terragna presented an analysis of a study comparing VTD and TD induction followed by transplantation, consolidation therapy with the same agents as the induction therapy, followed by maintenance with dexamethasone.
The findings of this main study were presented by Dr. Michele Cavo yesterday (see the summary of Dr. Cavo’s presentation). In particular, VTD had a higher CR+nCR rate (62%) than TD (45%).
Dr. Terragna’s substudy analysis focused on molecular remission after the consolidation phase of the study. Molecular remission was determined as the absence of minimal residual disease using a very sensitive test called PCR.
In the TD arm, 38% of patients achieved a molecular complete response (MCR). In the VTD arm, 45% achieved MCR. PFS of those who achieved MCR was better than those who did not achieve this level of remission: 3 year PFS was 90% for those achieving MCR compared to 47% for the rest.
Likewise, VTD reduced the tumor load more than TD, and those who experienced a reduction in tumor load also had a better PFS.
The findings of this main study were presented by Dr. Michele Cavo yesterday (see the summary of Dr. Cavo’s presentation). In particular, VTD had a higher CR+nCR rate (62%) than TD (45%).
Dr. Terragna’s substudy analysis focused on molecular remission after the consolidation phase of the study. Molecular remission was determined as the absence of minimal residual disease using a very sensitive test called PCR.
In the TD arm, 38% of patients achieved a molecular complete response (MCR). In the VTD arm, 45% achieved MCR. PFS of those who achieved MCR was better than those who did not achieve this level of remission: 3 year PFS was 90% for those achieving MCR compared to 47% for the rest.
Likewise, VTD reduced the tumor load more than TD, and those who experienced a reduction in tumor load also had a better PFS.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
Next, Dr. Andrzej Jakubowiak presented results from a study of carfilzomib in combination with Revlimid and low dose dexamethasone in newly diagnosed myeloma patients. Due to such positive findings with RVD, Dr. Jakubowiak’s group decided to study CRd to try to reduce the occurrence of peripheral neuropathy.
CRd was given for 4 cycles, then patients could undergo a transplant if they were eligible, which was followed by CRd consolidation for 4 cycles, and CRd maintenance with the frequency of carfilzomib reduced to once per month.
A dose as high as 36 mg/m2 carfilzomib was well tolerated. Side effects were mostly mild with relatively infrequent neutropenia and peripheral neuropathy in about 10 percent of patients. No patients had severe neuropathy, and dose modifications were infrequent.
After 8 cycles of CRd, 67% achieved CR/nCR, 83% > VGPR, and 100% > PR.
CRd did not have a negative impact on stem cell collection. All patients were able to collect enough cells.
No patients progressed, and all were alive at 6 months.
Dr. Jakubowiak concluded that CRd was highly active and gave rapid and deep responses.
A Phase 3 trial is comparing CRd with Rd in relapsed myeloma patients. Other carfilzomib combinations are going on as well.
This study received lots of praise from the physicians in the audience: “These are unprecedented CR rates, and this is very promising.” “Wonderful data.” “Very encouraging indeed.”
CRd was given for 4 cycles, then patients could undergo a transplant if they were eligible, which was followed by CRd consolidation for 4 cycles, and CRd maintenance with the frequency of carfilzomib reduced to once per month.
A dose as high as 36 mg/m2 carfilzomib was well tolerated. Side effects were mostly mild with relatively infrequent neutropenia and peripheral neuropathy in about 10 percent of patients. No patients had severe neuropathy, and dose modifications were infrequent.
After 8 cycles of CRd, 67% achieved CR/nCR, 83% > VGPR, and 100% > PR.
CRd did not have a negative impact on stem cell collection. All patients were able to collect enough cells.
No patients progressed, and all were alive at 6 months.
Dr. Jakubowiak concluded that CRd was highly active and gave rapid and deep responses.
A Phase 3 trial is comparing CRd with Rd in relapsed myeloma patients. Other carfilzomib combinations are going on as well.
This study received lots of praise from the physicians in the audience: “These are unprecedented CR rates, and this is very promising.” “Wonderful data.” “Very encouraging indeed.”
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
The last two talks of the evening were also about pomalidomide. Dr. Martha Lacy presented results from two studies comparing two different doses of pomalidomide (2 mg or 4 mg daily) in combination with 40 mg dexamethasone. The 2 mg results were presented at ASCO this summer.
All patients in the studies were refractory to Revlimid and Velcade, and almost 60% of the patients were high risk. Participants had received a median of 6 previous therapies.
26% of patients in both groups achieved at least a PR. 49% of the 2 mg group and 40% of the 4 mg group achieved at least an MR, but the difference was probably not significant. In high risk patients, 33% achieved at least a MR.
Time to response was 1 and 1.7 months for the two groups. Duration of response was 12 months for the 2 mg group.
Median follow-up time was 9 months for the 2 mg study and 5 months for the 4 mg study. 71% of patients were still alive at the time of analysis. 17% and 29% of the two study groups are still on treatment. Discontinuation was mostly due to progression, and some stopped due to side effects in the 4 mg group.
Overall survival at 6 months was 78% and 69% for the 2 and 4 mg groups.
Among the hematological side effects, neutropenia was the most common (49% for the 2 mg group and 66% for the 4 mg group). Among the non-hematological side effects, the most common were fatigue, peripheral neuropathy, and infection complications. 70% of participants had neuropathy before the trial started. Neuropathy possibly due to pomalidomide occurred in 20% of the 2 mg group and 29% of the 4 mg group.
All patients in the studies were refractory to Revlimid and Velcade, and almost 60% of the patients were high risk. Participants had received a median of 6 previous therapies.
26% of patients in both groups achieved at least a PR. 49% of the 2 mg group and 40% of the 4 mg group achieved at least an MR, but the difference was probably not significant. In high risk patients, 33% achieved at least a MR.
Time to response was 1 and 1.7 months for the two groups. Duration of response was 12 months for the 2 mg group.
Median follow-up time was 9 months for the 2 mg study and 5 months for the 4 mg study. 71% of patients were still alive at the time of analysis. 17% and 29% of the two study groups are still on treatment. Discontinuation was mostly due to progression, and some stopped due to side effects in the 4 mg group.
Overall survival at 6 months was 78% and 69% for the 2 and 4 mg groups.
Among the hematological side effects, neutropenia was the most common (49% for the 2 mg group and 66% for the 4 mg group). Among the non-hematological side effects, the most common were fatigue, peripheral neuropathy, and infection complications. 70% of participants had neuropathy before the trial started. Neuropathy possibly due to pomalidomide occurred in 20% of the 2 mg group and 29% of the 4 mg group.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASH 2010 Multiple Myeloma Discussion - Day 3
The last talk of the night was given by Dr. Paul Richardson. He spoke about a Phase 1/2 dose escalation study of pomalidomide. In Phase 1 of the trial, pomalidomide was tested at doses of 2, 3, 4, or 5 mg daily for 21/28 days. 40 mg/week dexamethasone could be added after 4 cycles if patients did not respond to pomalidomide alone.
All patients were relapsed/refractory and had to have received prior treatment with Revlimid and Velcade. The median number of prior therapies for the group turned out to be 6.
There was no treatment-related mortality. Myelosuppression dominated the side effects. Peripheral neuropathy was relatively low. 4 mg was selected as the maximum tolerated dose and used in Phase 2 of the study.
This phase showed that higher doses caused better responses. 25% achieved at least a partial response, and 50% achieved at least a minimal response.
In Phase 2, half of the participants received 4 mg pomalidomide plus dexamethasone, and the other half received 4 mg pomalidomide alone, but could add dexamethasone if they did not respond to pomalidomide alone. 221 patients have been enrolled. Data from the first 120 patients were reported.
Like Phase 1, patients had to be relapsed/refractory and received both Revlimid and Velcade before. The median number of prior therapies was 5. About 75% had received prior thalidomide, and 75% had also received a stem cell transplant.
Combining the two arms of the study, 25% achieved at least a partial response.
Once again, the main side effect was myelomasuppression, but Dr. Richardson said it was manageable. Peripheral neuropathy was low, with no severe neuropathy.
Dr. Richardson concluded that pomalidomide is promising in heavily treated myeloma patients and that responses appear to be durable and meaningful. He said that further steps would be to explore doses in less heavily treated patients and to look at pomalidomide in other combinations.
All patients were relapsed/refractory and had to have received prior treatment with Revlimid and Velcade. The median number of prior therapies for the group turned out to be 6.
There was no treatment-related mortality. Myelosuppression dominated the side effects. Peripheral neuropathy was relatively low. 4 mg was selected as the maximum tolerated dose and used in Phase 2 of the study.
This phase showed that higher doses caused better responses. 25% achieved at least a partial response, and 50% achieved at least a minimal response.
In Phase 2, half of the participants received 4 mg pomalidomide plus dexamethasone, and the other half received 4 mg pomalidomide alone, but could add dexamethasone if they did not respond to pomalidomide alone. 221 patients have been enrolled. Data from the first 120 patients were reported.
Like Phase 1, patients had to be relapsed/refractory and received both Revlimid and Velcade before. The median number of prior therapies was 5. About 75% had received prior thalidomide, and 75% had also received a stem cell transplant.
Combining the two arms of the study, 25% achieved at least a partial response.
Once again, the main side effect was myelomasuppression, but Dr. Richardson said it was manageable. Peripheral neuropathy was low, with no severe neuropathy.
Dr. Richardson concluded that pomalidomide is promising in heavily treated myeloma patients and that responses appear to be durable and meaningful. He said that further steps would be to explore doses in less heavily treated patients and to look at pomalidomide in other combinations.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
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