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Ixazomib/lenalidomide maintenance promising after ASCT in MM
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology. 
* Data in the presentation differ slightly from the abstract.
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology.
* Data in the presentation differ slightly from the abstract.
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology.
* Data in the presentation differ slightly from the abstract.
Carfilzomib poses higher risk of CVAEs, review suggests
Treatment with the proteasome inhibitor carfilzomib is associated with a “significant incidence” of cardiovascular adverse events (CVAEs) in patients with multiple myeloma (MM), according to researchers.
An analysis of 24 studies showed that 18% of MM patients receiving carfilzomib had CVAEs, and 8% had grade 3 or higher CVAEs.
The relative risk of CVAEs (all-grade or high-grade) was higher among patients who received carfilzomib than among those who did not.
These findings were published in JAMA Oncology.
The researchers gathered data from 24 studies reported from 2007 through 2017. The studies included 2594 MM patients.
The team looked at the incidence of CVAEs, which included heart failure, hypertension, ischemia, and arrhythmia.
The data showed that 18.1% of patients who took carfilzomib experienced CVAEs, and 8.2% of the patients had grade 3 or higher CVAEs.
For comparison, a similar review of bortezomib showed that 3.8% of patients experienced CVAEs, and 2.3% of patients had high-grade CVAEs.
Among the carfilzomib-treated patients, the most common CVAE was hypertension (12.2%), followed by heart failure (4.1%), arrhythmias (2.4%), and ischemic events (1.8%).
Higher doses of carfilzomib were associated with higher rates of high-grade CVAEs. The incidence of high-grade CVAEs was 6.4% in patients who received carfilzomib doses below 45 mg/m2 and 11.9% in patients who received the drug at doses of 45 mg/m2 or higher (P=0.02).
The researchers also compared CVAE rates in carfilzomib-treated patients and non-carfilzomib-treated patients enrolled in a trio of phase 3, randomized trials:
- ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)
- ENDEAVOR (carfilzomib and dexamethasone vs bortezomib and dexamethasone)
- FOCUS (carfilzomib and dexamethasone vs dexamethasone with or without cyclophosphamide).
The relative risk of all-grade CVAEs was 1.8 for carfilzomib-treated patients vs controls (P<0.001), and the relative risk of grade 3 or higher CVAEs was 2.2 (P<0.001).
“Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event,” said study author Adam J. Waxman, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly.”
Dr Waxman and his colleagues also called for further clinical trials to evaluate the association between carfilzomib and CVAEs, arguing that it may be underrepresented by current data.
“If you’re not specifically looking for this, you might report it differently,” Dr Waxman said.
This research was supported by the National Institutes of Health (T32-GM075766).
Treatment with the proteasome inhibitor carfilzomib is associated with a “significant incidence” of cardiovascular adverse events (CVAEs) in patients with multiple myeloma (MM), according to researchers.
An analysis of 24 studies showed that 18% of MM patients receiving carfilzomib had CVAEs, and 8% had grade 3 or higher CVAEs.
The relative risk of CVAEs (all-grade or high-grade) was higher among patients who received carfilzomib than among those who did not.
These findings were published in JAMA Oncology.
The researchers gathered data from 24 studies reported from 2007 through 2017. The studies included 2594 MM patients.
The team looked at the incidence of CVAEs, which included heart failure, hypertension, ischemia, and arrhythmia.
The data showed that 18.1% of patients who took carfilzomib experienced CVAEs, and 8.2% of the patients had grade 3 or higher CVAEs.
For comparison, a similar review of bortezomib showed that 3.8% of patients experienced CVAEs, and 2.3% of patients had high-grade CVAEs.
Among the carfilzomib-treated patients, the most common CVAE was hypertension (12.2%), followed by heart failure (4.1%), arrhythmias (2.4%), and ischemic events (1.8%).
Higher doses of carfilzomib were associated with higher rates of high-grade CVAEs. The incidence of high-grade CVAEs was 6.4% in patients who received carfilzomib doses below 45 mg/m2 and 11.9% in patients who received the drug at doses of 45 mg/m2 or higher (P=0.02).
The researchers also compared CVAE rates in carfilzomib-treated patients and non-carfilzomib-treated patients enrolled in a trio of phase 3, randomized trials:
- ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)
- ENDEAVOR (carfilzomib and dexamethasone vs bortezomib and dexamethasone)
- FOCUS (carfilzomib and dexamethasone vs dexamethasone with or without cyclophosphamide).
The relative risk of all-grade CVAEs was 1.8 for carfilzomib-treated patients vs controls (P<0.001), and the relative risk of grade 3 or higher CVAEs was 2.2 (P<0.001).
“Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event,” said study author Adam J. Waxman, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly.”
Dr Waxman and his colleagues also called for further clinical trials to evaluate the association between carfilzomib and CVAEs, arguing that it may be underrepresented by current data.
“If you’re not specifically looking for this, you might report it differently,” Dr Waxman said.
This research was supported by the National Institutes of Health (T32-GM075766).
Treatment with the proteasome inhibitor carfilzomib is associated with a “significant incidence” of cardiovascular adverse events (CVAEs) in patients with multiple myeloma (MM), according to researchers.
An analysis of 24 studies showed that 18% of MM patients receiving carfilzomib had CVAEs, and 8% had grade 3 or higher CVAEs.
The relative risk of CVAEs (all-grade or high-grade) was higher among patients who received carfilzomib than among those who did not.
These findings were published in JAMA Oncology.
The researchers gathered data from 24 studies reported from 2007 through 2017. The studies included 2594 MM patients.
The team looked at the incidence of CVAEs, which included heart failure, hypertension, ischemia, and arrhythmia.
The data showed that 18.1% of patients who took carfilzomib experienced CVAEs, and 8.2% of the patients had grade 3 or higher CVAEs.
For comparison, a similar review of bortezomib showed that 3.8% of patients experienced CVAEs, and 2.3% of patients had high-grade CVAEs.
Among the carfilzomib-treated patients, the most common CVAE was hypertension (12.2%), followed by heart failure (4.1%), arrhythmias (2.4%), and ischemic events (1.8%).
Higher doses of carfilzomib were associated with higher rates of high-grade CVAEs. The incidence of high-grade CVAEs was 6.4% in patients who received carfilzomib doses below 45 mg/m2 and 11.9% in patients who received the drug at doses of 45 mg/m2 or higher (P=0.02).
The researchers also compared CVAE rates in carfilzomib-treated patients and non-carfilzomib-treated patients enrolled in a trio of phase 3, randomized trials:
- ASPIRE (carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone)
- ENDEAVOR (carfilzomib and dexamethasone vs bortezomib and dexamethasone)
- FOCUS (carfilzomib and dexamethasone vs dexamethasone with or without cyclophosphamide).
The relative risk of all-grade CVAEs was 1.8 for carfilzomib-treated patients vs controls (P<0.001), and the relative risk of grade 3 or higher CVAEs was 2.2 (P<0.001).
“Taken together, these findings argue that carfilzomib is responsible for an elevated risk, and anyone who is treating patients with this drug needs to be aware that this is a common event,” said study author Adam J. Waxman, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“Clinicians should be paying attention to who may be at highest risk for these events so they can tailor their therapy accordingly.”
Dr Waxman and his colleagues also called for further clinical trials to evaluate the association between carfilzomib and CVAEs, arguing that it may be underrepresented by current data.
“If you’re not specifically looking for this, you might report it differently,” Dr Waxman said.
This research was supported by the National Institutes of Health (T32-GM075766).
Study highlights need for induction strategy in elderly, frail MM patients
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
ATLANTA—Initial results of the phase 2 HOVON-126 trial in newly diagnosed multiple myeloma (MM) patients have highlighted the need for an induction strategy in elderly and frail patients.
The trial showed high overall response rates (ORRs) after induction with ixazomib, thalidomide, and low-dose dexamethasone.
However, 62% of patients older than 75 and 60% of frail patients discontinued therapy prior to starting maintenance.
HOVON-126 was designed to determine the ORR of induction therapy with ixazomib, thalidomide, and dexamethasone but also compare progression-free survival in patients who received ixazomib maintenance and those who received placebo.
Sonja Zweegman, MD, of VUmc in Amsterdam, The Netherlands, presented induction results from HOVON-126 at the 2017 ASH Annual Meeting (abstract 433).
The study was supported by Takeda and the Dutch Cancer Society. Dr Zweegman disclosed research funding from, and advisory board participation for, Takeda.
Study design
Investigators enrolled patients with previously untreated, symptomatic MM who were not eligible for stem cell transplant. Patients had to have measurable disease and a WHO performance status of 0 to 3 for patients younger than 75 and 0 to 2 for patients 75 or older.
Patients were not eligible if they had grade 3 neuropathy or grade 2 with pain. They were also ineligible if their creatinine clearance was less than 30 mL/minute.
All patients received ixazomib at 4 mg on days 1, 8, and 15; thalidomide at 100 mg on days 1 to 28; and dexamethasone at 40 mg on days 1, 8, 15, and 22 for nine 28-day cycles.
They could then be randomized to ixazomib maintenance (on the aforementioned schedule) or placebo for 28-day cycles until progression.
Investigators performed subgroup analyses based on cytogenetic risk and frailty.
They defined frailty according to the modified IMWG frailty index, which takes into account age, the Charlson Comorbidity Index, and the WHO performance scale as a proxy for Activities of Daily Living.
They defined high-risk cytogenetics as del17p, t(4;14), or t(14;16).
Investigators planned to enroll 142 patients and expected 94 patients to be randomized.
Patient demographics
The first 120 patients enrolled had a median age of 74 (range, 64–90). Thirty percent (n=38) were older than 75, and 8% (n=10) were older than 80.
More than two-thirds had an ISS score of I or II, and three-quarters had a WHO performance status of 0 or 1. Twenty-four percent had a performance status of 2, and 1% had a performance status of 3.
Eighty percent had lytic bone disease.
One hundred thirteen patients (94%) had FISH analysis performed. Of those, 10% had del17p, 7% had t(4;14), and 1% had t(14;16).
Eighty-one percent of patients fell into the standard-risk category and 19% into the high-risk category.
Almost half of patients (47%) were considered frail, 28% unfit, 21% fit, and 4% unknown.
Response
The ORR for induction was 81%. Ten percent of patients achieved a complete response (CR), 34% had a very good partial response (VGPR), and 37% had a partial response (PR).
The median time to response was 1.1 months, and the median time to maximum response was 4.7 months.
The response rate was independent of cytogenetic risk. Standard-risk patients achieved an ORR of 84%, a VGPR rate of 48%, and a CR rate of 10%. High-risk patients had an ORR of 79%, VGPR of 42%, and CR of 11%.
The response rate was also independent of frailty. Fit patients had an ORR of 88%, unfit patients 85%, and frail patients 75%. The VGPR rate was 36% for fit, 53% for unfit, and 43% for frail patients. The CR rate was 16% for fit, 9% for unfit, and 9% for frail patients.
Safety
“Grade 3 and 4 toxicities were found to be limited, with mainly infections, [gastrointestinal], and skin toxicity,” Dr Zweegman noted. “There was also a very low incidence of neuropathy, with only 3% grade 3 neuropathy and no grade 4 neuropathy.”
Grade 3 adverse events (AEs) occurred in 50% of patients and grade 4 in 11%.
Hematologic AEs of grade 3 and 4, respectively, included anemia (5%, 1%), thrombocytopenia (3%, 1%), and neutropenia (1%, 0).
Nonhematologic AEs of grade 3 and 4, respectively, included infections (12%, 3%), neuropathy (3%, 0), cardiac events (7%, 3%), gastrointestinal events (8%, 0), skin AEs (10%, 0), and venous thromboembolism (0, 2%).
The incidence of severe neuropathy was low. Fifty-eight percent of patients had grade 0 neuropathy, 24% grade 1, 14% grade 2, 3% grade 3, and no grade 4.
Discontinuation
Fifty-four patients (45%) discontinued therapy. The reasons for discontinuation were:
- Progressive disease, 13%
- Toxicity, 15%
- Death, 4%
- Noncompliance, 8%
- Not eligible for randomization, 0.8%
- Other, 4%.
“And when looking in detail into the toxicity, it was shown that it was mainly asthenia and neuropathy being judged by the treating physicians as caused by thalidomide,” Dr Zweegman explained.
Investigators also evaluated discontinuation according to age and found that 35% of patients 75 or younger discontinued therapy, compared with 62% of those older than 75.
However, there was no significant difference in discontinuation rate during the first 6 cycles. Seventy-seven percent of the younger patients and 69% of the older group completed 6 cycles.
Older patients who discontinued early had rates of progressive disease and toxicity comparable to the younger patients, but “there was a difference in early mortality,” Dr Zweegman added.
Nine percent of older patients discontinued before maintenance due to early mortality, compared with 1% of younger patients. And mortality in the older group was mainly due to infections and 1 cardiac arrest.
“So I think that highlights the need for antibiotic prophylaxis, which was not mandatory in this study,” Dr Zweegman said.
And finally, the investigators evaluated discontinuation according to frailty. Twenty-four percent of fit patients discontinued prior to maintenance, 32% of unfit, and 60% of frail.
Again, investigators found no significant difference in discontinuation rate during the first 6 cycles of induction. Eighty percent of fit patients completed 6 cycles, as did 79% of unfit patients and 70% of frail patients.
Despite the feasibility of the treatment and an ORR of 81%, the investigators say novel approaches are needed for frail patients and those older than 75.
“One possibility is to limit the duration of induction therapy . . . ,” Dr Zweegman said. “That would allow the start of long-term administration of maintenance treatment.”
The investigators also suggest evaluating less toxic combinations, such as ixazomib and daratumumab with lower doses of dexamethasone, the combination used in the HOVON-143 study.
Ixazomib is approved by the US Food and Drug Administration, Health Canada, and conditionally approved by the European Commission for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior therapy.
Research explains why cisplatin causes hearing loss
Researchers have gained new insight into hearing loss caused by cisplatin.
By measuring and mapping cisplatin retention in mouse and human inner ear tissues, the researchers found that cisplatin builds up in the inner ear and can remain there for years.
The team also found that a region in the inner ear called the stria vascularis could be targeted to prevent hearing loss resulting from cisplatin.
Lisa L. Cunningham, PhD, of the National Institute on Deafness and other Communications Disorders (NIDCD) in Bethesda, Maryland, and her colleagues reported these findings in Nature Communications.
The researchers noted that cisplatin can cause permanent hearing loss in 40% to 80% of treated patients. The team’s new findings help explain why.
The researchers found that, in most areas of the body, cisplatin is eliminated within days or weeks of treatment, but, in the inner ear, the drug remains much longer.
The team developed a mouse model that represents cisplatin-induced hearing loss seen in human patients.
By looking at inner ear tissue of mice after the first, second, and third cisplatin treatment, the researchers saw that cisplatin remained in the mouse inner ear much longer than in most other body tissues, and the drug builds up with each successive treatment.
The team also studied inner ear tissue donated by deceased adults who had been treated with cisplatin and found the drug is retained in the inner ear months or years after treatment.
When the researchers examined inner ear tissue from a child, they found cisplatin buildup that was even higher than that seen in adults.
Taken together, these results suggest the inner ear readily takes up cisplatin but has limited ability to remove the drug.
In mice and human tissues, the researchers saw the highest buildup of cisplatin in a part of the inner ear called the stria vascularis, which helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound.
The team found the accumulation of cisplatin in the stria vascularis contributed to cisplatin-related hearing loss.
“Our findings suggest that if we can prevent cisplatin from entering the stria vascularis in the inner ear during treatment, we may be able to protect cancer patients from developing cisplatin-induced hearing loss,” Dr Cunningham said.
Researchers have gained new insight into hearing loss caused by cisplatin.
By measuring and mapping cisplatin retention in mouse and human inner ear tissues, the researchers found that cisplatin builds up in the inner ear and can remain there for years.
The team also found that a region in the inner ear called the stria vascularis could be targeted to prevent hearing loss resulting from cisplatin.
Lisa L. Cunningham, PhD, of the National Institute on Deafness and other Communications Disorders (NIDCD) in Bethesda, Maryland, and her colleagues reported these findings in Nature Communications.
The researchers noted that cisplatin can cause permanent hearing loss in 40% to 80% of treated patients. The team’s new findings help explain why.
The researchers found that, in most areas of the body, cisplatin is eliminated within days or weeks of treatment, but, in the inner ear, the drug remains much longer.
The team developed a mouse model that represents cisplatin-induced hearing loss seen in human patients.
By looking at inner ear tissue of mice after the first, second, and third cisplatin treatment, the researchers saw that cisplatin remained in the mouse inner ear much longer than in most other body tissues, and the drug builds up with each successive treatment.
The team also studied inner ear tissue donated by deceased adults who had been treated with cisplatin and found the drug is retained in the inner ear months or years after treatment.
When the researchers examined inner ear tissue from a child, they found cisplatin buildup that was even higher than that seen in adults.
Taken together, these results suggest the inner ear readily takes up cisplatin but has limited ability to remove the drug.
In mice and human tissues, the researchers saw the highest buildup of cisplatin in a part of the inner ear called the stria vascularis, which helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound.
The team found the accumulation of cisplatin in the stria vascularis contributed to cisplatin-related hearing loss.
“Our findings suggest that if we can prevent cisplatin from entering the stria vascularis in the inner ear during treatment, we may be able to protect cancer patients from developing cisplatin-induced hearing loss,” Dr Cunningham said.
Researchers have gained new insight into hearing loss caused by cisplatin.
By measuring and mapping cisplatin retention in mouse and human inner ear tissues, the researchers found that cisplatin builds up in the inner ear and can remain there for years.
The team also found that a region in the inner ear called the stria vascularis could be targeted to prevent hearing loss resulting from cisplatin.
Lisa L. Cunningham, PhD, of the National Institute on Deafness and other Communications Disorders (NIDCD) in Bethesda, Maryland, and her colleagues reported these findings in Nature Communications.
The researchers noted that cisplatin can cause permanent hearing loss in 40% to 80% of treated patients. The team’s new findings help explain why.
The researchers found that, in most areas of the body, cisplatin is eliminated within days or weeks of treatment, but, in the inner ear, the drug remains much longer.
The team developed a mouse model that represents cisplatin-induced hearing loss seen in human patients.
By looking at inner ear tissue of mice after the first, second, and third cisplatin treatment, the researchers saw that cisplatin remained in the mouse inner ear much longer than in most other body tissues, and the drug builds up with each successive treatment.
The team also studied inner ear tissue donated by deceased adults who had been treated with cisplatin and found the drug is retained in the inner ear months or years after treatment.
When the researchers examined inner ear tissue from a child, they found cisplatin buildup that was even higher than that seen in adults.
Taken together, these results suggest the inner ear readily takes up cisplatin but has limited ability to remove the drug.
In mice and human tissues, the researchers saw the highest buildup of cisplatin in a part of the inner ear called the stria vascularis, which helps maintain the positive electrical charge in inner ear fluid that certain cells need to detect sound.
The team found the accumulation of cisplatin in the stria vascularis contributed to cisplatin-related hearing loss.
“Our findings suggest that if we can prevent cisplatin from entering the stria vascularis in the inner ear during treatment, we may be able to protect cancer patients from developing cisplatin-induced hearing loss,” Dr Cunningham said.
Survival improvements lag for young Hispanic patients with myeloma
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
ATLANTA –
Among U.S. adults diagnosed with multiple myeloma by age 40 years, 5-year and 10-year survival improved significantly (P less than .0001) for non-Hispanic blacks and whites, but not for Hispanics (5-year survival, P = .08; 10-year survival, P = .13), Abdel-Ghani Azzouqa, MD, and colleagues reported in a poster at the annual meeting of the American Society of Hematology.
Other population-based studies have uncovered racial and ethnic disparities in myeloma outcomes but had not honed in on the experience of young adult patients, who make up a growing proportion of diagnosed patients, said Dr. Azzouqa.
He and his associates analyzed Surveillance Epidemiology and End Results (SEER) data on patients diagnosed between ages 18 and 40 years with histologically confirmed multiple myeloma. The dataset spanned 1973-2014 and included 1,460 patients, of whom about 60% were male. Median age at diagnosis was 37 years; 47% of patients were non-Hispanic white, 28% were non-Hispanic black, 18% were Hispanic, 5.5% were Asian, and about 1% were of other ethnicities.
For young Hispanic patients with myeloma, 5-year survival improved from 39% before 1996, when stem cell transplants and novel therapies became available, to 56% from 2002 onward. This change was not statistically significant (P = .08), and 10-year survival rates also did not change significantly (from 21% to 33%; P = .13).
Five-year and 10-year survival did improve significantly for both genders (P = .0001) and among non-Hispanic blacks (P = .0001) and non-Hispanic whites (P = .0001).
Racial/ethnic subgroups did not differ significantly by median age at diagnosis, gender distribution, or listed cause of death, Dr. Azzouqa noted. Thus, reasons for the difference in survival for Hispanic patients remain unclear. Perhaps they reflect differences in disease biology, treatment response, or access or use of effective novel therapies, he said.
The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed ties to funding Pharmacyclics, Amgen, Novartis, and Takeda.
SOURCE: Ailawadhi S et al. ASH Abstract 2149
REPORTING FROM ASH 2017
Key clinical point: Recent improvements in multiple myeloma survival have left young Hispanics behind.
Major finding: Five-year and 10-year survival have improved significantly among young blacks and non-Hispanic whites with multiple myeloma (P less than .0001 for all comparisons) but not Hispanics (5-year survival P = .08; 10-year survival P = .13).
Data source: Surveillance Epidemiology and End Results (SEER) data for 1,460 adults up to 40 years old when diagnosed with multiple myeloma.
Disclosures: The researchers had no external funding sources. Dr. Azzouqa had no conflicts of interest. Lead author Dr. Sikander Ailawadhi disclosed funding from Pharmacyclics, Amgen, Novartis, and Takeda.
Source: Ailawadhi S et al. ASH Abstract 2149.
Single-agent daratumumab active in smoldering multiple myeloma
ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.
Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.
Current guidelines recommend monitoring smoldering multiple myeloma every 3-6 months and treating only after patients progress. However, some experts pursue earlier treatment in the premalignant setting.
In CENTAURUS, 123 adults with smoldering multiple myeloma were randomly assigned to receive daratumumab (16 mg/kg IV) in 8-week cycles according to a long, intermediate, or short/intense schedule. The long schedule consisted of treatment weekly for cycle 1, every other week for cycles 2-3, monthly for cycles 4-7, and once every 8 weeks for up to 13 more cycles. The intermediate schedule consisted of treatment weekly in cycle 1 and every 8 weeks for up to 20 cycles. The short, intense schedule consisted of weekly treatment for 8 weeks (one cycle). Patients were followed for up to 4 years or until they progressed to multiple myeloma based on International Myeloma Working Group guidelines.
Over a median follow-up period of 15.8 months (range, 0 to 24 months), rates of complete response were 2% in the long treatment arm, 5% in the intermediate treatment arm, and 0% in the short treatment arm. Rates of at least very good partial response were 29%, 24%, and 15%, respectively. Overall response rates were 56%, 54%, and 38%, respectively. Median PFS was not reached in any arm, exceeding 24 months.
Treatment was generally well tolerated, said Dr. Hofmeister. The most common treatment-related adverse effects were fatigue, cough, upper respiratory tract infection, headache, and insomnia. Hypertension and hyperglycemia were the most common grade 3-4 treatment-emergent adverse events, affecting up to 5% of patients per arm. Fewer than 10% of patients in any arm developed treatment-emergent hematologic adverse events, and fewer than 5% developed grade 3-4 pneumonia or sepsis. There were three cases of a second primary malignancy, including one case of breast cancer and two cases of melanoma.
Rates of infusion-related reactions did not correlate with treatment duration. Grade 3-4 infusion-related reactions affected 0% to 3% of patients per arm. The sole death in this trial resulted from disease progression in a patient from the short treatment arm. “Taken together, efficacy and safety data support long dosing compared to intermediate and short dosing,” Dr. Hofmeister said.
The three arms were demographically similar. Patients tended to be white, in their late 50s to 60s, and to have ECOG scores of 0 with at least two risk factors for progression. About 70% had IgG disease and nearly half had less than 20% plasma cells in bone marrow.
Janssen, the maker of daratumumab, sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.
ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.
Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.
Current guidelines recommend monitoring smoldering multiple myeloma every 3-6 months and treating only after patients progress. However, some experts pursue earlier treatment in the premalignant setting.
In CENTAURUS, 123 adults with smoldering multiple myeloma were randomly assigned to receive daratumumab (16 mg/kg IV) in 8-week cycles according to a long, intermediate, or short/intense schedule. The long schedule consisted of treatment weekly for cycle 1, every other week for cycles 2-3, monthly for cycles 4-7, and once every 8 weeks for up to 13 more cycles. The intermediate schedule consisted of treatment weekly in cycle 1 and every 8 weeks for up to 20 cycles. The short, intense schedule consisted of weekly treatment for 8 weeks (one cycle). Patients were followed for up to 4 years or until they progressed to multiple myeloma based on International Myeloma Working Group guidelines.
Over a median follow-up period of 15.8 months (range, 0 to 24 months), rates of complete response were 2% in the long treatment arm, 5% in the intermediate treatment arm, and 0% in the short treatment arm. Rates of at least very good partial response were 29%, 24%, and 15%, respectively. Overall response rates were 56%, 54%, and 38%, respectively. Median PFS was not reached in any arm, exceeding 24 months.
Treatment was generally well tolerated, said Dr. Hofmeister. The most common treatment-related adverse effects were fatigue, cough, upper respiratory tract infection, headache, and insomnia. Hypertension and hyperglycemia were the most common grade 3-4 treatment-emergent adverse events, affecting up to 5% of patients per arm. Fewer than 10% of patients in any arm developed treatment-emergent hematologic adverse events, and fewer than 5% developed grade 3-4 pneumonia or sepsis. There were three cases of a second primary malignancy, including one case of breast cancer and two cases of melanoma.
Rates of infusion-related reactions did not correlate with treatment duration. Grade 3-4 infusion-related reactions affected 0% to 3% of patients per arm. The sole death in this trial resulted from disease progression in a patient from the short treatment arm. “Taken together, efficacy and safety data support long dosing compared to intermediate and short dosing,” Dr. Hofmeister said.
The three arms were demographically similar. Patients tended to be white, in their late 50s to 60s, and to have ECOG scores of 0 with at least two risk factors for progression. About 70% had IgG disease and nearly half had less than 20% plasma cells in bone marrow.
Janssen, the maker of daratumumab, sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.
ATLANTA – Daratumumab monotherapy led to durable partial responses among intermediate to high-risk patients with smoldering multiple myeloma, according to results from the phase II CENTAURUS trial.
Although less than 5% of patients had complete responses, 27% had at least a very good partial response to long-term therapy (up to 20 treatment cycles lasting 8 weeks each), Craig C. Hofmeister, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, said at the annual meeting of the American Society of Hematology. The coprimary endpoint, median progression-free survival, exceeded 24 months in all dose cohorts, and was the longest when patients were treated longest.
Current guidelines recommend monitoring smoldering multiple myeloma every 3-6 months and treating only after patients progress. However, some experts pursue earlier treatment in the premalignant setting.
In CENTAURUS, 123 adults with smoldering multiple myeloma were randomly assigned to receive daratumumab (16 mg/kg IV) in 8-week cycles according to a long, intermediate, or short/intense schedule. The long schedule consisted of treatment weekly for cycle 1, every other week for cycles 2-3, monthly for cycles 4-7, and once every 8 weeks for up to 13 more cycles. The intermediate schedule consisted of treatment weekly in cycle 1 and every 8 weeks for up to 20 cycles. The short, intense schedule consisted of weekly treatment for 8 weeks (one cycle). Patients were followed for up to 4 years or until they progressed to multiple myeloma based on International Myeloma Working Group guidelines.
Over a median follow-up period of 15.8 months (range, 0 to 24 months), rates of complete response were 2% in the long treatment arm, 5% in the intermediate treatment arm, and 0% in the short treatment arm. Rates of at least very good partial response were 29%, 24%, and 15%, respectively. Overall response rates were 56%, 54%, and 38%, respectively. Median PFS was not reached in any arm, exceeding 24 months.
Treatment was generally well tolerated, said Dr. Hofmeister. The most common treatment-related adverse effects were fatigue, cough, upper respiratory tract infection, headache, and insomnia. Hypertension and hyperglycemia were the most common grade 3-4 treatment-emergent adverse events, affecting up to 5% of patients per arm. Fewer than 10% of patients in any arm developed treatment-emergent hematologic adverse events, and fewer than 5% developed grade 3-4 pneumonia or sepsis. There were three cases of a second primary malignancy, including one case of breast cancer and two cases of melanoma.
Rates of infusion-related reactions did not correlate with treatment duration. Grade 3-4 infusion-related reactions affected 0% to 3% of patients per arm. The sole death in this trial resulted from disease progression in a patient from the short treatment arm. “Taken together, efficacy and safety data support long dosing compared to intermediate and short dosing,” Dr. Hofmeister said.
The three arms were demographically similar. Patients tended to be white, in their late 50s to 60s, and to have ECOG scores of 0 with at least two risk factors for progression. About 70% had IgG disease and nearly half had less than 20% plasma cells in bone marrow.
Janssen, the maker of daratumumab, sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.
REPORTING FROM ASH 2017
Key clinical point: Single-agent daratumumab therapy was active and its safety profile was acceptable in patients with smoldering multiple myeloma.
Major finding: Rates of at least very good partial response were 29%, 24%, and 15% among patients who received long, intermediate, and short/intense treatment schedules, respectively. Median progression-free survival exceeded 24 months in all three arms.
Data source: CENTAURUS, a phase II trial of 123 patients with smoldering multiple myeloma.
Disclosures: Janssen sponsored the trial. Dr. Hofmeister disclosed research funding from Janssen and research support, honoraria, and advisory relationships with Adaptive Biotechnologies, Thrasos, Celgene, Karyopharm, Takeda, and other pharmaceutical companies.
Source: Hofmeister C et al, ASH 2017, Abstract 510.
bb2121 induces durable, deepening responses in MM patients
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.
ATLANTA—Updated results from a phase 1 trial have shown that bb2121, a chimeric antigen receptor (CAR) T-cell product, can induce durable, deepening responses in patients with relapsed/refractory multiple myeloma (MM).
Responses continue to improve from very good partial responses to complete responses (CRs), even 15 months after infusion.
In 5 months, the CR rate increased from 27% to 56%, and ongoing responses have now surpassed 1 year.
The overall response rate (ORR) stands at 94%, and the median progression-free survival (PFS) has not been reached with a follow-up of 40 weeks.
bb2121 is a second-generation CAR T-cell product that targets the B-cell maturation antigen (BCMA).
BCMA is expressed nearly universally on MM cells, and its expression is largely restricted to plasma cells and some mature B cells, making it “an attractive target for immunotherapies,” said James N. Kochenderfer, MD, of the National Cancer Institute/National Institutes of Health in Bethesda, Maryland.
Dr Kochenderfer reported results from the phase 1 study of bb2121 (NCT02658929) at the 2017 ASH Annual Meeting (abstract 740*).
Study sponsors and collaborators were bluebird bio and Celgene Corporation. Dr Kochenderfer disclosed that he has multiple patents in the CAR field and has received research funding from bluebird bio and Kite Pharma.
Study design
Patients with relapsed or refractory MM who had 3 or more prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or who were double refractory were eligible for the dose-escalation cohort of the study. They had to have measurable disease, 50% or more BCMA expression, and adequate bone marrow, renal, and hepatic function.
BCMA expression was not required for the dose-expansion cohort. For this cohort, patients must have received daratumumab and have been refractory to their last line of therapy.
The dose-escalation cohort was a standard 3 + 3 design and included CAR T-cell doses of 50 x 106, 150 x 106, 450 x 106, and 800 x 106.
Patients were screened, underwent leukapheresis, and waited for the manufacture of their CAR T cells. One centralized manufacturing site produced the T-cell products for the 9 US clinical study sites.
“We had a manufacturing success rate of 100%,” Dr Kochenderfer noted, and the manufacturing took 10 days.
Five days prior to bb2121 infusion, patients received lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2).
Patient characteristics
Investigators dosed 21 patients as of the data cut-off of October 2.
Their median age was 58 (range, 37–74), 62% were male, and they had a median time since diagnosis of 4 years.
All patients had an ECOG performance status of 0 or 1, and 43% had high-risk cytogenetics, defined as del17p, t(4;14), and t(14;16).
“One of the most impressive things about our study was how heavily pretreated the patients were,” Dr Kochenderfer noted. “These patients had a median of 7 prior lines of therapy, and 100% of the patients had a prior autologous stem cell transplant.”
All patients were exposed to bortezomib and lenalidomide, and 67% and 86%, respectively, were refractory to those agents. Patients were also exposed to carfilzomib (91%), pomalidomide (91%), and daratumumab (71%) and had varying degrees of refractoriness to those agents.
Safety
“In general, the treatment was very well tolerated,” Dr Kochenderfer said. “[It was] well tolerated compared with other T-cell products I’ve had experience with.”
The investigators observed no dose-limiting toxicities.
Cytokine release syndrome (CRS) of all grades occurred in 15 (71%) patients, and grade 3 or higher CRS occurred in 2 (10%) patients. The latter resolved within 24 hours.
Five (24%) patients experienced neurotoxicity, none grade 3 or higher.
Dr Kochenderfer described 1 case of delayed-onset, grade 4, reversible neurotoxicity that was associated with tumor lysis syndrome (TLS) and CRS.
The patient had no toxicity until day 10. By day 12, magnetic resonance imaging showed cerebral edema.
The patient was transferred to the intensive care unit and required intubation. She was treated with high-dose methylprednisolone and tocilizumab. She also received hemodialysis for TLS.
“By day 17, she dramatically improved,” Dr Kochenderfer said.
Her mental status cleared, TLS resolved, she was extubated, and she was doing much better, he reported.
On day 30, the patient was out of the intensive care unit.
“So the whole course was fairly brief,” Dr Kochenderfer said. “And, today, she’s doing well. She’s actually asymptomatic.”
Cytopenias—neutropenia, thrombocytopenia, and anemia—were primarily related to the lymphodepleting drugs, and patients recovered to grade 3 or lower by month 2 after the infusion.
Fourteen patients experienced 1 or more serious adverse events. Four had grade 1-2 CRS that required hospitalization per protocol, and 2 had pyrexia.
Five patients died, 3 due to disease progression, all who received treatment at the lowest dose.
Two patients treated at active doses were in CR when they died. One had a cardiac arrest, and the other had myelodysplastic syndrome following discontinuation.
Efficacy
In addition to the high ORR (94%) and CR rate (56%) in this study, 9 of 10 patients evaluated for minimal residual disease were negative.
The median time to first response was 1.02 months, and median time to best response was 3.74 months. The median time to CR was 3.84 months.
The median duration of response and PFS have not been reached. The PFS rate was 81% at 6 months and 71% at 9 months.
“We found that all the doses between 150 million and 450 million were effective,” Dr Kochenderfer noted. “We didn’t see a clear difference in efficacy between those doses, so we’ve chosen to use the 150 – 300 million dose range for the follow-up study.”
The investigators observed robust expansion of bb2121, which peaked in the first week after the infusion. Six of 13 patients had evident CAR T cells at 6 months. One patient has persistence over 12 months.
The investigators also observed a robust decrease in M protein and rapid clearance of serum-free light chains and serum BCMA. They noted that the activity of the CAR-positive T cells was not inhibited by high baseline serum BCMA.
Four patients progressed. The investigators analyzed the patients’ tumor burden, bb2121 dose, best response, time to progression, BCMA expression, grades of CRS, and bb2121 persistence. And progression was independent of these factors.
“So we can’t pick out a very good factor of why they progressed,” Dr Kochenderfer said.
However, he noted that the patients are eligible for re-treatment.
Investigators have opened a global trial of bb2121 (NCT03361748) given at doses ranging from 150 – 300 million CAR T cells.
The US Food and Drug Administration and the European Medicines Agency recently fast-tracked bb2121.
*Data presented differ from the abstract.
NK cell product receives orphan designation
The European Commission has granted orphan designation to a natural killer (NK) cell product for the treatment of multiple myeloma.
The product, called CellProtect, is manufactured from a patient’s own blood.
It consists of NK cells that have been activated and expanded so they can recognize and attack cancer cells.
CellProtect has been studied in a phase 1/2 trial of patients with multiple myeloma.
In this trial, the NK cell product was used as a supplement to autologous stem cell transplant.
CellProtect exhibited a good safety profile and signals of effect in the trial, according to CellProtect Nordic Pharmaceuticals AB, the company developing CellProtect.
Results from the trial are expected to be published in 2018.
“The decision from the commission is based on a recommendation from the European Medicines Agency’s Committee for Orphan Medicinal Products and confirms that a future product is considered to be of significant benefit to those suffering from multiple myeloma,” said Karin Mellström, chief executive officer of CellProtect Nordic Pharmaceuticals AB.
“We can now proceed and plan for additional clinical trials in order to receive approval to market CellProtect.”
Orphan designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Medicines Agency’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
The European Commission has granted orphan designation to a natural killer (NK) cell product for the treatment of multiple myeloma.
The product, called CellProtect, is manufactured from a patient’s own blood.
It consists of NK cells that have been activated and expanded so they can recognize and attack cancer cells.
CellProtect has been studied in a phase 1/2 trial of patients with multiple myeloma.
In this trial, the NK cell product was used as a supplement to autologous stem cell transplant.
CellProtect exhibited a good safety profile and signals of effect in the trial, according to CellProtect Nordic Pharmaceuticals AB, the company developing CellProtect.
Results from the trial are expected to be published in 2018.
“The decision from the commission is based on a recommendation from the European Medicines Agency’s Committee for Orphan Medicinal Products and confirms that a future product is considered to be of significant benefit to those suffering from multiple myeloma,” said Karin Mellström, chief executive officer of CellProtect Nordic Pharmaceuticals AB.
“We can now proceed and plan for additional clinical trials in order to receive approval to market CellProtect.”
Orphan designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Medicines Agency’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
The European Commission has granted orphan designation to a natural killer (NK) cell product for the treatment of multiple myeloma.
The product, called CellProtect, is manufactured from a patient’s own blood.
It consists of NK cells that have been activated and expanded so they can recognize and attack cancer cells.
CellProtect has been studied in a phase 1/2 trial of patients with multiple myeloma.
In this trial, the NK cell product was used as a supplement to autologous stem cell transplant.
CellProtect exhibited a good safety profile and signals of effect in the trial, according to CellProtect Nordic Pharmaceuticals AB, the company developing CellProtect.
Results from the trial are expected to be published in 2018.
“The decision from the commission is based on a recommendation from the European Medicines Agency’s Committee for Orphan Medicinal Products and confirms that a future product is considered to be of significant benefit to those suffering from multiple myeloma,” said Karin Mellström, chief executive officer of CellProtect Nordic Pharmaceuticals AB.
“We can now proceed and plan for additional clinical trials in order to receive approval to market CellProtect.”
Orphan designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Medicines Agency’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
CRB-410 update: Multiple myeloma response rates remain high with bb2121 CAR T-cell therapy
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The overall response rate was 94%.
Study details: An update from the phase 1 CRB-410 dose trial of 21 patients.
Disclosures: The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
Source: Berdeja J et al. ASH 2017 Abstract 740.
CRP drives bone destruction in myeloma, team says
New research suggests that C-reactive protein (CRP) drives multiple myeloma (MM) to destroy bone.
Researchers found that CRP accelerated the onset of bone destruction and made bone damage more severe in mouse models of MM.
The team also observed an association between elevated serum CRP levels and greater degree of bone damage in newly diagnosed MM patients.
The researchers therefore believe that CRP might be targeted to prevent or treat MM-associated bone disease.
Qing Yi, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic in Ohio, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers noted that high levels of circulating CRP have been associated with poor prognosis in many cancers, including MM.
In a previous study, the team found that CRP enhanced MM cell proliferation under stressed conditions and protected MM cells from chemotherapy-induced apoptosis.
Now, the researchers have found that CRP activates MM cells to promote osteoclastogenesis and bone destruction.
In experiments with mouse models, the team found that CRP promoted MM-cell-mediated lytic bone disease. The researchers said CRP enhanced osteoclast differentiation and bone resorption activity.
In vitro experiments showed that CRP stimulates MM cells to produce osteoclast activators such as RANKL, MCP-1, and MIP-1a.
Further investigation revealed that CRP binds to CD32 on MM cells. This activates a pathway mediated by the kinase p38 MAPK and the transcription factor Twist, which increases MM cells’ production of osteolytic cytokines.
Finally, the researchers analyzed samples from newly diagnosed MM patients.
The team found that serum CRP levels “significantly and positively” correlated with the number of bone lesions patients had. And CRP was abundant in lesion biopsies from individuals with severe skeletal disease.
New research suggests that C-reactive protein (CRP) drives multiple myeloma (MM) to destroy bone.
Researchers found that CRP accelerated the onset of bone destruction and made bone damage more severe in mouse models of MM.
The team also observed an association between elevated serum CRP levels and greater degree of bone damage in newly diagnosed MM patients.
The researchers therefore believe that CRP might be targeted to prevent or treat MM-associated bone disease.
Qing Yi, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic in Ohio, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers noted that high levels of circulating CRP have been associated with poor prognosis in many cancers, including MM.
In a previous study, the team found that CRP enhanced MM cell proliferation under stressed conditions and protected MM cells from chemotherapy-induced apoptosis.
Now, the researchers have found that CRP activates MM cells to promote osteoclastogenesis and bone destruction.
In experiments with mouse models, the team found that CRP promoted MM-cell-mediated lytic bone disease. The researchers said CRP enhanced osteoclast differentiation and bone resorption activity.
In vitro experiments showed that CRP stimulates MM cells to produce osteoclast activators such as RANKL, MCP-1, and MIP-1a.
Further investigation revealed that CRP binds to CD32 on MM cells. This activates a pathway mediated by the kinase p38 MAPK and the transcription factor Twist, which increases MM cells’ production of osteolytic cytokines.
Finally, the researchers analyzed samples from newly diagnosed MM patients.
The team found that serum CRP levels “significantly and positively” correlated with the number of bone lesions patients had. And CRP was abundant in lesion biopsies from individuals with severe skeletal disease.
New research suggests that C-reactive protein (CRP) drives multiple myeloma (MM) to destroy bone.
Researchers found that CRP accelerated the onset of bone destruction and made bone damage more severe in mouse models of MM.
The team also observed an association between elevated serum CRP levels and greater degree of bone damage in newly diagnosed MM patients.
The researchers therefore believe that CRP might be targeted to prevent or treat MM-associated bone disease.
Qing Yi, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic in Ohio, and his colleagues conducted this research and reported the results in Science Translational Medicine.
The researchers noted that high levels of circulating CRP have been associated with poor prognosis in many cancers, including MM.
In a previous study, the team found that CRP enhanced MM cell proliferation under stressed conditions and protected MM cells from chemotherapy-induced apoptosis.
Now, the researchers have found that CRP activates MM cells to promote osteoclastogenesis and bone destruction.
In experiments with mouse models, the team found that CRP promoted MM-cell-mediated lytic bone disease. The researchers said CRP enhanced osteoclast differentiation and bone resorption activity.
In vitro experiments showed that CRP stimulates MM cells to produce osteoclast activators such as RANKL, MCP-1, and MIP-1a.
Further investigation revealed that CRP binds to CD32 on MM cells. This activates a pathway mediated by the kinase p38 MAPK and the transcription factor Twist, which increases MM cells’ production of osteolytic cytokines.
Finally, the researchers analyzed samples from newly diagnosed MM patients.
The team found that serum CRP levels “significantly and positively” correlated with the number of bone lesions patients had. And CRP was abundant in lesion biopsies from individuals with severe skeletal disease.