Multiple Myeloma

The Food and Drug Administration has expanded the indications for denosumab (Xgeva), previously indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, to include patients with multiple myeloma, according to a press release from Amgen, the manufacturer of Xgeva.

[email protected]

The Food and Drug Administration has expanded the indications for denosumab (Xgeva), previously indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, to include patients with multiple myeloma, according to a press release from Amgen, the manufacturer of Xgeva.

[email protected]

The Food and Drug Administration has expanded the indications for denosumab (Xgeva), previously indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, to include patients with multiple myeloma, according to a press release from Amgen, the manufacturer of Xgeva.

[email protected]

High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents, according to a recent systematic review and two meta-analyses.

Given the “unprecedented efficacy” of “modern induction therapy with immunomodulatory drugs and proteasome inhibitors (also called ‘novel agents’),” investigators “have sought to reevaluate the role of HDT/ASCT,” wrote Binod Dhakal, MD, of the Medical College of Wisconsin, and his colleagues. The report is in JAMA Oncology.

To solve the issue, they analyzed five randomized controlled trials conducted since 2000 and concluded that HDT/ASCT is still the preferred treatment approach.

Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma, the researchers noted.

The combined odds for complete response were 1.27 (95% confidence interval, 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT). The combined hazard ratio (HR) for PFS was 0.55 (95% CI, 0.41-0.7, P less than .001) and 0.76 for overall survival (95% CI, 0.42-1.36, P = .20) in favor of HDT.

PFS was best with tandem HDT/ASCT (HR, 0.49, 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation (HR, 0.53, 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68, 95% CI, 0.53-0.87), compared with SDT. However, none of the HDT/ASCT approaches had a significant impact on overall survival.

Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.

“The achievement of high [minimal residual disease] rates with HDT/ASCT may render this approach the ideal platform for testing novel approaches (e.g., immunotherapy) aiming at disease eradication and cures,” the researchers wrote.

The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.

[email protected]

SOURCE: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.

High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents, according to a recent systematic review and two meta-analyses.

Given the “unprecedented efficacy” of “modern induction therapy with immunomodulatory drugs and proteasome inhibitors (also called ‘novel agents’),” investigators “have sought to reevaluate the role of HDT/ASCT,” wrote Binod Dhakal, MD, of the Medical College of Wisconsin, and his colleagues. The report is in JAMA Oncology.

To solve the issue, they analyzed five randomized controlled trials conducted since 2000 and concluded that HDT/ASCT is still the preferred treatment approach.

Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma, the researchers noted.

The combined odds for complete response were 1.27 (95% confidence interval, 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT). The combined hazard ratio (HR) for PFS was 0.55 (95% CI, 0.41-0.7, P less than .001) and 0.76 for overall survival (95% CI, 0.42-1.36, P = .20) in favor of HDT.

PFS was best with tandem HDT/ASCT (HR, 0.49, 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation (HR, 0.53, 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68, 95% CI, 0.53-0.87), compared with SDT. However, none of the HDT/ASCT approaches had a significant impact on overall survival.

Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.

“The achievement of high [minimal residual disease] rates with HDT/ASCT may render this approach the ideal platform for testing novel approaches (e.g., immunotherapy) aiming at disease eradication and cures,” the researchers wrote.

The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.

[email protected]

SOURCE: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.

High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents, according to a recent systematic review and two meta-analyses.

Given the “unprecedented efficacy” of “modern induction therapy with immunomodulatory drugs and proteasome inhibitors (also called ‘novel agents’),” investigators “have sought to reevaluate the role of HDT/ASCT,” wrote Binod Dhakal, MD, of the Medical College of Wisconsin, and his colleagues. The report is in JAMA Oncology.

To solve the issue, they analyzed five randomized controlled trials conducted since 2000 and concluded that HDT/ASCT is still the preferred treatment approach.

Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma, the researchers noted.

The combined odds for complete response were 1.27 (95% confidence interval, 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT). The combined hazard ratio (HR) for PFS was 0.55 (95% CI, 0.41-0.7, P less than .001) and 0.76 for overall survival (95% CI, 0.42-1.36, P = .20) in favor of HDT.

PFS was best with tandem HDT/ASCT (HR, 0.49, 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation (HR, 0.53, 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68, 95% CI, 0.53-0.87), compared with SDT. However, none of the HDT/ASCT approaches had a significant impact on overall survival.

Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.

“The achievement of high [minimal residual disease] rates with HDT/ASCT may render this approach the ideal platform for testing novel approaches (e.g., immunotherapy) aiming at disease eradication and cures,” the researchers wrote.

The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.

[email protected]

SOURCE: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.

ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

Amy Karon/Frontline Medical News

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.

ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

Amy Karon/Frontline Medical News

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.

ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

Amy Karon/Frontline Medical News

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.

© Todd Buchanan 2017

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.

© Todd Buchanan 2017

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.

© Todd Buchanan 2017

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.

Photo courtesy of Amgen

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).

Photo courtesy of Amgen

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).

Photo courtesy of Amgen

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).

Sign at the 2017 ASH Annual Meeting

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.

Sign at the 2017 ASH Annual Meeting

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.

Sign at the 2017 ASH Annual Meeting

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.

Image from NIDCD

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.

Image from NIDCD

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.

Image from NIDCD

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.

ATLANTA – Recent improvements in multiple myeloma survival have left young Hispanic patients behind, the results of a national longitudinal study suggest.

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.

Amy Karon/Frontline Medical News

SOURCE: Ailawadhi S et al. ASH Abstract 2149

ATLANTA – Recent improvements in multiple myeloma survival have left young Hispanic patients behind, the results of a national longitudinal study suggest.

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.

Amy Karon/Frontline Medical News

SOURCE: Ailawadhi S et al. ASH Abstract 2149

ATLANTA – Recent improvements in multiple myeloma survival have left young Hispanic patients behind, the results of a national longitudinal study suggest.

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.

Amy Karon/Frontline Medical News

SOURCE: Ailawadhi S et al. ASH Abstract 2149

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.

Amy Karon/Frontline Medical News

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.

Amy Karon/Frontline Medical News

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.

Amy Karon/Frontline Medical News

SOURCE: Hofmeister C et al, ASH 2017, Abstract 510.

© Phil McCarten 2017

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.

© Phil McCarten 2017

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.

© Phil McCarten 2017

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.