Multiple Myeloma

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.

If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).

Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.

The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.

Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.

If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).

Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.

The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.

Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.

If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).

Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.

The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.

Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.

Micrograph showing MM

Preclinical research suggests an AKT inhibitor could be effective against multiple myeloma (MM).

The inhibitor, HS1793, is a derivative of the antioxidant compound resveratrol.

Investigators found that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in MM cells.

HS1793 was cytotoxic to MM cells in a mouse model of human metastatic myeloma and in human MM cells in vitro.

Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues reported these results in Cancer Letters.

“AKT is frequently activated in MM cells, and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They had screened 400 compounds and identified HS1793 as the most promising AKT inhibitor. Experiments suggested that HS1793 inhibits AKT activation by interfering with the interaction between AKT and its promoter, HSP90.

HS1793 exhibited antimyeloma activity in human MM cell lines. The investigators said this appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In additional experiments, the team found that HS1793’s inhibition of AKT/HSP90 interaction results in cell death by suppressing NF-κB signaling. HS1793-induced cell death was caused by the direct inhibition of AKT that, in turn, suppressed NF-κB activation.

The investigators found that HS1793 “dramatically decreased” lytic skull and femur lesions in a mouse model of MM metastatic to bone. And mice that received HS1793 had superior survival, when compared to mice that received vehicle control.

The investigators also showed that HS1793 was cytotoxic to MM cells but not normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” the authors wrote.

This research was supported by grants from the Korean government. The investigators reported no potential conflicts of interest.

Micrograph showing MM

Preclinical research suggests an AKT inhibitor could be effective against multiple myeloma (MM).

The inhibitor, HS1793, is a derivative of the antioxidant compound resveratrol.

Investigators found that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in MM cells.

HS1793 was cytotoxic to MM cells in a mouse model of human metastatic myeloma and in human MM cells in vitro.

Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues reported these results in Cancer Letters.

“AKT is frequently activated in MM cells, and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They had screened 400 compounds and identified HS1793 as the most promising AKT inhibitor. Experiments suggested that HS1793 inhibits AKT activation by interfering with the interaction between AKT and its promoter, HSP90.

HS1793 exhibited antimyeloma activity in human MM cell lines. The investigators said this appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In additional experiments, the team found that HS1793’s inhibition of AKT/HSP90 interaction results in cell death by suppressing NF-κB signaling. HS1793-induced cell death was caused by the direct inhibition of AKT that, in turn, suppressed NF-κB activation.

The investigators found that HS1793 “dramatically decreased” lytic skull and femur lesions in a mouse model of MM metastatic to bone. And mice that received HS1793 had superior survival, when compared to mice that received vehicle control.

The investigators also showed that HS1793 was cytotoxic to MM cells but not normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” the authors wrote.

This research was supported by grants from the Korean government. The investigators reported no potential conflicts of interest.

Micrograph showing MM

Preclinical research suggests an AKT inhibitor could be effective against multiple myeloma (MM).

The inhibitor, HS1793, is a derivative of the antioxidant compound resveratrol.

Investigators found that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in MM cells.

HS1793 was cytotoxic to MM cells in a mouse model of human metastatic myeloma and in human MM cells in vitro.

Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues reported these results in Cancer Letters.

“AKT is frequently activated in MM cells, and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They had screened 400 compounds and identified HS1793 as the most promising AKT inhibitor. Experiments suggested that HS1793 inhibits AKT activation by interfering with the interaction between AKT and its promoter, HSP90.

HS1793 exhibited antimyeloma activity in human MM cell lines. The investigators said this appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In additional experiments, the team found that HS1793’s inhibition of AKT/HSP90 interaction results in cell death by suppressing NF-κB signaling. HS1793-induced cell death was caused by the direct inhibition of AKT that, in turn, suppressed NF-κB activation.

The investigators found that HS1793 “dramatically decreased” lytic skull and femur lesions in a mouse model of MM metastatic to bone. And mice that received HS1793 had superior survival, when compared to mice that received vehicle control.

The investigators also showed that HS1793 was cytotoxic to MM cells but not normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” the authors wrote.

This research was supported by grants from the Korean government. The investigators reported no potential conflicts of interest.

Photo by Esther Dyson

The American Society of Clinical Oncology (ASCO) has issued a policy statement addressing financial barriers to patient participation in cancer clinical trials.

ASCO’s policy statement outlines a series of recommendations designed to address multiple financial barriers that impede access to clinical trials, including patient costs that aren’t covered consistently by health insurance; a lack of information provided to patients about clinical trial costs; and limited available research data on financial hardships related to participation in clinical trials.

“Clinical trials are essential for evaluating the safety and efficacy of new cancer treatments, but cancer researchers have seen consistently low patient participation levels—especially among underserved patient populations—in part, due to the financial burdens facing many patients with cancer,” said ASCO President Monica M. Bertagnolli, MD.

“Addressing financial barriers will help improve the enrollment rate and the efficiency, quality, and applicability of cancer research. By including more—and more diverse—participants in our research studies, we expand our ability to care for all patients.”

The recommendations in ASCO’s policy statement include:

1. Improve payer clinical trial coverage policies. Payment policies should be revised to be made consistent, streamlined, and transparent to all stakeholders.

   1. Payers should have clear definitions of “routine costs.”
   2. Payers should streamline prior authorization processes and facilitate trial enrollment through provider reimbursement of clinical trial-related services.
   3. State Medicaid programs should universally guarantee coverage of routine care costs of clinical trials for their beneficiaries.
   4. The U.S. Centers for Medicare & Medicaid Services (CMS) should revise current policy that requires Medicare Advantage beneficiaries to revert to fee-for-service coverage during clinical trials.
   5. CMS’s Innovation Center should explore the effectiveness of alternative payment models in support of clinical trial accrual.

2. During the clinical trials development and enrollment process, provide patients with clear, transparent information about potential trial-related out-of-pocket costs and include mechanisms to support patient financial/health literacy.

   1. Clinical trial sponsors should perform—and make available to enrolling institutions—comprehensive, prospective coverage analyses.
   2. Research sites should consider offering in-house financial navigation/counseling to patients or consider partnering with organizations that provide such services.
   3. Design clinical trials to minimize incremental costs, consistent with scientific objectives and participant safety.

3. Remove impediments to ethically appropriate financial compensation for trial-related out-of-pocket costs. Provision of such financial support should not be considered undue inducement.

   1. Office for Human Research Protections should develop guidance on targeted financial support.

4. Incentivize research that will better characterize patient costs incurred for participating in cancer clinical trials and support the longer-term development of tools to identify and mitigate the risk of trial-associated financial hardship.

“Continued progress against cancer depends on improving patient access to participation in clinical research,” Dr. Bertagnolli said.

“The recommendations in ASCO’s statement aim to ensure that no patient is denied access to a clinical trial for financial reasons and that patients are not harmed financially because of their contributions to advancing science. Ultimately, this is about strengthening the nation’s cancer research enterprise as a whole.”

Photo by Esther Dyson

The American Society of Clinical Oncology (ASCO) has issued a policy statement addressing financial barriers to patient participation in cancer clinical trials.

ASCO’s policy statement outlines a series of recommendations designed to address multiple financial barriers that impede access to clinical trials, including patient costs that aren’t covered consistently by health insurance; a lack of information provided to patients about clinical trial costs; and limited available research data on financial hardships related to participation in clinical trials.

“Clinical trials are essential for evaluating the safety and efficacy of new cancer treatments, but cancer researchers have seen consistently low patient participation levels—especially among underserved patient populations—in part, due to the financial burdens facing many patients with cancer,” said ASCO President Monica M. Bertagnolli, MD.

“Addressing financial barriers will help improve the enrollment rate and the efficiency, quality, and applicability of cancer research. By including more—and more diverse—participants in our research studies, we expand our ability to care for all patients.”

The recommendations in ASCO’s policy statement include:

1. Improve payer clinical trial coverage policies. Payment policies should be revised to be made consistent, streamlined, and transparent to all stakeholders.

   1. Payers should have clear definitions of “routine costs.”
   2. Payers should streamline prior authorization processes and facilitate trial enrollment through provider reimbursement of clinical trial-related services.
   3. State Medicaid programs should universally guarantee coverage of routine care costs of clinical trials for their beneficiaries.
   4. The U.S. Centers for Medicare & Medicaid Services (CMS) should revise current policy that requires Medicare Advantage beneficiaries to revert to fee-for-service coverage during clinical trials.
   5. CMS’s Innovation Center should explore the effectiveness of alternative payment models in support of clinical trial accrual.

2. During the clinical trials development and enrollment process, provide patients with clear, transparent information about potential trial-related out-of-pocket costs and include mechanisms to support patient financial/health literacy.

   1. Clinical trial sponsors should perform—and make available to enrolling institutions—comprehensive, prospective coverage analyses.
   2. Research sites should consider offering in-house financial navigation/counseling to patients or consider partnering with organizations that provide such services.
   3. Design clinical trials to minimize incremental costs, consistent with scientific objectives and participant safety.

3. Remove impediments to ethically appropriate financial compensation for trial-related out-of-pocket costs. Provision of such financial support should not be considered undue inducement.

   1. Office for Human Research Protections should develop guidance on targeted financial support.

4. Incentivize research that will better characterize patient costs incurred for participating in cancer clinical trials and support the longer-term development of tools to identify and mitigate the risk of trial-associated financial hardship.

“Continued progress against cancer depends on improving patient access to participation in clinical research,” Dr. Bertagnolli said.

“The recommendations in ASCO’s statement aim to ensure that no patient is denied access to a clinical trial for financial reasons and that patients are not harmed financially because of their contributions to advancing science. Ultimately, this is about strengthening the nation’s cancer research enterprise as a whole.”

Photo by Esther Dyson

The American Society of Clinical Oncology (ASCO) has issued a policy statement addressing financial barriers to patient participation in cancer clinical trials.

ASCO’s policy statement outlines a series of recommendations designed to address multiple financial barriers that impede access to clinical trials, including patient costs that aren’t covered consistently by health insurance; a lack of information provided to patients about clinical trial costs; and limited available research data on financial hardships related to participation in clinical trials.

“Clinical trials are essential for evaluating the safety and efficacy of new cancer treatments, but cancer researchers have seen consistently low patient participation levels—especially among underserved patient populations—in part, due to the financial burdens facing many patients with cancer,” said ASCO President Monica M. Bertagnolli, MD.

“Addressing financial barriers will help improve the enrollment rate and the efficiency, quality, and applicability of cancer research. By including more—and more diverse—participants in our research studies, we expand our ability to care for all patients.”

The recommendations in ASCO’s policy statement include:

1. Improve payer clinical trial coverage policies. Payment policies should be revised to be made consistent, streamlined, and transparent to all stakeholders.

   1. Payers should have clear definitions of “routine costs.”
   2. Payers should streamline prior authorization processes and facilitate trial enrollment through provider reimbursement of clinical trial-related services.
   3. State Medicaid programs should universally guarantee coverage of routine care costs of clinical trials for their beneficiaries.
   4. The U.S. Centers for Medicare & Medicaid Services (CMS) should revise current policy that requires Medicare Advantage beneficiaries to revert to fee-for-service coverage during clinical trials.
   5. CMS’s Innovation Center should explore the effectiveness of alternative payment models in support of clinical trial accrual.

2. During the clinical trials development and enrollment process, provide patients with clear, transparent information about potential trial-related out-of-pocket costs and include mechanisms to support patient financial/health literacy.

   1. Clinical trial sponsors should perform—and make available to enrolling institutions—comprehensive, prospective coverage analyses.
   2. Research sites should consider offering in-house financial navigation/counseling to patients or consider partnering with organizations that provide such services.
   3. Design clinical trials to minimize incremental costs, consistent with scientific objectives and participant safety.

3. Remove impediments to ethically appropriate financial compensation for trial-related out-of-pocket costs. Provision of such financial support should not be considered undue inducement.

   1. Office for Human Research Protections should develop guidance on targeted financial support.

4. Incentivize research that will better characterize patient costs incurred for participating in cancer clinical trials and support the longer-term development of tools to identify and mitigate the risk of trial-associated financial hardship.

“Continued progress against cancer depends on improving patient access to participation in clinical research,” Dr. Bertagnolli said.

“The recommendations in ASCO’s statement aim to ensure that no patient is denied access to a clinical trial for financial reasons and that patients are not harmed financially because of their contributions to advancing science. Ultimately, this is about strengthening the nation’s cancer research enterprise as a whole.”

Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma.

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome (CRS), but the condition resolved without use of tocilizumab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated multiple myeloma. They had a median of six prior therapies. The median age was 60 years, and most of the patients were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51 x 10⁶ (n = 3), 152 x 10⁶ (n = 7), and 430 x 10⁶ (n = 1).

As of Aug. 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and five had thrombocytopenia.

Researchers suspected CRS in one patient, but the condition resolved without tocilizumab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was evaluable only by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

[email protected]

Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma.

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome (CRS), but the condition resolved without use of tocilizumab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated multiple myeloma. They had a median of six prior therapies. The median age was 60 years, and most of the patients were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51 x 10⁶ (n = 3), 152 x 10⁶ (n = 7), and 430 x 10⁶ (n = 1).

As of Aug. 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and five had thrombocytopenia.

Researchers suspected CRS in one patient, but the condition resolved without tocilizumab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was evaluable only by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

[email protected]

Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma.

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome (CRS), but the condition resolved without use of tocilizumab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated multiple myeloma. They had a median of six prior therapies. The median age was 60 years, and most of the patients were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51 x 10⁶ (n = 3), 152 x 10⁶ (n = 7), and 430 x 10⁶ (n = 1).

As of Aug. 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and five had thrombocytopenia.

Researchers suspected CRS in one patient, but the condition resolved without tocilizumab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was evaluable only by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

[email protected]

Photo by Bill Branson

HOUSTON—Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma (MM), according to the principal investigator of the STORM trial.

Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%.

The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

The trial’s principal investigator, Sundar Jagannath, MBBS, of the Mount Sinai School of Medicine in New York, N.Y., presented these results at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting as abstract MM-255.*

“The additional phase 2b clinical results ... are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said.

“Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM study.”

The study (NCT02336815) included 122 patients with penta-refractory MM. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.

The patients had received a median of 7 (range, 3-18) prior treatment regimens. Their median age was 65 (range, 40-86), 58% were male, and 53% had high-risk cytogenetics.

Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.

Response and survival

Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10^-6 and one at 1 x 10^-4.

Six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses (PRs), 16 (13.1%) had minimal responses (MRs), and 48 (39.3%) had stable disease (SD).

Sixteen patients (13.1%) had progressive disease (PD), and 10 (8.2%) were not evaluable for response.

The overall response rate (PR or better) was 26.2% (n=32), the clinical benefit rate (MR or better) was 39.3% (n=48), and the disease control rate (SD or better) was 78.7% (n=98).

The median duration of response was 4.4 months (range, <1 to 12.2 months).

The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had PD or were not evaluable.

The median overall survival was 8.6 months for the entire cohort. It was 15.6 months in patients with an MR or better and 1.7 months in patients who had PD or were not evaluable (P<0.0001).

Safety

The most common non-hematologic treatment-related adverse events (AEs) were fatigue/asthenia (69.9%), nausea (69.1%), anorexia (52.0%), weight loss (47.2%), vomiting (35.0%), diarrhea (33.3%), and hyponatremia (30.9%).

Hematologic treatment-related AEs included thrombocytopenia (67.5%), anemia (48.0%), neutropenia (35.8%), leukopenia (29.3%), and lymphopenia (13.8%).

The “most important” grade 3/4 AEs, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%).

Twenty-three patients (19.5%) discontinued treatment due to a related AE.

This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GSK.

*Information in the abstract differs from the presentation.

Photo by Bill Branson

HOUSTON—Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma (MM), according to the principal investigator of the STORM trial.

Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%.

The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

The trial’s principal investigator, Sundar Jagannath, MBBS, of the Mount Sinai School of Medicine in New York, N.Y., presented these results at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting as abstract MM-255.*

“The additional phase 2b clinical results ... are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said.

“Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM study.”

The study (NCT02336815) included 122 patients with penta-refractory MM. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.

The patients had received a median of 7 (range, 3-18) prior treatment regimens. Their median age was 65 (range, 40-86), 58% were male, and 53% had high-risk cytogenetics.

Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.

Response and survival

Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10^-6 and one at 1 x 10^-4.

Six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses (PRs), 16 (13.1%) had minimal responses (MRs), and 48 (39.3%) had stable disease (SD).

Sixteen patients (13.1%) had progressive disease (PD), and 10 (8.2%) were not evaluable for response.

The overall response rate (PR or better) was 26.2% (n=32), the clinical benefit rate (MR or better) was 39.3% (n=48), and the disease control rate (SD or better) was 78.7% (n=98).

The median duration of response was 4.4 months (range, <1 to 12.2 months).

The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had PD or were not evaluable.

The median overall survival was 8.6 months for the entire cohort. It was 15.6 months in patients with an MR or better and 1.7 months in patients who had PD or were not evaluable (P<0.0001).

Safety

The most common non-hematologic treatment-related adverse events (AEs) were fatigue/asthenia (69.9%), nausea (69.1%), anorexia (52.0%), weight loss (47.2%), vomiting (35.0%), diarrhea (33.3%), and hyponatremia (30.9%).

Hematologic treatment-related AEs included thrombocytopenia (67.5%), anemia (48.0%), neutropenia (35.8%), leukopenia (29.3%), and lymphopenia (13.8%).

The “most important” grade 3/4 AEs, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%).

Twenty-three patients (19.5%) discontinued treatment due to a related AE.

This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GSK.

*Information in the abstract differs from the presentation.

Photo by Bill Branson

HOUSTON—Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma (MM), according to the principal investigator of the STORM trial.

Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%.

The median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

The trial’s principal investigator, Sundar Jagannath, MBBS, of the Mount Sinai School of Medicine in New York, N.Y., presented these results at the Society of Hematologic Oncology (SOHO) 2018 Annual Meeting as abstract MM-255.*

“The additional phase 2b clinical results ... are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said.

“Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM study.”

The study (NCT02336815) included 122 patients with penta-refractory MM. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.

The patients had received a median of 7 (range, 3-18) prior treatment regimens. Their median age was 65 (range, 40-86), 58% were male, and 53% had high-risk cytogenetics.

Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.

Response and survival

Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10^-6 and one at 1 x 10^-4.

Six patients (4.9%) had very good partial responses, 24 (19.7%) had partial responses (PRs), 16 (13.1%) had minimal responses (MRs), and 48 (39.3%) had stable disease (SD).

Sixteen patients (13.1%) had progressive disease (PD), and 10 (8.2%) were not evaluable for response.

The overall response rate (PR or better) was 26.2% (n=32), the clinical benefit rate (MR or better) was 39.3% (n=48), and the disease control rate (SD or better) was 78.7% (n=98).

The median duration of response was 4.4 months (range, <1 to 12.2 months).

The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had PD or were not evaluable.

The median overall survival was 8.6 months for the entire cohort. It was 15.6 months in patients with an MR or better and 1.7 months in patients who had PD or were not evaluable (P<0.0001).

Safety

The most common non-hematologic treatment-related adverse events (AEs) were fatigue/asthenia (69.9%), nausea (69.1%), anorexia (52.0%), weight loss (47.2%), vomiting (35.0%), diarrhea (33.3%), and hyponatremia (30.9%).

Hematologic treatment-related AEs included thrombocytopenia (67.5%), anemia (48.0%), neutropenia (35.8%), leukopenia (29.3%), and lymphopenia (13.8%).

The “most important” grade 3/4 AEs, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%).

Twenty-three patients (19.5%) discontinued treatment due to a related AE.

This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GSK.

*Information in the abstract differs from the presentation.

Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.

Nephron/Wikimedia Commons

Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.

The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.

“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”

STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.

The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10^–6 and one at 1 x 10^–4.

Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.

[email protected]

SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255

Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.

Nephron/Wikimedia Commons

Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.

The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.

“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”

STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.

The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10^–6 and one at 1 x 10^–4.

Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.

[email protected]

SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255

Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.

Nephron/Wikimedia Commons

Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.

The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.

“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”

STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.

The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10^–6 and one at 1 x 10^–4.

Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.

[email protected]

SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255

multiple myeloma

BOSTON—Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma (MM).

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome, but the condition resolved without use of tociluzimab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated MM. They had a median of six prior therapies. Their median age was 60, and 73% were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51×10⁶ (n=3), 152×10⁶ (n=7), and 430×10⁶ (n=1).

As of August 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and 5 had thrombocytopenia.

Researchers suspected cytokine release syndrome in one patient, but the condition resolved without tociluzimab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was only evaluable by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

“We believe our advantages of a purified product, where all cells express the CAR molecule, and a product with high levels of stem cell memory T cells, producing a more gradual and prolonged immune response against tumor cells, provide a significantly better therapeutic index when compared with other CAR-T therapeutics. We are also encouraged that P-BCMA-101 is demonstrating significant efficacy even at doses that have been ineffective for other anti-BCMA CAR-T therapies and that our response rates continue to improve as the dose increases.”

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

multiple myeloma

BOSTON—Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma (MM).

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome, but the condition resolved without use of tociluzimab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated MM. They had a median of six prior therapies. Their median age was 60, and 73% were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51×10⁶ (n=3), 152×10⁶ (n=7), and 430×10⁶ (n=1).

As of August 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and 5 had thrombocytopenia.

Researchers suspected cytokine release syndrome in one patient, but the condition resolved without tociluzimab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was only evaluable by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

“We believe our advantages of a purified product, where all cells express the CAR molecule, and a product with high levels of stem cell memory T cells, producing a more gradual and prolonged immune response against tumor cells, provide a significantly better therapeutic index when compared with other CAR-T therapeutics. We are also encouraged that P-BCMA-101 is demonstrating significant efficacy even at doses that have been ineffective for other anti-BCMA CAR-T therapies and that our response rates continue to improve as the dose increases.”

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

multiple myeloma

BOSTON—Early results from a phase 1 trial suggest the chimeric antigen receptor (CAR) T-cell therapy P-BCMA-101 can produce responses in patients with relapsed/refractory multiple myeloma (MM).

All 11 patients treated have experienced some clinical response, with 8 patients achieving a partial response (PR) or better.

The most common adverse events were neutropenia and thrombocytopenia. One patient was suspected to have cytokine release syndrome, but the condition resolved without use of tociluzimab or steroids.

These results were presented at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics Inc., the company developing P-BCMA-101.

Dr. Ostertag presented data on 11 patients with heavily pretreated MM. They had a median of six prior therapies. Their median age was 60, and 73% were considered high risk.

Prior to receiving P-BCMA-101, patients received conditioning with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days.

Patients were then treated across three dose groups with average CAR T-cell doses of 51×10⁶ (n=3), 152×10⁶ (n=7), and 430×10⁶ (n=1).

As of August 10, 2018, all 11 patients were still on study.

There were no dose-limiting toxicities. Eight patients developed neutropenia, and 5 had thrombocytopenia.

Researchers suspected cytokine release syndrome in one patient, but the condition resolved without tociluzimab or steroid treatment. There was no neurotoxicity reported, and none of the patients required admission to an intensive care unit.

All patients showed improvement in biomarkers following treatment.

Ten patients were evaluable for response by International Myeloma Working Group criteria. Seven of these patients achieved at least a PR, including very good partial responses (VGPRs) and stringent complete response (CR).

The eleventh patient also responded to treatment, but this patient has oligosecretory disease and was only evaluable by PET. The patient had a near-CR by PET.

Poseida Therapeutics would not disclose additional details regarding how many patients achieved a PR, VGPR, or CR, but the company plans to release more information on response at an upcoming meeting.

“The latest data results show that P-BCMA-101 induces deep responses in a heavily pretreated population with relapsed/refractory multiple myeloma, with some patients reaching VGPR and even stringent CR at early efficacy assessments,” Dr. Ostertag said.

“We believe our advantages of a purified product, where all cells express the CAR molecule, and a product with high levels of stem cell memory T cells, producing a more gradual and prolonged immune response against tumor cells, provide a significantly better therapeutic index when compared with other CAR-T therapeutics. We are also encouraged that P-BCMA-101 is demonstrating significant efficacy even at doses that have been ineffective for other anti-BCMA CAR-T therapies and that our response rates continue to improve as the dose increases.”

This study (NCT03288493) is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.

A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.

In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.

When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.

“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.

This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.

They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.

Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.

Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.

They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.

The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.

SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.

A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.

In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.

When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.

“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.

This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.

They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.

Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.

Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.

They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.

The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.

SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.

A novel inhibitor of AKT pathway signaling showed significant cytotoxic activity in mouse models and in human cells isolated from patients with primary or relapsed multiple myeloma (MM), investigators reported.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The experimental agent, labeled HS1793, is a derivative of the naturally occurring antioxidant compound resveratrol. In preclinical studies, HS1793 was shown to offer “great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients,” according to Jin Han, MD, PhD, of Inje University in Busan, South Korea, and colleagues.

In a series of experiments, described in the journal Cancer Letters, the investigators demonstrated that HS1793 decreased AKT signaling to induce mitochondria-mediated cell death in multiple myeloma cells, and was cytotoxic and specific for myeloma cells in a mouse model of human metastatic myeloma, and in samples of human multiple myeloma cells.

When activated, AKT promotes oncogenesis by in turn activating other downstream pathways involved in proliferation or survival of malignant cells.

“AKT is frequently activated in MM cells and the incidence of AKT activation correlates positively with disease activity,” the authors noted.

They first screened 400 compounds, and narrowed in on resveratrol analogs, eventually choosing HS1793 as the most promising candidate.

This first experiment found evidence that suggested that the compound inhibits AKT activation by interfering with the interaction between AKT and its promoter HSP90.

They then showed in human MM cell lines that the antimyeloma action of HS1793 appeared to be from a dose-dependent effect that allowed for mitochondria-mediated programmed cell death.

In a separate series of experiments, they found that the inhibition by HS1793 of AKT/HSP90 interaction results in cell death by suppressing nuclear factor kappa–B (NF-KB) pathway signaling. The investigators had previously reported that a different compound, an inhibitor of spindle protein kinesin, induced MM cell death via inhibition of NF-KB signaling.

Next, the investigators showed that HS1793-induced cell death was caused by the direct inhibition of AKT that in turn suppressed NF-KB activation.

Finally, they showed in a mouse model of multiple myeloma metastatic to bone that HS1793 “dramatically decreased” lytic skull and femur lesions in treated mice, compared with mice treated with a vehicle placebo, and increased survival of the mice that received the AKT inhibitor.

They also showed that HS1793 was cytotoxic to multiple myeloma cells but not to normal plasma cells isolated from patients with MM.

“Given that HS1793 treatment specifically induced the death of primary and relapsed MM cells, HS1793 offers excellent translational potential as a novel MM therapy,” they wrote.

The study was supported by grants from the Korean government. The researchers reported having no potential conflicts of interest.

SOURCE: Song IS et al. Cancer Lett. 2018;432:205-15.

Photo by Rhoda Baer

Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.

The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.

The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.

For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.

However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.

Recommendations

The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.

Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.

Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.

However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.

Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.

Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.

Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.

Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.

Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.

The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.

The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.

Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.

Photo by Rhoda Baer

Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.

The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.

The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.

For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.

However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.

Recommendations

The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.

Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.

Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.

However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.

Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.

Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.

Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.

Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.

Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.

The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.

The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.

Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.

Photo by Rhoda Baer

Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.

The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.

The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.

For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.

However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.

Recommendations

The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.

Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.

Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.

However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.

Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.

Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.

Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.

Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.

Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.

The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.

The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.

Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.