Multiple Myeloma

Photo from Business Wire

Researchers say they’ve discovered why multiple myeloma (MM) patients may experience chemotherapy-induced peripheral neuropathy (CIPN) when treated with bortezomib.

The group’s study also suggests fingolimod—a drug approved to treat multiple sclerosis—could mitigate CIPN without compromising the efficacy of bortezomib.

Daniela Salvemini, PhD, of the Saint Louis University School of Medicine in St. Louis, Missouri, and her colleagues reported these findings in the Journal of Experimental Medicine.

The researchers said bortezomib causes CIPN in more than 40% of patients, but the reasons for this are unclear.

With their study, Dr Salvemini and her colleagues found that bortezomib accelerates the production of sphingolipids, which have been linked to neuropathic pain.

Rats treated with bortezomib began to accumulate 2 sphingolipid metabolites—sphingosine 1-phosphate and dihydrosphingosine 1-phosphate—in their spinal cords at the time they began to show signs of neuropathic pain.

Blocking the production of these molecules prevented the animals from developing CIPN in response to bortezomib.

Sphingosine 1-phosphate and dihydrosphingosine 1-phosphate can activate a cell surface receptor protein called S1PR1. Dr Salvemini and her colleagues determined that the 2 metabolites cause CIPN by activating S1PR1 on the surface of astrocytes, resulting in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.

Drugs that inhibit S1PR1 prevented rats from developing CIPN in response to bortezomib. One such inhibitor was fingolimod, a drug approved by the US Food and Drug Administration (FDA) to treat multiple sclerosis.

In addition to preventing CIPN, fingolimod did not inhibit bortezomib’s ability to kill MM cells. In fact, fingolimod has demonstrated anticancer activity in past studies.

“Because fingolimod shows promising anticancer potential and is already FDA-approved, we think that our findings in rats can be rapidly translated to the clinic to prevent and treat bortezomib-induced neuropathic pain,” Dr Salvemini said.

Photo from Business Wire

Researchers say they’ve discovered why multiple myeloma (MM) patients may experience chemotherapy-induced peripheral neuropathy (CIPN) when treated with bortezomib.

The group’s study also suggests fingolimod—a drug approved to treat multiple sclerosis—could mitigate CIPN without compromising the efficacy of bortezomib.

Daniela Salvemini, PhD, of the Saint Louis University School of Medicine in St. Louis, Missouri, and her colleagues reported these findings in the Journal of Experimental Medicine.

The researchers said bortezomib causes CIPN in more than 40% of patients, but the reasons for this are unclear.

With their study, Dr Salvemini and her colleagues found that bortezomib accelerates the production of sphingolipids, which have been linked to neuropathic pain.

Rats treated with bortezomib began to accumulate 2 sphingolipid metabolites—sphingosine 1-phosphate and dihydrosphingosine 1-phosphate—in their spinal cords at the time they began to show signs of neuropathic pain.

Blocking the production of these molecules prevented the animals from developing CIPN in response to bortezomib.

Sphingosine 1-phosphate and dihydrosphingosine 1-phosphate can activate a cell surface receptor protein called S1PR1. Dr Salvemini and her colleagues determined that the 2 metabolites cause CIPN by activating S1PR1 on the surface of astrocytes, resulting in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.

Drugs that inhibit S1PR1 prevented rats from developing CIPN in response to bortezomib. One such inhibitor was fingolimod, a drug approved by the US Food and Drug Administration (FDA) to treat multiple sclerosis.

In addition to preventing CIPN, fingolimod did not inhibit bortezomib’s ability to kill MM cells. In fact, fingolimod has demonstrated anticancer activity in past studies.

“Because fingolimod shows promising anticancer potential and is already FDA-approved, we think that our findings in rats can be rapidly translated to the clinic to prevent and treat bortezomib-induced neuropathic pain,” Dr Salvemini said.

Photo from Business Wire

Researchers say they’ve discovered why multiple myeloma (MM) patients may experience chemotherapy-induced peripheral neuropathy (CIPN) when treated with bortezomib.

The group’s study also suggests fingolimod—a drug approved to treat multiple sclerosis—could mitigate CIPN without compromising the efficacy of bortezomib.

Daniela Salvemini, PhD, of the Saint Louis University School of Medicine in St. Louis, Missouri, and her colleagues reported these findings in the Journal of Experimental Medicine.

The researchers said bortezomib causes CIPN in more than 40% of patients, but the reasons for this are unclear.

With their study, Dr Salvemini and her colleagues found that bortezomib accelerates the production of sphingolipids, which have been linked to neuropathic pain.

Rats treated with bortezomib began to accumulate 2 sphingolipid metabolites—sphingosine 1-phosphate and dihydrosphingosine 1-phosphate—in their spinal cords at the time they began to show signs of neuropathic pain.

Blocking the production of these molecules prevented the animals from developing CIPN in response to bortezomib.

Sphingosine 1-phosphate and dihydrosphingosine 1-phosphate can activate a cell surface receptor protein called S1PR1. Dr Salvemini and her colleagues determined that the 2 metabolites cause CIPN by activating S1PR1 on the surface of astrocytes, resulting in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.

Drugs that inhibit S1PR1 prevented rats from developing CIPN in response to bortezomib. One such inhibitor was fingolimod, a drug approved by the US Food and Drug Administration (FDA) to treat multiple sclerosis.

In addition to preventing CIPN, fingolimod did not inhibit bortezomib’s ability to kill MM cells. In fact, fingolimod has demonstrated anticancer activity in past studies.

“Because fingolimod shows promising anticancer potential and is already FDA-approved, we think that our findings in rats can be rapidly translated to the clinic to prevent and treat bortezomib-induced neuropathic pain,” Dr Salvemini said.

 

NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.

This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.

Bruce Jancin/MDedge News

Embedded within the larger Icelandic project is a randomized, controlled clinical trial. In that trial, individuals who screen positive for monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma will be assigned to early intervention or the standard watch-and-wait approach to establish whether a proactive intervention strategy favorably alters the natural history of multiple myeloma and improves survival, explained Dr. Mikhael, chief medical officer at the International Myeloma Foundation.

The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).

The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.

In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.

Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.

 

In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.

Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.

An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.

When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.

A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).

 

CRAB vs. SLiM CRAB

Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).

If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).

“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”

The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.

 

Not all MGUS needs a bone marrow biopsy

A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.

The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.

“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”

Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.

[email protected]

 

NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.

This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.

Bruce Jancin/MDedge News

Embedded within the larger Icelandic project is a randomized, controlled clinical trial. In that trial, individuals who screen positive for monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma will be assigned to early intervention or the standard watch-and-wait approach to establish whether a proactive intervention strategy favorably alters the natural history of multiple myeloma and improves survival, explained Dr. Mikhael, chief medical officer at the International Myeloma Foundation.

The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).

The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.

In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.

Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.

 

In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.

Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.

An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.

When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.

A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).

 

CRAB vs. SLiM CRAB

Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).

If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).

“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”

The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.

 

Not all MGUS needs a bone marrow biopsy

A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.

The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.

“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”

Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.

[email protected]

 

NEW ORLEANS – Everyone aged 40 years and older on the island nation of Iceland is being screened for monoclonal gammopathy of undetermined significance, smoldering myeloma, and full-blown multiple myeloma in an unprecedented project to identify the malignancy’s genetic roots, Joseph Mikhael, MD, said at the annual meeting of the American College of Physicians.

This effort to decode the underlying genetics of multiple myeloma is enormously facilitated by the fact that the DNA sequencing of the entire Icelandic population is already known, and everyone’s blood samples are stored in the national health care system.

Bruce Jancin/MDedge News

Embedded within the larger Icelandic project is a randomized, controlled clinical trial. In that trial, individuals who screen positive for monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma will be assigned to early intervention or the standard watch-and-wait approach to establish whether a proactive intervention strategy favorably alters the natural history of multiple myeloma and improves survival, explained Dr. Mikhael, chief medical officer at the International Myeloma Foundation.

The International Myeloma Foundation is funding the Icelandic project, called iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).

The results of iStopMM could be far reaching, in part because the findings will show whether screening an asymptomatic general population for MGUS – as for example, all American adults – is worthwhile.

In the interim, it’s important for primary care physicians to recognize when it is and isn’t appropriate to order a serum protein electrophoresis (SPE) study, on which the diagnosis of MGUS hinges. It’s also essential to recognize the difference between smoldering and full-blown multiple myeloma, because the distinction has implications for patient monitoring and treatment, added Dr. Mikhael, a hematologist at the City of Hope Cancer Center in Duarte, Calif.

Multiple myeloma accounts for 1% of all cancers and 10% of hematologic malignancies. MGUS is an obligate precursor of multiple myeloma. But MGUS is common, and therein lies a challenge for physicians – as well as a major source of anxiety for many MGUS-positive patients.

 

In a 12-year-old study, MGUS had a 3% prevalence in the general U.S. population older than age 50 years, and a greater than 5% prevalence after age 70. However, Dr. Mikhael thinks that more refined testing will show the true figure to be close to 10%. Thus, the great majority of patients with MGUS will never develop multiple myeloma.

Pending the potentially practice-changing outcome of iStopMM, Dr. Mikhael said SPE shouldn’t be ordered routinely in an asymptomatic patient, even one with a positive family history for multiple myeloma. The annual cost of monitoring the roughly 540,000 U.S. patients who now carry a diagnosis of MGUS – typically established as an incidental finding by primary care physicians while doing a work-up for another reason – is at least $110 million. And there’s no point in adding to that burden until the benefit of mass screening has been established.

An SPE is appropriate, however, in an older patient with unexplained anemia, known low immunoglobulin levels, unexplained renal insufficiency or neuropathy, or osteopenia or osteoporosis inconsistent with the patient’s age or gender – provided the patient doesn’t have a coexisting plasma cell dyscrasia or B-cell lymphoproliferative disorder, which would throw off the prognostic value of the test results, he continued.

When ordering an SPE to rule in/out MGUS, it’s essential to also order serum free light-chain testing, because it provides key prognostic information.

A landmark study led by investigators at the Mayo Clinic demonstrated that the risk of progression of MGUS to multiple myeloma or a related disorder is independently predicted by three key factors: a high serum M-protein spike of 15 g/L or more on the SPE; the presence of non-IgG MGUS; and an abnormal serum free light-chain ratio of less than 0.26 or more than 1.65. In this study, the 20-year risk of malignant transformation of MGUS ranged from 58% if all three risk factors were present, to just 5% if none were (Blood. 2005 Aug 1;106[3]:812-7).

 

CRAB vs. SLiM CRAB

Myeloma, smoldering myeloma, and MGUS were redefined a few years ago to reflect differences in prognosis. MGUS still requires the presence of a serum monoclonal protein in a concentration of 3 g/dL or less, less than 10% plasmacytosis in the bone marrow, asymptomatic status, and absence of end-organ damage as traditionally defined in the acronym CRAB (calcium elevation, renal insufficiency, anemia, or bony disease).

If CRAB is present in a patient with at least 10% plasma cells in bone marrow, that is by definition multiple myeloma warranting treatment. Smoldering myeloma requires at least 10% plasmacytosis in bone marrow and absence of the CRAB criteria. However, in a significant change, ultra–high-risk smoldering melanoma, defined by the acronym SLiM CRAB, is now considered active myeloma and should be treated (Lancet Oncol. 2014 Nov;15[12]:e538-48).

“Traditionally, we waited until CRAB [to define myeloma],” Dr. Mikhael explained. “But if you’re running toward a cliff, I don’t have to wait until you’re falling off to know you’re in trouble.”

The SLiM half of SLiM CRAB consists of 60% or more plasmacytosis in bone marrow, light chains in a kappa-to-lambda or lambda-to-kappa ratio of greater than 100, and MRI showing one or more focal lesions. If a patient is SLiM, with or without CRAB, that is now considered active myeloma warranting treatment.

 

Not all MGUS needs a bone marrow biopsy

A bone marrow biopsy and skeletal survey via whole-body CT or conventional radiographs can be deferred in patients with low-risk MGUS and no bony symptoms. Using the Mayo Clinic risk stratification model, low risk is defined as a serum M protein of 1.5 g/dL or less on SPE, an IgG isotype, and a normal free light-chain ratio.

The lifetime risk of progression in patients with MGUS who meet all three criteria is only about 2%. They can be followed at 6 months with an SPE, free light-chain testing, a CBC, and serum calcium and creatinine, then annually thereafter.

“For those who aren’t in this low-risk category, we actually do need to do a bone marrow test,” according to Dr. Mikhael. “Then, based on that, if they have malignancy, send them to a myeloma geek like me or to another hematologist. And if they don’t have a malignancy, they can be followed at 6 months and then subsequently at least every year.”

Dr. Mikhael has received research grants from AbbVie, Celgene, and Sanofi.

[email protected]

Photo by Barry Riley

Exposure to the 9/11 World Trade Center (WTC) disaster site may increase the risk of monoclonal gammopathy of undetermined significance (MGUS) and early development of multiple myeloma (MM).

Researchers found that firefighters exposed to the site had a nearly 2-fold higher risk of MGUS than a control population.

And those firefighters who developed MM were diagnosed 12 years earlier than MM patients in the general US population.

These findings were published in JAMA Oncology.

Previous studies suggested that MGUS and MM tend to develop after exposure to toxic chemicals, and individuals exposed to the WTC disaster site have an increased risk of developing cancers.

The aerosolized dust from the collapsed WTC towers exposed firefighters and other first responders to high levels of polychlorinated biphenyls, polycyclic aromatic hydrocarbons, dioxins, asbestos, and other potential carcinogens, as well as diesel smoke from heavy machinery used in the 10-month rescue and recovery effort.

“With our 2011 study in The Lancet, we were the first to show that first responders were more likely to get many different types of cancer,” said David J. Prezant, MD, of Albert Einstein College of Medicine in Bronx, New York.

“We carried out this new study to do more than just treat cancer. We wanted to find early, predictive signs of cancer that would allow us to screen people and monitor those found to be at risk. By detecting MGUS, which predicts the development of multiple myeloma, we are able to do that.”

For statistical reasons, the study population was limited to 781 white, male WTC-exposed firefighters ages 50 to 79.

The researchers assess the prevalence of MGUS in these firefighters and compared it to the prevalence of MGUS in a non-exposed comparison group—men living in Olmsted County, Minnesota.

The prevalence of MGUS was 1.8-fold higher in the firefighters. There were 7.63 cases of MGUS per 100 firefighters and 4.34 cases per 100 non-exposed men.

The researchers also found the prevalence of light-chain MGUS was 3.1-fold higher in the firefighters than in the controls. The prevalence rate of light-chain MGUS was 3.08 and 0.98 per 100 persons, respectively.

“We saw a significantly higher incidence of MGUS in these first responders, and they’re developing it at a young age,” said study author Amit Verma, MBBS, of Albert Einstein College of Medicine.

The subjects’ early development of MGUS suggests they may face an increased risk for early onset MM as well.

In a separate analysis, the researchers examined 16 cases of MM among white, male WTC-exposed firefighters diagnosed between September 12, 2001, and July 1, 2017.

Their average age at diagnosis was 57, or 12 years younger than the average age for MM diagnosis in the US.

The researchers also found that 7 of 14 evaluable cases were light-chain MM. They said this is more than double the rate observed in other populations—50% vs 20%.

In the population of firefighters screened for MGUS, 38% (18/47) of those who had MGUS were found to have the light-chain subtype.

The researchers said these findings are of interest because previous research revealed associations between light-chain MM/MGUS and exposure to toxins and chronic immune stimulation.

The team also assessed CD20 expression in a subset of 7 MM patients. Five of these patients (71%) had CD20-positive cells, which is associated with poor prognosis.

Based on these findings, the researchers recommend that physicians screen first responders exposed to the WTC disaster site for MGUS.

“Screening for multiple myeloma risk by testing for MGUS is something we can offer these first responders, which is why this study is important,” Dr Prezant said.

Photo by Barry Riley

Exposure to the 9/11 World Trade Center (WTC) disaster site may increase the risk of monoclonal gammopathy of undetermined significance (MGUS) and early development of multiple myeloma (MM).

Researchers found that firefighters exposed to the site had a nearly 2-fold higher risk of MGUS than a control population.

And those firefighters who developed MM were diagnosed 12 years earlier than MM patients in the general US population.

These findings were published in JAMA Oncology.

Previous studies suggested that MGUS and MM tend to develop after exposure to toxic chemicals, and individuals exposed to the WTC disaster site have an increased risk of developing cancers.

The aerosolized dust from the collapsed WTC towers exposed firefighters and other first responders to high levels of polychlorinated biphenyls, polycyclic aromatic hydrocarbons, dioxins, asbestos, and other potential carcinogens, as well as diesel smoke from heavy machinery used in the 10-month rescue and recovery effort.

“With our 2011 study in The Lancet, we were the first to show that first responders were more likely to get many different types of cancer,” said David J. Prezant, MD, of Albert Einstein College of Medicine in Bronx, New York.

“We carried out this new study to do more than just treat cancer. We wanted to find early, predictive signs of cancer that would allow us to screen people and monitor those found to be at risk. By detecting MGUS, which predicts the development of multiple myeloma, we are able to do that.”

For statistical reasons, the study population was limited to 781 white, male WTC-exposed firefighters ages 50 to 79.

The researchers assess the prevalence of MGUS in these firefighters and compared it to the prevalence of MGUS in a non-exposed comparison group—men living in Olmsted County, Minnesota.

The prevalence of MGUS was 1.8-fold higher in the firefighters. There were 7.63 cases of MGUS per 100 firefighters and 4.34 cases per 100 non-exposed men.

The researchers also found the prevalence of light-chain MGUS was 3.1-fold higher in the firefighters than in the controls. The prevalence rate of light-chain MGUS was 3.08 and 0.98 per 100 persons, respectively.

“We saw a significantly higher incidence of MGUS in these first responders, and they’re developing it at a young age,” said study author Amit Verma, MBBS, of Albert Einstein College of Medicine.

The subjects’ early development of MGUS suggests they may face an increased risk for early onset MM as well.

In a separate analysis, the researchers examined 16 cases of MM among white, male WTC-exposed firefighters diagnosed between September 12, 2001, and July 1, 2017.

Their average age at diagnosis was 57, or 12 years younger than the average age for MM diagnosis in the US.

The researchers also found that 7 of 14 evaluable cases were light-chain MM. They said this is more than double the rate observed in other populations—50% vs 20%.

In the population of firefighters screened for MGUS, 38% (18/47) of those who had MGUS were found to have the light-chain subtype.

The researchers said these findings are of interest because previous research revealed associations between light-chain MM/MGUS and exposure to toxins and chronic immune stimulation.

The team also assessed CD20 expression in a subset of 7 MM patients. Five of these patients (71%) had CD20-positive cells, which is associated with poor prognosis.

Based on these findings, the researchers recommend that physicians screen first responders exposed to the WTC disaster site for MGUS.

“Screening for multiple myeloma risk by testing for MGUS is something we can offer these first responders, which is why this study is important,” Dr Prezant said.

Photo by Barry Riley

Exposure to the 9/11 World Trade Center (WTC) disaster site may increase the risk of monoclonal gammopathy of undetermined significance (MGUS) and early development of multiple myeloma (MM).

Researchers found that firefighters exposed to the site had a nearly 2-fold higher risk of MGUS than a control population.

And those firefighters who developed MM were diagnosed 12 years earlier than MM patients in the general US population.

These findings were published in JAMA Oncology.

Previous studies suggested that MGUS and MM tend to develop after exposure to toxic chemicals, and individuals exposed to the WTC disaster site have an increased risk of developing cancers.

The aerosolized dust from the collapsed WTC towers exposed firefighters and other first responders to high levels of polychlorinated biphenyls, polycyclic aromatic hydrocarbons, dioxins, asbestos, and other potential carcinogens, as well as diesel smoke from heavy machinery used in the 10-month rescue and recovery effort.

“With our 2011 study in The Lancet, we were the first to show that first responders were more likely to get many different types of cancer,” said David J. Prezant, MD, of Albert Einstein College of Medicine in Bronx, New York.

“We carried out this new study to do more than just treat cancer. We wanted to find early, predictive signs of cancer that would allow us to screen people and monitor those found to be at risk. By detecting MGUS, which predicts the development of multiple myeloma, we are able to do that.”

For statistical reasons, the study population was limited to 781 white, male WTC-exposed firefighters ages 50 to 79.

The researchers assess the prevalence of MGUS in these firefighters and compared it to the prevalence of MGUS in a non-exposed comparison group—men living in Olmsted County, Minnesota.

The prevalence of MGUS was 1.8-fold higher in the firefighters. There were 7.63 cases of MGUS per 100 firefighters and 4.34 cases per 100 non-exposed men.

The researchers also found the prevalence of light-chain MGUS was 3.1-fold higher in the firefighters than in the controls. The prevalence rate of light-chain MGUS was 3.08 and 0.98 per 100 persons, respectively.

“We saw a significantly higher incidence of MGUS in these first responders, and they’re developing it at a young age,” said study author Amit Verma, MBBS, of Albert Einstein College of Medicine.

The subjects’ early development of MGUS suggests they may face an increased risk for early onset MM as well.

In a separate analysis, the researchers examined 16 cases of MM among white, male WTC-exposed firefighters diagnosed between September 12, 2001, and July 1, 2017.

Their average age at diagnosis was 57, or 12 years younger than the average age for MM diagnosis in the US.

The researchers also found that 7 of 14 evaluable cases were light-chain MM. They said this is more than double the rate observed in other populations—50% vs 20%.

In the population of firefighters screened for MGUS, 38% (18/47) of those who had MGUS were found to have the light-chain subtype.

The researchers said these findings are of interest because previous research revealed associations between light-chain MM/MGUS and exposure to toxins and chronic immune stimulation.

The team also assessed CD20 expression in a subset of 7 MM patients. Five of these patients (71%) had CD20-positive cells, which is associated with poor prognosis.

Based on these findings, the researchers recommend that physicians screen first responders exposed to the WTC disaster site for MGUS.

“Screening for multiple myeloma risk by testing for MGUS is something we can offer these first responders, which is why this study is important,” Dr Prezant said.

 

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, and will “completely transform oncology,” according to Carl June, MD.

That approval is anticipated sometime in 2019.

“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.

The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.

Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.

Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.

“Now he considers himself cured,” Dr. June said.

 

More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.

The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.

Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

 

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.

Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.

Sharon Worcester/MDedge News

The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.

LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.

 

The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.

Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.

“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.

With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.

 

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.

Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.

That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.

“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

 

CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.

“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”

Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

 

[email protected]

 

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, and will “completely transform oncology,” according to Carl June, MD.

That approval is anticipated sometime in 2019.

“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.

The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.

Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.

Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.

“Now he considers himself cured,” Dr. June said.

 

More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.

The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.

Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

 

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.

Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.

Sharon Worcester/MDedge News

The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.

LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.

 

The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.

Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.

“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.

With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.

 

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.

Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.

That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.

“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

 

CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.

“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”

Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

 

[email protected]

 

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, and will “completely transform oncology,” according to Carl June, MD.

That approval is anticipated sometime in 2019.

“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.

The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.

Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.

Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.

“Now he considers himself cured,” Dr. June said.

 

More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.

The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.

Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

 

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.

Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.

Sharon Worcester/MDedge News

The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.

LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.

 

The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.

Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.

“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.

With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.

 

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.

Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.

That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.

“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

 

CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.

“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”

Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

 

[email protected]

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Photo by Petr Kratochvil

CHICAGO—Researchers have identified a link between habitual physical activity (PA) and mortality among cancer patients.

Engaging in regular PA, both pre- and post-diagnosis, was associated with a significantly lower risk of death for the entire population studied and for patients with 8 specific types of cancer.

However, the association was not significant for patients with other cancer types, including hematologic malignancies.

Rikki Cannioto, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues presented these findings at the AACR Annual Meeting 2018 (abstract 5254*).

The researchers examined the association between habitual PA and outcomes in 5807 cancer patients enrolled in the Data Bank and BioRepository at Roswell Park between 2003 and 2016.

The population was 54.8% female and 93% white. The average age at diagnosis was 60.6 years.

The researchers looked at patterns of PA over time, from the decade before the cancer was diagnosed and continuing for up to 1 year after diagnosis.

Patients who engaged in regular, moderate- to vigorous-intensity PA (such as walking, running, aerobics, or other cardiovascular exercise) both before and after their diagnosis were considered habitually active, whereas those who did not exercise regularly were considered habitually inactive.

Overall, 52% of patients reported habitual activity, and 19% reported habitual inactivity. Twenty-three percent of patients said their activity level decreased after diagnosis, and 6% said their activity level increased.

Patients were followed through January 31, 2018. The median time to follow-up was 53 months, and 33.7% of patients (n=1956) died during the follow-up period.

Results

The researchers found that patients who were active before and after diagnosis were 40% more likely to survive than those who were habitually inactive (P<0.001). Habitually inactive patients had a 66% increased risk of mortality compared to active patients.

The habitually active patients had a 37-month mean survival advantage over the inactive patients.

In addition, patients whose activity level increased after diagnosis had a 25% lower risk of death than patients who remained inactive after diagnosis.

The researchers observed a significant (P<0.05) association between habitual PA and decreased mortality in patients with breast, colon, prostate, bladder, endometrial, ovarian, esophageal, and skin cancers.

However, the association between PA and mortality was not significant for patients with hematologic malignancies (P=0.59) or kidney, liver, lung, pancreas, stomach, or “other” cancers.

The researchers said the associations between habitual PA and decreased mortality remained consistent regardless of a patient’s sex, tumor stage, smoking status, or body mass index.

“[W]hen it comes to exercise, something is better than nothing, but regular, weekly exercise seems to really make a difference,” Dr Cannioto said.

“In fact, patients who were physically active 3 or 4 days a week experienced an even greater benefit than those who exercised daily, and patients who had only 1 or 2 days of regular activity per week did nearly as well. This is particularly encouraging, as cancer patients and survivors can be overwhelmed by current physical activity recommendations.”

*Information in the abstract differs from the presentation.

Image from Ed Uthman

Prothena Corporation plc is discontinuing development of NEOD001, an investigational antibody intended for the treatment of AL amyloidosis.

The company’s decision was based on results from the phase 2b PRONTO study and a futility analysis of the phase 3 VITAL study.

NEOD001 did not meet the primary or secondary endpoints of the PRONTO study, so Prothena asked an independent data monitoring committee to review a futility analysis of the ongoing VITAL study.

The committee recommended discontinuation of the VITAL study, so Prothena decided to discontinue all development of NEOD001, including the VITAL study and open-label extension studies.

“We are deeply disappointed by this outcome, particularly for patients suffering from this devastating disease,” said Gene Kinney, PhD, president and chief executive officer of Prothena.

“We are surprised by the results from these 2 placebo-controlled studies and will continue to analyze the resulting data to share insights with our collaborators in the scientific, medical, and advocacy communities.”

Phase 3 VITAL study

The VITAL study was a multicenter, randomized, double-blind, placebo-controlled study of NEOD001 in treatment-naïve patients with AL amyloidosis and cardiac dysfunction.

The study enrolled 260 patients who were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 or placebo via intravenous infusion every 28 days. Patients in both arms received concurrent standard of care therapy.

The composite primary endpoint was event-based, with all-cause mortality or cardiac hospitalizations counted as events.

The futility analysis, based on 103 adjudicated events of the 156 events specified to complete the study, was not statistically significant. The hazard ratio was 0.84 favoring NEOD001 versus the control arm.

Phase 2b PRONTO study

The PRONTO study was a multicenter, randomized, double-blind, placebo-controlled study of NEOD001 in previously treated patients with AL amyloidosis and persistent cardiac dysfunction.

The study enrolled 129 patients who were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 (n=66) or placebo (n=63) via intravenous infusion every 28 days.

There was no significant difference between the treatment arms for any of the study’s endpoints.

The primary endpoint was cardiac best response, as assessed by N-terminal pro B-type natriuretic peptide (NT-proBNP) through 12 months of treatment. This endpoint was achieved by 39.4% of patients in the NEOD001 arm and 47.6% in the placebo arm.

The NT-proBNP rate of change (slope) through 12 months of treatment was 9.80 in the NEOD001 arm and 81.42 in the placebo arm.

The mean change in Short-form 36 Physical Component Summary Score after 12 months of treatment was 0.19 and 0.97, respectively.

The median change in 6-Minute Walk Test distance after 12 months of treatment was 19.25 m and 8.00 m, respectively.

And the mean change in Neuropathy Impairment Score of the Lower Limb after 12 months of treatment was -1.20 and -0.60, respectively.

The rate of renal best response (as assessed by proteinuria and estimated glomerular filtration rate) through 12 months of treatment was 53.8% in the NEOD001 arm and 33.3% in the placebo arm.

The rate of all-cause mortality was 4.5% (n=3) and 9.5% (n=6), respectively.

Prothena said NEOD001 was generally safe and well tolerated in this trial.

Image from Ed Uthman

Prothena Corporation plc is discontinuing development of NEOD001, an investigational antibody intended for the treatment of AL amyloidosis.

The company’s decision was based on results from the phase 2b PRONTO study and a futility analysis of the phase 3 VITAL study.

NEOD001 did not meet the primary or secondary endpoints of the PRONTO study, so Prothena asked an independent data monitoring committee to review a futility analysis of the ongoing VITAL study.

The committee recommended discontinuation of the VITAL study, so Prothena decided to discontinue all development of NEOD001, including the VITAL study and open-label extension studies.

“We are deeply disappointed by this outcome, particularly for patients suffering from this devastating disease,” said Gene Kinney, PhD, president and chief executive officer of Prothena.

“We are surprised by the results from these 2 placebo-controlled studies and will continue to analyze the resulting data to share insights with our collaborators in the scientific, medical, and advocacy communities.”

Phase 3 VITAL study

The VITAL study was a multicenter, randomized, double-blind, placebo-controlled study of NEOD001 in treatment-naïve patients with AL amyloidosis and cardiac dysfunction.

The study enrolled 260 patients who were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 or placebo via intravenous infusion every 28 days. Patients in both arms received concurrent standard of care therapy.

The composite primary endpoint was event-based, with all-cause mortality or cardiac hospitalizations counted as events.

The futility analysis, based on 103 adjudicated events of the 156 events specified to complete the study, was not statistically significant. The hazard ratio was 0.84 favoring NEOD001 versus the control arm.

Phase 2b PRONTO study

The PRONTO study was a multicenter, randomized, double-blind, placebo-controlled study of NEOD001 in previously treated patients with AL amyloidosis and persistent cardiac dysfunction.

The study enrolled 129 patients who were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 (n=66) or placebo (n=63) via intravenous infusion every 28 days.

There was no significant difference between the treatment arms for any of the study’s endpoints.

The primary endpoint was cardiac best response, as assessed by N-terminal pro B-type natriuretic peptide (NT-proBNP) through 12 months of treatment. This endpoint was achieved by 39.4% of patients in the NEOD001 arm and 47.6% in the placebo arm.

The NT-proBNP rate of change (slope) through 12 months of treatment was 9.80 in the NEOD001 arm and 81.42 in the placebo arm.

The mean change in Short-form 36 Physical Component Summary Score after 12 months of treatment was 0.19 and 0.97, respectively.

The median change in 6-Minute Walk Test distance after 12 months of treatment was 19.25 m and 8.00 m, respectively.

And the mean change in Neuropathy Impairment Score of the Lower Limb after 12 months of treatment was -1.20 and -0.60, respectively.

The rate of renal best response (as assessed by proteinuria and estimated glomerular filtration rate) through 12 months of treatment was 53.8% in the NEOD001 arm and 33.3% in the placebo arm.

The rate of all-cause mortality was 4.5% (n=3) and 9.5% (n=6), respectively.

Prothena said NEOD001 was generally safe and well tolerated in this trial.

Image from Ed Uthman

Prothena Corporation plc is discontinuing development of NEOD001, an investigational antibody intended for the treatment of AL amyloidosis.

The company’s decision was based on results from the phase 2b PRONTO study and a futility analysis of the phase 3 VITAL study.

NEOD001 did not meet the primary or secondary endpoints of the PRONTO study, so Prothena asked an independent data monitoring committee to review a futility analysis of the ongoing VITAL study.

The committee recommended discontinuation of the VITAL study, so Prothena decided to discontinue all development of NEOD001, including the VITAL study and open-label extension studies.

“We are deeply disappointed by this outcome, particularly for patients suffering from this devastating disease,” said Gene Kinney, PhD, president and chief executive officer of Prothena.

“We are surprised by the results from these 2 placebo-controlled studies and will continue to analyze the resulting data to share insights with our collaborators in the scientific, medical, and advocacy communities.”

Phase 3 VITAL study

The VITAL study was a multicenter, randomized, double-blind, placebo-controlled study of NEOD001 in treatment-naïve patients with AL amyloidosis and cardiac dysfunction.

The study enrolled 260 patients who were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 or placebo via intravenous infusion every 28 days. Patients in both arms received concurrent standard of care therapy.

The composite primary endpoint was event-based, with all-cause mortality or cardiac hospitalizations counted as events.

The futility analysis, based on 103 adjudicated events of the 156 events specified to complete the study, was not statistically significant. The hazard ratio was 0.84 favoring NEOD001 versus the control arm.

Phase 2b PRONTO study

The PRONTO study was a multicenter, randomized, double-blind, placebo-controlled study of NEOD001 in previously treated patients with AL amyloidosis and persistent cardiac dysfunction.

The study enrolled 129 patients who were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 (n=66) or placebo (n=63) via intravenous infusion every 28 days.

There was no significant difference between the treatment arms for any of the study’s endpoints.

The primary endpoint was cardiac best response, as assessed by N-terminal pro B-type natriuretic peptide (NT-proBNP) through 12 months of treatment. This endpoint was achieved by 39.4% of patients in the NEOD001 arm and 47.6% in the placebo arm.

The NT-proBNP rate of change (slope) through 12 months of treatment was 9.80 in the NEOD001 arm and 81.42 in the placebo arm.

The mean change in Short-form 36 Physical Component Summary Score after 12 months of treatment was 0.19 and 0.97, respectively.

The median change in 6-Minute Walk Test distance after 12 months of treatment was 19.25 m and 8.00 m, respectively.

And the mean change in Neuropathy Impairment Score of the Lower Limb after 12 months of treatment was -1.20 and -0.60, respectively.

The rate of renal best response (as assessed by proteinuria and estimated glomerular filtration rate) through 12 months of treatment was 53.8% in the NEOD001 arm and 33.3% in the placebo arm.

The rate of all-cause mortality was 4.5% (n=3) and 9.5% (n=6), respectively.

Prothena said NEOD001 was generally safe and well tolerated in this trial.

Photo courtesy of CDC

New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.

The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.

After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.

Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.

The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.

The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).

Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.

Intervention

The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.

Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.

Results

The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.

After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).

Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).

In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.

Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.

All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.

The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.

Photo courtesy of CDC

New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.

The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.

After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.

Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.

The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.

The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).

Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.

Intervention

The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.

Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.

Results

The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.

After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).

Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).

In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.

Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.

All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.

The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.

Photo courtesy of CDC

New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.

The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.

After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.

Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.

The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.

The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).

Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.

Intervention

The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.

Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.

Results

The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.

After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).

Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).

In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.

Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.

All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.

The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.

multiple myeloma

CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).

The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.

However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.

There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).

“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.

Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.

The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.

Conditioning consists of standard cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.

The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 10⁶ P-BCMA-101 cells/kg.

The 3 patients who have received this dose had 6 to 9 prior therapies.

Patient 1

The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).

Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.

The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12.  She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.

The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.

Patient 2

The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).

Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.

Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.

AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.

Patient 3

The third patient was a 65-year-old female with lambda light chain MM and del13q14.

Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.

AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).

“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.

In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 10⁶ P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.

 

About P-BCMA-101

P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).

Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.

P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).

The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.

multiple myeloma

CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).

The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.

However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.

There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).

“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.

Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.

The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.

Conditioning consists of standard cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.

The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 10⁶ P-BCMA-101 cells/kg.

The 3 patients who have received this dose had 6 to 9 prior therapies.

Patient 1

The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).

Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.

The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12.  She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.

The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.

Patient 2

The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).

Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.

Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.

AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.

Patient 3

The third patient was a 65-year-old female with lambda light chain MM and del13q14.

Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.

AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).

“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.

In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 10⁶ P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.

 

About P-BCMA-101

P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).

Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.

P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).

The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.

multiple myeloma

CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).

The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.

However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.

There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).

“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.

Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.

The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.

Conditioning consists of standard cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.

The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 10⁶ P-BCMA-101 cells/kg.

The 3 patients who have received this dose had 6 to 9 prior therapies.

Patient 1

The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).

Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.

The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12.  She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.

The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.

Patient 2

The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).

Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.

Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.

AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.

Patient 3

The third patient was a 65-year-old female with lambda light chain MM and del13q14.

Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.

AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).

“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.

In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 10⁶ P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.

 

About P-BCMA-101

P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).

Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.

P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).

The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”

Photo by Aaron Logan

CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.

The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.

TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.

Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.

This research was presented at the AACR Annual Meeting 2018 (abstract 5790).

The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.

In vitro activity

Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.

The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC₅₀ values were below 100 nM.

In the leukemia cell lines, EC₅₀ values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).

In the MM cell lines, EC₅₀ values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).

In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.

In vivo activity

For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.

At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.

For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.

At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.

The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.

The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.

Pharmacodynamic activity

In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.

The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.

The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.

The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.

“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.

“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”