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When is denosumab an option in myeloma?
CHICAGO – , G. David Roodman, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“We use denosumab in patients with compromised renal function,” said Dr. Roodman, director of the Division of Hematology-Oncology at Indiana University, Indianapolis, noting one such scenario. That use of denosumab echoes recently published ASCO guidelines on bone-modifying therapy.
The second scenario for denosumab use is in patients who aren’t tolerating bisphosphonates: “We switch them from zoledronic acid to pamidronate, and they still have terrible acute phase reactions,” Dr. Roodman said.
Dr. Roodman’s comments on use of denosumab were in response to an audience question about when he would use denosumab, given the considerable cost difference between the RANK ligand inhibitor and bisphosphonates.
The recent ASCO guidelines, of which Dr. Roodman is a coauthor, state that denosumab “is more expensive than zoledronic acid or pamidronate and must be considered in treatment decisions.”
Previously, ASCO guidelines recommended use of intravenous bisphosphonates for patients with myeloma and evidence of bone disease. Based on consideration of new evidence, the guideline authors eliminated the requirement for evidence of bone disease and added denosumab as an alternative treatment choice.
The addition of denosumab was based in part on results of a recent randomized phase 3 trial that comprised 1,718 myeloma patients who were treated with either denosumab or zoledronic acid.
The primary endpoint, time to first on-study skeletal-related event, was evaluated after 676 skeletal-related events had accrued on study. The investigators found no difference in time to first event (hazard ratio [HR], 0.98; 95% confidence interval, 0.85-1.14; P = 0.82).
Likewise, the secondary endpoint of overall survival showed no difference between arms (HR, 0.90; 95% CI, 0.70-1.16), though an exploratory analysis did suggest denosumab was superior on the endpoint of progression-free survival (HR, 0.82; 95% CI, 0.68-0.99).
The ASCO guidelines also recommend that clinicians consider less-frequent dosing in patients with responsive or stable disease. That recommendation is based on results of two studies of less-frequent dosing prompted by concerns over the risk of osteonecrosis of the jaw, an uncommon but potentially serious complication associated with bone-modifying agents.
Both studies suggested every-3-months dosing of zoledronic acid could be effective. However, Dr. Roodman noted that both studies had limitations that need to be considered, including small numbers of myeloma patients, limited duration of therapy studied, and a high dropout rate in the case of one study. Due to those limitations, “it’s very difficult to draw conclusions about this today,” Dr. Roodman said.
Dr. Roodman reported that he had a consulting or advisory role with Amgen.
CHICAGO – , G. David Roodman, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“We use denosumab in patients with compromised renal function,” said Dr. Roodman, director of the Division of Hematology-Oncology at Indiana University, Indianapolis, noting one such scenario. That use of denosumab echoes recently published ASCO guidelines on bone-modifying therapy.
The second scenario for denosumab use is in patients who aren’t tolerating bisphosphonates: “We switch them from zoledronic acid to pamidronate, and they still have terrible acute phase reactions,” Dr. Roodman said.
Dr. Roodman’s comments on use of denosumab were in response to an audience question about when he would use denosumab, given the considerable cost difference between the RANK ligand inhibitor and bisphosphonates.
The recent ASCO guidelines, of which Dr. Roodman is a coauthor, state that denosumab “is more expensive than zoledronic acid or pamidronate and must be considered in treatment decisions.”
Previously, ASCO guidelines recommended use of intravenous bisphosphonates for patients with myeloma and evidence of bone disease. Based on consideration of new evidence, the guideline authors eliminated the requirement for evidence of bone disease and added denosumab as an alternative treatment choice.
The addition of denosumab was based in part on results of a recent randomized phase 3 trial that comprised 1,718 myeloma patients who were treated with either denosumab or zoledronic acid.
The primary endpoint, time to first on-study skeletal-related event, was evaluated after 676 skeletal-related events had accrued on study. The investigators found no difference in time to first event (hazard ratio [HR], 0.98; 95% confidence interval, 0.85-1.14; P = 0.82).
Likewise, the secondary endpoint of overall survival showed no difference between arms (HR, 0.90; 95% CI, 0.70-1.16), though an exploratory analysis did suggest denosumab was superior on the endpoint of progression-free survival (HR, 0.82; 95% CI, 0.68-0.99).
The ASCO guidelines also recommend that clinicians consider less-frequent dosing in patients with responsive or stable disease. That recommendation is based on results of two studies of less-frequent dosing prompted by concerns over the risk of osteonecrosis of the jaw, an uncommon but potentially serious complication associated with bone-modifying agents.
Both studies suggested every-3-months dosing of zoledronic acid could be effective. However, Dr. Roodman noted that both studies had limitations that need to be considered, including small numbers of myeloma patients, limited duration of therapy studied, and a high dropout rate in the case of one study. Due to those limitations, “it’s very difficult to draw conclusions about this today,” Dr. Roodman said.
Dr. Roodman reported that he had a consulting or advisory role with Amgen.
CHICAGO – , G. David Roodman, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
“We use denosumab in patients with compromised renal function,” said Dr. Roodman, director of the Division of Hematology-Oncology at Indiana University, Indianapolis, noting one such scenario. That use of denosumab echoes recently published ASCO guidelines on bone-modifying therapy.
The second scenario for denosumab use is in patients who aren’t tolerating bisphosphonates: “We switch them from zoledronic acid to pamidronate, and they still have terrible acute phase reactions,” Dr. Roodman said.
Dr. Roodman’s comments on use of denosumab were in response to an audience question about when he would use denosumab, given the considerable cost difference between the RANK ligand inhibitor and bisphosphonates.
The recent ASCO guidelines, of which Dr. Roodman is a coauthor, state that denosumab “is more expensive than zoledronic acid or pamidronate and must be considered in treatment decisions.”
Previously, ASCO guidelines recommended use of intravenous bisphosphonates for patients with myeloma and evidence of bone disease. Based on consideration of new evidence, the guideline authors eliminated the requirement for evidence of bone disease and added denosumab as an alternative treatment choice.
The addition of denosumab was based in part on results of a recent randomized phase 3 trial that comprised 1,718 myeloma patients who were treated with either denosumab or zoledronic acid.
The primary endpoint, time to first on-study skeletal-related event, was evaluated after 676 skeletal-related events had accrued on study. The investigators found no difference in time to first event (hazard ratio [HR], 0.98; 95% confidence interval, 0.85-1.14; P = 0.82).
Likewise, the secondary endpoint of overall survival showed no difference between arms (HR, 0.90; 95% CI, 0.70-1.16), though an exploratory analysis did suggest denosumab was superior on the endpoint of progression-free survival (HR, 0.82; 95% CI, 0.68-0.99).
The ASCO guidelines also recommend that clinicians consider less-frequent dosing in patients with responsive or stable disease. That recommendation is based on results of two studies of less-frequent dosing prompted by concerns over the risk of osteonecrosis of the jaw, an uncommon but potentially serious complication associated with bone-modifying agents.
Both studies suggested every-3-months dosing of zoledronic acid could be effective. However, Dr. Roodman noted that both studies had limitations that need to be considered, including small numbers of myeloma patients, limited duration of therapy studied, and a high dropout rate in the case of one study. Due to those limitations, “it’s very difficult to draw conclusions about this today,” Dr. Roodman said.
Dr. Roodman reported that he had a consulting or advisory role with Amgen.
EXPERT ANALYSIS FROM ASCO 2018
Over 1100 new meds, vaccines being developed to treat cancer
Currently, 1,120 new medicines and vaccines are being developed to treat cancer, according to a new report of the Pharmaceutical Research and Manufacturers of America (PhRMA).
And all of them, the organization states, are in clinical trials or awaiting review by the US Food and Drug Administration (FDA).
Leading the way are treatments for solid tumors, with 397 in development. Treatments for blood cancers are not far behind, with nearly 340 medicines in development: 137 for leukemias, 135 for lymphomas, and 62 for multiple myeloma.
Immuno-oncology and personalized medicine have a hand in this increase.
In the last year, according to PhRMA’s "Medicines in Development for Cancer 2018 Report," 47 new immune-oncology treatments have been added to the development pipeline, including CAR-T therapies and checkpoint inhibitors.
This brings the total to 295 immuno-oncology medicines and vaccines in the development pipeline this year.
The report also states that about 85% of these medicines in the oncology pipeline are first-in-class.
And PhRMA attributes the approximately 73% of survival gains in cancer to the new medicines.
Despite the bright picture, PhRMA acknowledges the financial burden and medical care challenges patients encounter.
It addresses them in a new chart pack, "Cancer Medicines: Value in Context," which puts cancer costs in perspective and offers solutions for improving the current system in the United States.
The association reports the top medical financial concerns of patients to be diagnostic tests or scans (53%), prescription medicines (43%), physician office visits (39%), outpatient treatments-including radiation (37%), and surgery (36%).
Spending on cancer medicines represents about 1% of overall healthcare spending, according to the organization, with cancer medications accounting for $49.8 billion of the $3.49 trillion healthcare spending in the United States.
Cancer medicines represent about 20% of spending on cancer, PhrMA notes, and some insurance plans place treatments for certain high-cost conditions on the highest drug formulary cost-sharing tier.
And patients with the highest copay were 5 times more likely to abandon treatment than the lowest copay group, PhRMA points out.
“No patient should struggle to afford their needed treatments,” PhRMA stated in a release, “and it is important that we address patient access challenges.”
Currently, 1,120 new medicines and vaccines are being developed to treat cancer, according to a new report of the Pharmaceutical Research and Manufacturers of America (PhRMA).
And all of them, the organization states, are in clinical trials or awaiting review by the US Food and Drug Administration (FDA).
Leading the way are treatments for solid tumors, with 397 in development. Treatments for blood cancers are not far behind, with nearly 340 medicines in development: 137 for leukemias, 135 for lymphomas, and 62 for multiple myeloma.
Immuno-oncology and personalized medicine have a hand in this increase.
In the last year, according to PhRMA’s "Medicines in Development for Cancer 2018 Report," 47 new immune-oncology treatments have been added to the development pipeline, including CAR-T therapies and checkpoint inhibitors.
This brings the total to 295 immuno-oncology medicines and vaccines in the development pipeline this year.
The report also states that about 85% of these medicines in the oncology pipeline are first-in-class.
And PhRMA attributes the approximately 73% of survival gains in cancer to the new medicines.
Despite the bright picture, PhRMA acknowledges the financial burden and medical care challenges patients encounter.
It addresses them in a new chart pack, "Cancer Medicines: Value in Context," which puts cancer costs in perspective and offers solutions for improving the current system in the United States.
The association reports the top medical financial concerns of patients to be diagnostic tests or scans (53%), prescription medicines (43%), physician office visits (39%), outpatient treatments-including radiation (37%), and surgery (36%).
Spending on cancer medicines represents about 1% of overall healthcare spending, according to the organization, with cancer medications accounting for $49.8 billion of the $3.49 trillion healthcare spending in the United States.
Cancer medicines represent about 20% of spending on cancer, PhrMA notes, and some insurance plans place treatments for certain high-cost conditions on the highest drug formulary cost-sharing tier.
And patients with the highest copay were 5 times more likely to abandon treatment than the lowest copay group, PhRMA points out.
“No patient should struggle to afford their needed treatments,” PhRMA stated in a release, “and it is important that we address patient access challenges.”
Currently, 1,120 new medicines and vaccines are being developed to treat cancer, according to a new report of the Pharmaceutical Research and Manufacturers of America (PhRMA).
And all of them, the organization states, are in clinical trials or awaiting review by the US Food and Drug Administration (FDA).
Leading the way are treatments for solid tumors, with 397 in development. Treatments for blood cancers are not far behind, with nearly 340 medicines in development: 137 for leukemias, 135 for lymphomas, and 62 for multiple myeloma.
Immuno-oncology and personalized medicine have a hand in this increase.
In the last year, according to PhRMA’s "Medicines in Development for Cancer 2018 Report," 47 new immune-oncology treatments have been added to the development pipeline, including CAR-T therapies and checkpoint inhibitors.
This brings the total to 295 immuno-oncology medicines and vaccines in the development pipeline this year.
The report also states that about 85% of these medicines in the oncology pipeline are first-in-class.
And PhRMA attributes the approximately 73% of survival gains in cancer to the new medicines.
Despite the bright picture, PhRMA acknowledges the financial burden and medical care challenges patients encounter.
It addresses them in a new chart pack, "Cancer Medicines: Value in Context," which puts cancer costs in perspective and offers solutions for improving the current system in the United States.
The association reports the top medical financial concerns of patients to be diagnostic tests or scans (53%), prescription medicines (43%), physician office visits (39%), outpatient treatments-including radiation (37%), and surgery (36%).
Spending on cancer medicines represents about 1% of overall healthcare spending, according to the organization, with cancer medications accounting for $49.8 billion of the $3.49 trillion healthcare spending in the United States.
Cancer medicines represent about 20% of spending on cancer, PhrMA notes, and some insurance plans place treatments for certain high-cost conditions on the highest drug formulary cost-sharing tier.
And patients with the highest copay were 5 times more likely to abandon treatment than the lowest copay group, PhRMA points out.
“No patient should struggle to afford their needed treatments,” PhRMA stated in a release, “and it is important that we address patient access challenges.”
Ruxolitinib overcame lenalidomide resistance in myeloma
based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
The clinical trial is the first to demonstrate the activity of a JAK inhibitor in the treatment of myeloma patients, according to investigator James R. Berenson, MD, medical and scientific director for the Institute for Myeloma & Bone Cancer Research (IMBCR), West Hollywood, Calif.
“These promising results have led to the expansion of the current clinical trial and provide the basis for exploration of this and other JAK inhibitor-containing combinations for treating patients with myeloma and other malignant diseases,” he added.
The dose-escalation study enrolled 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor. Subjects received ruxolitinib twice daily continuously, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts. In DL0, patients received ruxolitinib 5 mg, lenalidomide 5 mg, and methylprednisolone 40 mg. In DL+1 and +2, both doses of lenalidomide and methylprednisolone remained unchanged, and ruxolitinib was escalated to 10 and 15 mg, respectively. In DL+3, lenalidomide was escalated to 10 mg with methylprednisolone unchanged and ruxolitinib at 15 mg. A total of 19 patients were treated at the highest dose level, which was ruxolitinib 15 mg twice daily on days 1-28, lenalidomide 10 mg daily on days 1-21, and methylprednisolone 40 mg every other day.
The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
These results are encouraging, though challenges remain, said Craig Hofmeister, MD, MPH, of Winship Cancer Institute, Emory University, Atlanta.
“Clearly in these patients who are 100% lenalidomide refractory, the overall response rate of anything greater than or close to 20, 30, 40% is very appealing,” Dr. Hofmeister said in an ASCO presentation discussing the results of this trial.
The usual rationale for JAK inhibition is targeting of the bone microenvironment, but the microenvironment is a formidable opponent, Dr. Hofmeister said in his presentation.
“That’s an uphill battle,” he said. “There is an upcoming carfilzomib and ruxolitinib trial in multiple myeloma moving forward, and I’d be excited to see” the results.
The study (NCT03110822) was sponsored by Oncotherapeutics in collaboration with Incyte, the maker of ruxolitinib (Jakafi). Dr. Berenson, the presenting author, had disclosures related to Incyte, as well as Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and OncoTracker.
SOURCE: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
The clinical trial is the first to demonstrate the activity of a JAK inhibitor in the treatment of myeloma patients, according to investigator James R. Berenson, MD, medical and scientific director for the Institute for Myeloma & Bone Cancer Research (IMBCR), West Hollywood, Calif.
“These promising results have led to the expansion of the current clinical trial and provide the basis for exploration of this and other JAK inhibitor-containing combinations for treating patients with myeloma and other malignant diseases,” he added.
The dose-escalation study enrolled 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor. Subjects received ruxolitinib twice daily continuously, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts. In DL0, patients received ruxolitinib 5 mg, lenalidomide 5 mg, and methylprednisolone 40 mg. In DL+1 and +2, both doses of lenalidomide and methylprednisolone remained unchanged, and ruxolitinib was escalated to 10 and 15 mg, respectively. In DL+3, lenalidomide was escalated to 10 mg with methylprednisolone unchanged and ruxolitinib at 15 mg. A total of 19 patients were treated at the highest dose level, which was ruxolitinib 15 mg twice daily on days 1-28, lenalidomide 10 mg daily on days 1-21, and methylprednisolone 40 mg every other day.
The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
These results are encouraging, though challenges remain, said Craig Hofmeister, MD, MPH, of Winship Cancer Institute, Emory University, Atlanta.
“Clearly in these patients who are 100% lenalidomide refractory, the overall response rate of anything greater than or close to 20, 30, 40% is very appealing,” Dr. Hofmeister said in an ASCO presentation discussing the results of this trial.
The usual rationale for JAK inhibition is targeting of the bone microenvironment, but the microenvironment is a formidable opponent, Dr. Hofmeister said in his presentation.
“That’s an uphill battle,” he said. “There is an upcoming carfilzomib and ruxolitinib trial in multiple myeloma moving forward, and I’d be excited to see” the results.
The study (NCT03110822) was sponsored by Oncotherapeutics in collaboration with Incyte, the maker of ruxolitinib (Jakafi). Dr. Berenson, the presenting author, had disclosures related to Incyte, as well as Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and OncoTracker.
SOURCE: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
based on phase I trial results presented at the annual meeting of the American Society of Clinical Oncology (ASCO).
The clinical trial is the first to demonstrate the activity of a JAK inhibitor in the treatment of myeloma patients, according to investigator James R. Berenson, MD, medical and scientific director for the Institute for Myeloma & Bone Cancer Research (IMBCR), West Hollywood, Calif.
“These promising results have led to the expansion of the current clinical trial and provide the basis for exploration of this and other JAK inhibitor-containing combinations for treating patients with myeloma and other malignant diseases,” he added.
The dose-escalation study enrolled 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor. Subjects received ruxolitinib twice daily continuously, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts. In DL0, patients received ruxolitinib 5 mg, lenalidomide 5 mg, and methylprednisolone 40 mg. In DL+1 and +2, both doses of lenalidomide and methylprednisolone remained unchanged, and ruxolitinib was escalated to 10 and 15 mg, respectively. In DL+3, lenalidomide was escalated to 10 mg with methylprednisolone unchanged and ruxolitinib at 15 mg. A total of 19 patients were treated at the highest dose level, which was ruxolitinib 15 mg twice daily on days 1-28, lenalidomide 10 mg daily on days 1-21, and methylprednisolone 40 mg every other day.
The overall response rate was 39% (10 of 26 evaluable patients), Dr. Berenson reported. The clinical benefit rate was 50% (13 of 26 patients), with a median duration of response of 5.6 months in that group.
There were no dose-limiting toxicities. Grade 3 toxicities reported included thrombocytopenia in 11% (3 patients, gastrointestinal bleeding in 11% (3 patients), and anemia in 7% (2 patients).
These results are encouraging, though challenges remain, said Craig Hofmeister, MD, MPH, of Winship Cancer Institute, Emory University, Atlanta.
“Clearly in these patients who are 100% lenalidomide refractory, the overall response rate of anything greater than or close to 20, 30, 40% is very appealing,” Dr. Hofmeister said in an ASCO presentation discussing the results of this trial.
The usual rationale for JAK inhibition is targeting of the bone microenvironment, but the microenvironment is a formidable opponent, Dr. Hofmeister said in his presentation.
“That’s an uphill battle,” he said. “There is an upcoming carfilzomib and ruxolitinib trial in multiple myeloma moving forward, and I’d be excited to see” the results.
The study (NCT03110822) was sponsored by Oncotherapeutics in collaboration with Incyte, the maker of ruxolitinib (Jakafi). Dr. Berenson, the presenting author, had disclosures related to Incyte, as well as Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and OncoTracker.
SOURCE: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
REPORTING FROM ASCO 2018
Key clinical point: The JAK 1/2 inhibitor ruxolitinib, in combination with lenalidomide and methylprednisolone, overcame resistance to lenalidomide in about half of heavily pre-treated patients with relapsed/refractory multiple myeloma in a phase I trial.
Major finding: The overall response rate was 39%, and the clinical benefit rate was 50% (13 of 26 patients).
Study details: A phase 1 study including 28 patients with relapsed/refractory multiple myeloma who had previous treatment with lenalidomide/steroids and a proteasome inhibitor.
Disclosures: Dr. Berenson, the presenting author, had disclosures related to Amgen, Bristol-Myers Squibb, Celgene, Incyte, Janssen, Takeda, and OncoTracker.
Source: Berenson JR, et al. J Clin Oncol 36, 2018 (suppl; abstr 8005).
Liquid biopsies may be the future in managing MM patients
Scientists from the Dana-Farber Cancer Institute and the Broad Institute in Boston, Massachusetts, have shown that in multiple myeloma (MM), liquid biopsies provide similar genetic information as tumor biopsies.
Unlike tumor biopsies, liquid biopsies are noninvasive and, in the future, may offer a cost-effective way of following disease state, disease progression, and response to treatment.
The scientists used cell-free DNA (cfDNA) from 107 patients, circulating tumor cells (CTCs) from 56 patients, and compared their genomic profiling with bone marrow biopsies from 9 patients with MM.
The researchers used a two-step approach using the 2 kinds of liquid biopsies—CTCs and cfDNA. They first used “ultra-low pass” whole genome sequencing, which was a rapid and cost-effective method to identify blood samples with tumor DNA of at least 5%-10% (tumor fraction).
These samples were then subject to whole-exome sequencing (WES), which analyzes protein-coding sequence of the genome.
The researchers found genetic alterations in MM such as copy number alterations (1p, 13q deletions or 11q gain) and somatic single nucleotide variations (SSNVs), among others, which they observed in matched cfDNA, CTCs, and tumor DNA (tDNA) from tumor biopsies.
The liquid biopsies also captured the clonal heterogeneity characteristic of MM—99% of clonal mutations present in tDNA were also seen in cfDNA or CTCs, and 94% of mutations present in cfDNA or CTCs were seen in tDNA.
In addition, CTCs or cfDNA samples with higher tumor purity uncovered more mutations than were seen in tDNA.
“[The] combination of CTCs and cfDNA was able to detect almost all clonal mutations identified in the bone marrow biopsy sample and defined other subclones that were not identified in the bone marrow,” the scientists noted.
This increased sensitivity was “potentially due to the limitation of sampling site of the bone marrow,” they pointed out.
The scientists also showed that the tumor fraction in cfDNA and enriched CTCs correlated with disease progression from MGUS (monoclonal gammopathy of undetermined significance) and SMM (smoldering MM), to overt MM.
The scientists also evaluated liquid biopsies to determine response to treatment.
For example, a patient who responded to carfilzomib, lenalidomide, and dexamethasone, had a decreased cfDNA tumor fraction—from 22% to 2%.
Another patient who progressed on daratumumab over a period of 2 months showed an increase in tumor fraction—from 11% to 46%.
CTCs and cfDNA captured the mutational landscape of MM and provided a non-invasive profiling of tumor evolution. The liquid biopsy approach may be used as a novel biomarker for disease progression and response to therapy, the scientists suggest.
"Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding,” said co-senior author Irene Ghobrial, MD, “because this means that routine genetic profiling of patient tumors from blood would be feasible."
"Our ultimate goal is to eventually use all the samples to monitor disease progression," added Jihye Park, PhD, researcher in the Ghobrial lab and co-first author on the paper.
Currently, bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of MM.
However, due to their invasive nature and associated costs, they are not done at every visit. Liquid biopsies are an attractive way forward.
Nevertheless, before they can be used in the clinical management of patients with MM, these results need to be confirmed in larger prospective studies.
The investigators reported their findings in Nature Communications.
Scientists from the Dana-Farber Cancer Institute and the Broad Institute in Boston, Massachusetts, have shown that in multiple myeloma (MM), liquid biopsies provide similar genetic information as tumor biopsies.
Unlike tumor biopsies, liquid biopsies are noninvasive and, in the future, may offer a cost-effective way of following disease state, disease progression, and response to treatment.
The scientists used cell-free DNA (cfDNA) from 107 patients, circulating tumor cells (CTCs) from 56 patients, and compared their genomic profiling with bone marrow biopsies from 9 patients with MM.
The researchers used a two-step approach using the 2 kinds of liquid biopsies—CTCs and cfDNA. They first used “ultra-low pass” whole genome sequencing, which was a rapid and cost-effective method to identify blood samples with tumor DNA of at least 5%-10% (tumor fraction).
These samples were then subject to whole-exome sequencing (WES), which analyzes protein-coding sequence of the genome.
The researchers found genetic alterations in MM such as copy number alterations (1p, 13q deletions or 11q gain) and somatic single nucleotide variations (SSNVs), among others, which they observed in matched cfDNA, CTCs, and tumor DNA (tDNA) from tumor biopsies.
The liquid biopsies also captured the clonal heterogeneity characteristic of MM—99% of clonal mutations present in tDNA were also seen in cfDNA or CTCs, and 94% of mutations present in cfDNA or CTCs were seen in tDNA.
In addition, CTCs or cfDNA samples with higher tumor purity uncovered more mutations than were seen in tDNA.
“[The] combination of CTCs and cfDNA was able to detect almost all clonal mutations identified in the bone marrow biopsy sample and defined other subclones that were not identified in the bone marrow,” the scientists noted.
This increased sensitivity was “potentially due to the limitation of sampling site of the bone marrow,” they pointed out.
The scientists also showed that the tumor fraction in cfDNA and enriched CTCs correlated with disease progression from MGUS (monoclonal gammopathy of undetermined significance) and SMM (smoldering MM), to overt MM.
The scientists also evaluated liquid biopsies to determine response to treatment.
For example, a patient who responded to carfilzomib, lenalidomide, and dexamethasone, had a decreased cfDNA tumor fraction—from 22% to 2%.
Another patient who progressed on daratumumab over a period of 2 months showed an increase in tumor fraction—from 11% to 46%.
CTCs and cfDNA captured the mutational landscape of MM and provided a non-invasive profiling of tumor evolution. The liquid biopsy approach may be used as a novel biomarker for disease progression and response to therapy, the scientists suggest.
"Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding,” said co-senior author Irene Ghobrial, MD, “because this means that routine genetic profiling of patient tumors from blood would be feasible."
"Our ultimate goal is to eventually use all the samples to monitor disease progression," added Jihye Park, PhD, researcher in the Ghobrial lab and co-first author on the paper.
Currently, bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of MM.
However, due to their invasive nature and associated costs, they are not done at every visit. Liquid biopsies are an attractive way forward.
Nevertheless, before they can be used in the clinical management of patients with MM, these results need to be confirmed in larger prospective studies.
The investigators reported their findings in Nature Communications.
Scientists from the Dana-Farber Cancer Institute and the Broad Institute in Boston, Massachusetts, have shown that in multiple myeloma (MM), liquid biopsies provide similar genetic information as tumor biopsies.
Unlike tumor biopsies, liquid biopsies are noninvasive and, in the future, may offer a cost-effective way of following disease state, disease progression, and response to treatment.
The scientists used cell-free DNA (cfDNA) from 107 patients, circulating tumor cells (CTCs) from 56 patients, and compared their genomic profiling with bone marrow biopsies from 9 patients with MM.
The researchers used a two-step approach using the 2 kinds of liquid biopsies—CTCs and cfDNA. They first used “ultra-low pass” whole genome sequencing, which was a rapid and cost-effective method to identify blood samples with tumor DNA of at least 5%-10% (tumor fraction).
These samples were then subject to whole-exome sequencing (WES), which analyzes protein-coding sequence of the genome.
The researchers found genetic alterations in MM such as copy number alterations (1p, 13q deletions or 11q gain) and somatic single nucleotide variations (SSNVs), among others, which they observed in matched cfDNA, CTCs, and tumor DNA (tDNA) from tumor biopsies.
The liquid biopsies also captured the clonal heterogeneity characteristic of MM—99% of clonal mutations present in tDNA were also seen in cfDNA or CTCs, and 94% of mutations present in cfDNA or CTCs were seen in tDNA.
In addition, CTCs or cfDNA samples with higher tumor purity uncovered more mutations than were seen in tDNA.
“[The] combination of CTCs and cfDNA was able to detect almost all clonal mutations identified in the bone marrow biopsy sample and defined other subclones that were not identified in the bone marrow,” the scientists noted.
This increased sensitivity was “potentially due to the limitation of sampling site of the bone marrow,” they pointed out.
The scientists also showed that the tumor fraction in cfDNA and enriched CTCs correlated with disease progression from MGUS (monoclonal gammopathy of undetermined significance) and SMM (smoldering MM), to overt MM.
The scientists also evaluated liquid biopsies to determine response to treatment.
For example, a patient who responded to carfilzomib, lenalidomide, and dexamethasone, had a decreased cfDNA tumor fraction—from 22% to 2%.
Another patient who progressed on daratumumab over a period of 2 months showed an increase in tumor fraction—from 11% to 46%.
CTCs and cfDNA captured the mutational landscape of MM and provided a non-invasive profiling of tumor evolution. The liquid biopsy approach may be used as a novel biomarker for disease progression and response to therapy, the scientists suggest.
"Our discovery that cfDNA and CTC analyses agree with each other at the comprehensive level is an important finding,” said co-senior author Irene Ghobrial, MD, “because this means that routine genetic profiling of patient tumors from blood would be feasible."
"Our ultimate goal is to eventually use all the samples to monitor disease progression," added Jihye Park, PhD, researcher in the Ghobrial lab and co-first author on the paper.
Currently, bone marrow biopsies are the gold standard for diagnosing and monitoring the progression of MM.
However, due to their invasive nature and associated costs, they are not done at every visit. Liquid biopsies are an attractive way forward.
Nevertheless, before they can be used in the clinical management of patients with MM, these results need to be confirmed in larger prospective studies.
The investigators reported their findings in Nature Communications.
CAR T therapy to enter early testing in multiple myeloma
Janssen Biotech is launching a phase 1b/2 trial of an .
The trial, which was cleared by the Food and Drug Administration to begin in the second half of 2018, will evaluate the safety and efficacy of LCAR-B38M (JNJ-68284528). The CAR T therapy targets B-cell Maturation Antigen and expresses a CAR protein that is identical to a product that was developed by Legend Biotech and evaluated in a first-in-human clinical study in China.
The drug is being developed as part of a collaboration between Legend Biotech and Janssen Biotech.
Janssen Biotech is launching a phase 1b/2 trial of an .
The trial, which was cleared by the Food and Drug Administration to begin in the second half of 2018, will evaluate the safety and efficacy of LCAR-B38M (JNJ-68284528). The CAR T therapy targets B-cell Maturation Antigen and expresses a CAR protein that is identical to a product that was developed by Legend Biotech and evaluated in a first-in-human clinical study in China.
The drug is being developed as part of a collaboration between Legend Biotech and Janssen Biotech.
Janssen Biotech is launching a phase 1b/2 trial of an .
The trial, which was cleared by the Food and Drug Administration to begin in the second half of 2018, will evaluate the safety and efficacy of LCAR-B38M (JNJ-68284528). The CAR T therapy targets B-cell Maturation Antigen and expresses a CAR protein that is identical to a product that was developed by Legend Biotech and evaluated in a first-in-human clinical study in China.
The drug is being developed as part of a collaboration between Legend Biotech and Janssen Biotech.
Study of daratumamb with anti-PD-1 antibody in MM discontinued
Janssen is discontinuing the phase 1 MMY2036 study of daratumumab in combination with the anti PD-1 antibody JNJ-63723283 in patients with multiple myeloma (MM).
Janssen made the decision based on a Data Monitoring Committee review of Genmab’s phase 1b/2 study (LUC2001) of daratumumab plus the anti-PD-L1 antibody atezolizumab in non-small cell lung cancer (NSCLC).
Based on the DMC findings, Janssen also decided to discontinue its daratumumab-PD-1 combination study.
Janssen has an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
In the planned review, the DMC determined there was no observed benefit within the daratumumab plus atezolizumab arm compared to the atezolizumab monotherapy arm. The DMC recommended termination of the NSCLC study.
The DMC also noted an increase in mortality-related events in the combination arm.
Janssen has informed health authorities about these events and has contacted its partner companies conducting daratumumab and anti-PD-1 combination studies to discuss ceasing enrollment and dosing of the combination while the data is being further investigated.
MMY2036 study (NCT03357952)
The randomized, multicenter, multiphase study was expected to enroll up to 386 patients with relapsed or refractory MM who had received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory (IMiD) agent. Refractory patients had to be double refractory to both a PI and an IMiD.
The trial was to be conducted in 3 parts. Part 1 was to assess the safety of the combination of JNJ-63723283 and daratumumab. Part 2 was intended to compare the overall response rate in patients treated with the combination compared to those treated with daratumumab alone. And Part 3 was to compare progression-free survival between the 2 arms.
Daratumumab dose was planned to be 16 mg/kg weekly for 8 weeks, then once every other week for 16 weeks; then once every 4 weeks.
JNJ-63723283 dose was planned to be 240 milligrams IV fixed dose during week 1 on cycle 1 (28 days) day 2, cycle 1 day 15, then every 2 weeks thereafter.
The study was started in November 2017 and planned to be completed in December 2019.
In a news release, Genmab’s chief executive officer, Jan van de Winkel, PhD, expressed disappointment that the studies will be discontinued. He said Genmab “fully supports Janssen’s decision as patient safety is paramount in drug development. We look forward to gaining a better understanding of the data upon further analysis.”
Janssen is discontinuing the phase 1 MMY2036 study of daratumumab in combination with the anti PD-1 antibody JNJ-63723283 in patients with multiple myeloma (MM).
Janssen made the decision based on a Data Monitoring Committee review of Genmab’s phase 1b/2 study (LUC2001) of daratumumab plus the anti-PD-L1 antibody atezolizumab in non-small cell lung cancer (NSCLC).
Based on the DMC findings, Janssen also decided to discontinue its daratumumab-PD-1 combination study.
Janssen has an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
In the planned review, the DMC determined there was no observed benefit within the daratumumab plus atezolizumab arm compared to the atezolizumab monotherapy arm. The DMC recommended termination of the NSCLC study.
The DMC also noted an increase in mortality-related events in the combination arm.
Janssen has informed health authorities about these events and has contacted its partner companies conducting daratumumab and anti-PD-1 combination studies to discuss ceasing enrollment and dosing of the combination while the data is being further investigated.
MMY2036 study (NCT03357952)
The randomized, multicenter, multiphase study was expected to enroll up to 386 patients with relapsed or refractory MM who had received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory (IMiD) agent. Refractory patients had to be double refractory to both a PI and an IMiD.
The trial was to be conducted in 3 parts. Part 1 was to assess the safety of the combination of JNJ-63723283 and daratumumab. Part 2 was intended to compare the overall response rate in patients treated with the combination compared to those treated with daratumumab alone. And Part 3 was to compare progression-free survival between the 2 arms.
Daratumumab dose was planned to be 16 mg/kg weekly for 8 weeks, then once every other week for 16 weeks; then once every 4 weeks.
JNJ-63723283 dose was planned to be 240 milligrams IV fixed dose during week 1 on cycle 1 (28 days) day 2, cycle 1 day 15, then every 2 weeks thereafter.
The study was started in November 2017 and planned to be completed in December 2019.
In a news release, Genmab’s chief executive officer, Jan van de Winkel, PhD, expressed disappointment that the studies will be discontinued. He said Genmab “fully supports Janssen’s decision as patient safety is paramount in drug development. We look forward to gaining a better understanding of the data upon further analysis.”
Janssen is discontinuing the phase 1 MMY2036 study of daratumumab in combination with the anti PD-1 antibody JNJ-63723283 in patients with multiple myeloma (MM).
Janssen made the decision based on a Data Monitoring Committee review of Genmab’s phase 1b/2 study (LUC2001) of daratumumab plus the anti-PD-L1 antibody atezolizumab in non-small cell lung cancer (NSCLC).
Based on the DMC findings, Janssen also decided to discontinue its daratumumab-PD-1 combination study.
Janssen has an exclusive worldwide license from Genmab to develop, manufacture, and commercialize daratumumab.
In the planned review, the DMC determined there was no observed benefit within the daratumumab plus atezolizumab arm compared to the atezolizumab monotherapy arm. The DMC recommended termination of the NSCLC study.
The DMC also noted an increase in mortality-related events in the combination arm.
Janssen has informed health authorities about these events and has contacted its partner companies conducting daratumumab and anti-PD-1 combination studies to discuss ceasing enrollment and dosing of the combination while the data is being further investigated.
MMY2036 study (NCT03357952)
The randomized, multicenter, multiphase study was expected to enroll up to 386 patients with relapsed or refractory MM who had received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory (IMiD) agent. Refractory patients had to be double refractory to both a PI and an IMiD.
The trial was to be conducted in 3 parts. Part 1 was to assess the safety of the combination of JNJ-63723283 and daratumumab. Part 2 was intended to compare the overall response rate in patients treated with the combination compared to those treated with daratumumab alone. And Part 3 was to compare progression-free survival between the 2 arms.
Daratumumab dose was planned to be 16 mg/kg weekly for 8 weeks, then once every other week for 16 weeks; then once every 4 weeks.
JNJ-63723283 dose was planned to be 240 milligrams IV fixed dose during week 1 on cycle 1 (28 days) day 2, cycle 1 day 15, then every 2 weeks thereafter.
The study was started in November 2017 and planned to be completed in December 2019.
In a news release, Genmab’s chief executive officer, Jan van de Winkel, PhD, expressed disappointment that the studies will be discontinued. He said Genmab “fully supports Janssen’s decision as patient safety is paramount in drug development. We look forward to gaining a better understanding of the data upon further analysis.”
Multiple myeloma rates rising fastest in East Asia
The global incidence of multiple myeloma rose by 126% from 1990 to 2016, with the largest regional increases occurring in East Asia and tropical Latin America, according to data from the Global Burden of Disease 2016 study.
East Asia (China, North Korea, and Taiwan) saw incident cases of multiple myeloma jump by 262% – up to 1.0 per 100,000 population – from 1990 to 2016, which was the largest increase among any of the 21 global regions; tropical Latin America’s 256% rise took its age-standardized incidence rate to 1.8 per 100,000. Worldwide, incidence of multiple myeloma was 2.1 cases per 100,000 in 2016, Andrew J. Cowan, MD, and his associates reported in JAMA Oncology.
They also looked at treatment availability, with data on stem cell transplants for 2010 coming from the Worldwide Network for Blood & Marrow Transplantation (Lancet Haematol. 2015 Mar;2[3]:e91-100). The countries with the highest rates for all indications that year were Israel (814 per 10 million population), Italy (671), Germany (665), Sweden (625), and the Netherlands (614).
“Some regions of the world lack access to stem cell transplantation entirely, particularly sub-Saharan Africa (with the exception of South Africa),” wrote Dr. Cowan of the University of Washington, Seattle, and his associates.
The approval status of lenalidomide (Revlimid) and bortezomib (Velcade) in 2016 was used as a surrogate for availability of drug treatment: Lenalidomide had been approved in 73 countries out of 195 countries and territories and bortezomib in 103 countries. “On a global level, there are marked discrepancies in the availability of effective therapies. In addition to ensuring universal access to health care … it is imperative to at least ensure access to highly effective medications,” they wrote.
Dr. Cowan reported that he has received research funding from Janssen and AbbVie.
SOURCE: Cowan AJ et al. JAMA Oncol. 2018 May 16. doi: 10.1001/jamaoncol.2018.2128.
The global incidence of multiple myeloma rose by 126% from 1990 to 2016, with the largest regional increases occurring in East Asia and tropical Latin America, according to data from the Global Burden of Disease 2016 study.
East Asia (China, North Korea, and Taiwan) saw incident cases of multiple myeloma jump by 262% – up to 1.0 per 100,000 population – from 1990 to 2016, which was the largest increase among any of the 21 global regions; tropical Latin America’s 256% rise took its age-standardized incidence rate to 1.8 per 100,000. Worldwide, incidence of multiple myeloma was 2.1 cases per 100,000 in 2016, Andrew J. Cowan, MD, and his associates reported in JAMA Oncology.
They also looked at treatment availability, with data on stem cell transplants for 2010 coming from the Worldwide Network for Blood & Marrow Transplantation (Lancet Haematol. 2015 Mar;2[3]:e91-100). The countries with the highest rates for all indications that year were Israel (814 per 10 million population), Italy (671), Germany (665), Sweden (625), and the Netherlands (614).
“Some regions of the world lack access to stem cell transplantation entirely, particularly sub-Saharan Africa (with the exception of South Africa),” wrote Dr. Cowan of the University of Washington, Seattle, and his associates.
The approval status of lenalidomide (Revlimid) and bortezomib (Velcade) in 2016 was used as a surrogate for availability of drug treatment: Lenalidomide had been approved in 73 countries out of 195 countries and territories and bortezomib in 103 countries. “On a global level, there are marked discrepancies in the availability of effective therapies. In addition to ensuring universal access to health care … it is imperative to at least ensure access to highly effective medications,” they wrote.
Dr. Cowan reported that he has received research funding from Janssen and AbbVie.
SOURCE: Cowan AJ et al. JAMA Oncol. 2018 May 16. doi: 10.1001/jamaoncol.2018.2128.
The global incidence of multiple myeloma rose by 126% from 1990 to 2016, with the largest regional increases occurring in East Asia and tropical Latin America, according to data from the Global Burden of Disease 2016 study.
East Asia (China, North Korea, and Taiwan) saw incident cases of multiple myeloma jump by 262% – up to 1.0 per 100,000 population – from 1990 to 2016, which was the largest increase among any of the 21 global regions; tropical Latin America’s 256% rise took its age-standardized incidence rate to 1.8 per 100,000. Worldwide, incidence of multiple myeloma was 2.1 cases per 100,000 in 2016, Andrew J. Cowan, MD, and his associates reported in JAMA Oncology.
They also looked at treatment availability, with data on stem cell transplants for 2010 coming from the Worldwide Network for Blood & Marrow Transplantation (Lancet Haematol. 2015 Mar;2[3]:e91-100). The countries with the highest rates for all indications that year were Israel (814 per 10 million population), Italy (671), Germany (665), Sweden (625), and the Netherlands (614).
“Some regions of the world lack access to stem cell transplantation entirely, particularly sub-Saharan Africa (with the exception of South Africa),” wrote Dr. Cowan of the University of Washington, Seattle, and his associates.
The approval status of lenalidomide (Revlimid) and bortezomib (Velcade) in 2016 was used as a surrogate for availability of drug treatment: Lenalidomide had been approved in 73 countries out of 195 countries and territories and bortezomib in 103 countries. “On a global level, there are marked discrepancies in the availability of effective therapies. In addition to ensuring universal access to health care … it is imperative to at least ensure access to highly effective medications,” they wrote.
Dr. Cowan reported that he has received research funding from Janssen and AbbVie.
SOURCE: Cowan AJ et al. JAMA Oncol. 2018 May 16. doi: 10.1001/jamaoncol.2018.2128.
FROM JAMA ONCOLOGY
Galinpepimut-S receives orphan designation for MM
The US Food and Drug Administration (FDA) has granted orphan drug designation to galinpepimut-S (GPS) as a treatment for multiple myeloma (MM).
GPS is an immunotherapeutic that targets malignancies characterized by overexpression of the Wilms tumor 1 (WT1) antigen.
GPS consists of 4 peptide chains, 2 of which are modified chains that induce an innate immune response (CD4+/CD8+) against the WT1 antigen and access a range of HLA types.
When GPS is administered to a patient, the induced immune response has the potential to recognize and destroy cancer cells and provide ongoing support to the immune system so it can continue to target and destroy residual cancer cells.
GPS also has orphan designation from the FDA for the treatment of acute myeloid leukemia and malignant plural mesothelioma.
Phase 2 trial
GPS has been investigated in a phase 2 trial of MM patients. Results from this trial were recently presented at the 44th Annual Meeting of the EBMT.
Researchers evaluated GPS in combination with lenalidomide as maintenance therapy in MM patients who received an autologous stem cell transplant (ASCT).
The study enrolled 19 patients who began receiving GPS within 22 days of ASCT. They received 6 doses every 2 weeks. (Injection sites were pre-stimulated with granulocyte-macrophage colony-stimulating factor.)
Patients received 6 additional monthly doses of GPS as well as lenalidomide maintenance (10 mg daily) starting on day 100 post-ASCT.
Twelve patients received all 12 doses of GPS. Eleven patients achieved a complete response or very good partial response. All of these patients had CD4 immune responses, and 9 of them had CD8 immune responses.
The progression-free survival was 81% at 12 months and 62% at 18 months. The median progression-free survival was 23.6 months (range, 15.2 to not reached).
The overall survival was 88% at 18 months, and the median overall survival was not reached.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to galinpepimut-S (GPS) as a treatment for multiple myeloma (MM).
GPS is an immunotherapeutic that targets malignancies characterized by overexpression of the Wilms tumor 1 (WT1) antigen.
GPS consists of 4 peptide chains, 2 of which are modified chains that induce an innate immune response (CD4+/CD8+) against the WT1 antigen and access a range of HLA types.
When GPS is administered to a patient, the induced immune response has the potential to recognize and destroy cancer cells and provide ongoing support to the immune system so it can continue to target and destroy residual cancer cells.
GPS also has orphan designation from the FDA for the treatment of acute myeloid leukemia and malignant plural mesothelioma.
Phase 2 trial
GPS has been investigated in a phase 2 trial of MM patients. Results from this trial were recently presented at the 44th Annual Meeting of the EBMT.
Researchers evaluated GPS in combination with lenalidomide as maintenance therapy in MM patients who received an autologous stem cell transplant (ASCT).
The study enrolled 19 patients who began receiving GPS within 22 days of ASCT. They received 6 doses every 2 weeks. (Injection sites were pre-stimulated with granulocyte-macrophage colony-stimulating factor.)
Patients received 6 additional monthly doses of GPS as well as lenalidomide maintenance (10 mg daily) starting on day 100 post-ASCT.
Twelve patients received all 12 doses of GPS. Eleven patients achieved a complete response or very good partial response. All of these patients had CD4 immune responses, and 9 of them had CD8 immune responses.
The progression-free survival was 81% at 12 months and 62% at 18 months. The median progression-free survival was 23.6 months (range, 15.2 to not reached).
The overall survival was 88% at 18 months, and the median overall survival was not reached.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to galinpepimut-S (GPS) as a treatment for multiple myeloma (MM).
GPS is an immunotherapeutic that targets malignancies characterized by overexpression of the Wilms tumor 1 (WT1) antigen.
GPS consists of 4 peptide chains, 2 of which are modified chains that induce an innate immune response (CD4+/CD8+) against the WT1 antigen and access a range of HLA types.
When GPS is administered to a patient, the induced immune response has the potential to recognize and destroy cancer cells and provide ongoing support to the immune system so it can continue to target and destroy residual cancer cells.
GPS also has orphan designation from the FDA for the treatment of acute myeloid leukemia and malignant plural mesothelioma.
Phase 2 trial
GPS has been investigated in a phase 2 trial of MM patients. Results from this trial were recently presented at the 44th Annual Meeting of the EBMT.
Researchers evaluated GPS in combination with lenalidomide as maintenance therapy in MM patients who received an autologous stem cell transplant (ASCT).
The study enrolled 19 patients who began receiving GPS within 22 days of ASCT. They received 6 doses every 2 weeks. (Injection sites were pre-stimulated with granulocyte-macrophage colony-stimulating factor.)
Patients received 6 additional monthly doses of GPS as well as lenalidomide maintenance (10 mg daily) starting on day 100 post-ASCT.
Twelve patients received all 12 doses of GPS. Eleven patients achieved a complete response or very good partial response. All of these patients had CD4 immune responses, and 9 of them had CD8 immune responses.
The progression-free survival was 81% at 12 months and 62% at 18 months. The median progression-free survival was 23.6 months (range, 15.2 to not reached).
The overall survival was 88% at 18 months, and the median overall survival was not reached.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Daratumumab approved for newly diagnosed MM
The US Food and Drug Administration (FDA) has granted another approval for the CD38-directed antibody daratumumab (Darzalex®).
Daratumumab is now approved for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.
Daratumumab was first approved by the FDA in 2015 as a monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
In 2016, daratumumab was approved for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat MM patients who have received at least 1 prior therapy.
In 2017, daratumumab was approved for use in combination with pomalidomide and dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a PI.
For full prescribing information, visit www.darzalex.com.
Phase 3 trial
The FDA’s approval of daratumumab in combination with VMP is supported by data from the phase 3 ALCYONE (MMY3007) study. Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).
The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. And rates of minimal residual disease negativity were 22% and 6%, respectively.
The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
The rate of discontinuation due to AEs was 5% in the D-VMP arm and 9% in the VMP arm.
The US Food and Drug Administration (FDA) has granted another approval for the CD38-directed antibody daratumumab (Darzalex®).
Daratumumab is now approved for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.
Daratumumab was first approved by the FDA in 2015 as a monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
In 2016, daratumumab was approved for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat MM patients who have received at least 1 prior therapy.
In 2017, daratumumab was approved for use in combination with pomalidomide and dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a PI.
For full prescribing information, visit www.darzalex.com.
Phase 3 trial
The FDA’s approval of daratumumab in combination with VMP is supported by data from the phase 3 ALCYONE (MMY3007) study. Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).
The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. And rates of minimal residual disease negativity were 22% and 6%, respectively.
The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
The rate of discontinuation due to AEs was 5% in the D-VMP arm and 9% in the VMP arm.
The US Food and Drug Administration (FDA) has granted another approval for the CD38-directed antibody daratumumab (Darzalex®).
Daratumumab is now approved for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.
Daratumumab was first approved by the FDA in 2015 as a monotherapy for MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
In 2016, daratumumab was approved for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat MM patients who have received at least 1 prior therapy.
In 2017, daratumumab was approved for use in combination with pomalidomide and dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a PI.
For full prescribing information, visit www.darzalex.com.
Phase 3 trial
The FDA’s approval of daratumumab in combination with VMP is supported by data from the phase 3 ALCYONE (MMY3007) study. Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).
The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. And rates of minimal residual disease negativity were 22% and 6%, respectively.
The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.
The most common treatment-emergent adverse events (TEAEs; in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.
The most common grade 3/4 TEAEs (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
The rate of discontinuation due to AEs was 5% in the D-VMP arm and 9% in the VMP arm.
FDA approves anti-CD38 with VMP in myeloma
The who are ineligible for autologous stem cell transplant (ASCT).
The drug is approved in combination with a standard VMP regimen – bortezomib (Velcade), melphalan, and prednisone. The FDA had granted priority review to the drug application in January 2018 based on the results of the phase 3 ALCYONE study (NCT02195479).
Daratumumab, an anti-CD38 monoclonal antibody, reduced the risk of disease progression or death by 50%, compared with VMP alone in the ALCYONE study. The median progression-free survival had not yet been reached in the daratumumab arm; the median progression-free survival was 18.1 months in the VMP-only arm (N Engl J Med. 2018;378:518-28).
Daratumumab is marketed by Janssen Biotech as Darzalex.
The who are ineligible for autologous stem cell transplant (ASCT).
The drug is approved in combination with a standard VMP regimen – bortezomib (Velcade), melphalan, and prednisone. The FDA had granted priority review to the drug application in January 2018 based on the results of the phase 3 ALCYONE study (NCT02195479).
Daratumumab, an anti-CD38 monoclonal antibody, reduced the risk of disease progression or death by 50%, compared with VMP alone in the ALCYONE study. The median progression-free survival had not yet been reached in the daratumumab arm; the median progression-free survival was 18.1 months in the VMP-only arm (N Engl J Med. 2018;378:518-28).
Daratumumab is marketed by Janssen Biotech as Darzalex.
The who are ineligible for autologous stem cell transplant (ASCT).
The drug is approved in combination with a standard VMP regimen – bortezomib (Velcade), melphalan, and prednisone. The FDA had granted priority review to the drug application in January 2018 based on the results of the phase 3 ALCYONE study (NCT02195479).
Daratumumab, an anti-CD38 monoclonal antibody, reduced the risk of disease progression or death by 50%, compared with VMP alone in the ALCYONE study. The median progression-free survival had not yet been reached in the daratumumab arm; the median progression-free survival was 18.1 months in the VMP-only arm (N Engl J Med. 2018;378:518-28).
Daratumumab is marketed by Janssen Biotech as Darzalex.