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Bright light therapy improves sleep in cancer survivors
Results of a pilot study suggest that systematic bright light exposure can improve sleep in fatigued cancer survivors.
Subjects who were exposed to bright light every morning for 4 weeks had a significantly greater improvement in sleep efficiency than those who were exposed to dim light over the same period.
In fact, subjects in the bright light group were able to achieve clinically normal levels of sleep efficiency, and subjects in the dim light group were not.
Sleep efficiency is the percentage of time in bed that subjects spent sleeping.
Lisa M. Wu, PhD, of Northwestern University in Chicago, Illinois, and her colleagues reported these results in the Journal of Clinical Sleep Medicine.
The team noted that cancer patients report sleep disturbances at a significantly higher rate than the general population. Between 23% and 44% of cancer patients experience insomnia symptoms even years after treatment.
With this in mind, the researchers studied 44 individuals who had completed cancer treatment and met criteria for clinically significant fatigue at screening.
The subjects had an average age of 53.6, and 75% percent were female. Roughly 55% (n=24) had been diagnosed with a hematologic malignancy.
The subjects were randomized to a bright white light intervention or a dim red light intervention. Subjects in both treatment arms were provided with a light box and instructed to use it every morning for 30 minutes for 4 weeks. Sleep was evaluated using wrist actigraphy and the Pittsburgh Sleep Quality Index.
At baseline, 52.6% of subjects in the dim light group and 60% in the bright light group exceeded the clinical cutoff for poor sleep efficiency (≤ 85%). The mean sleep efficiency was 81.8% and 82.8%, respectively.
During the study period, sleep efficiency improved significantly more among subjects exposed to the bright light than those exposed to the dim light (P=0.003).
The mean sleep efficiency was in the clinically normal range for subjects in the bright light group at the end of the intervention (86.06%) and 3 weeks after (85.77%).
However, the cutoff for poor sleep efficiency was not reached in the dim light group, either at the end of the intervention (mean=79.35%) or 3 weeks after (mean=80.88%).
Total sleep time tended to increase over the study period for subjects in the bright light group, but there was no significant difference in total sleep time between the bright light and dim light groups.
Likewise, there was no significant between-group difference in waking after sleep onset, although this outcome tended to decrease over the study period for subjects in the bright light group.
“Systematic light exposure using bright white light is a low-cost and easily disseminated intervention that offers a feasible and potentially effective alternative to improve sleep in cancer survivors,” Dr Wu said.
However, she and her colleagues noted that larger-scale studies are needed. 
Results of a pilot study suggest that systematic bright light exposure can improve sleep in fatigued cancer survivors.
Subjects who were exposed to bright light every morning for 4 weeks had a significantly greater improvement in sleep efficiency than those who were exposed to dim light over the same period.
In fact, subjects in the bright light group were able to achieve clinically normal levels of sleep efficiency, and subjects in the dim light group were not.
Sleep efficiency is the percentage of time in bed that subjects spent sleeping.
Lisa M. Wu, PhD, of Northwestern University in Chicago, Illinois, and her colleagues reported these results in the Journal of Clinical Sleep Medicine.
The team noted that cancer patients report sleep disturbances at a significantly higher rate than the general population. Between 23% and 44% of cancer patients experience insomnia symptoms even years after treatment.
With this in mind, the researchers studied 44 individuals who had completed cancer treatment and met criteria for clinically significant fatigue at screening.
The subjects had an average age of 53.6, and 75% percent were female. Roughly 55% (n=24) had been diagnosed with a hematologic malignancy.
The subjects were randomized to a bright white light intervention or a dim red light intervention. Subjects in both treatment arms were provided with a light box and instructed to use it every morning for 30 minutes for 4 weeks. Sleep was evaluated using wrist actigraphy and the Pittsburgh Sleep Quality Index.
At baseline, 52.6% of subjects in the dim light group and 60% in the bright light group exceeded the clinical cutoff for poor sleep efficiency (≤ 85%). The mean sleep efficiency was 81.8% and 82.8%, respectively.
During the study period, sleep efficiency improved significantly more among subjects exposed to the bright light than those exposed to the dim light (P=0.003).
The mean sleep efficiency was in the clinically normal range for subjects in the bright light group at the end of the intervention (86.06%) and 3 weeks after (85.77%).
However, the cutoff for poor sleep efficiency was not reached in the dim light group, either at the end of the intervention (mean=79.35%) or 3 weeks after (mean=80.88%).
Total sleep time tended to increase over the study period for subjects in the bright light group, but there was no significant difference in total sleep time between the bright light and dim light groups.
Likewise, there was no significant between-group difference in waking after sleep onset, although this outcome tended to decrease over the study period for subjects in the bright light group.
“Systematic light exposure using bright white light is a low-cost and easily disseminated intervention that offers a feasible and potentially effective alternative to improve sleep in cancer survivors,” Dr Wu said.
However, she and her colleagues noted that larger-scale studies are needed.
Results of a pilot study suggest that systematic bright light exposure can improve sleep in fatigued cancer survivors.
Subjects who were exposed to bright light every morning for 4 weeks had a significantly greater improvement in sleep efficiency than those who were exposed to dim light over the same period.
In fact, subjects in the bright light group were able to achieve clinically normal levels of sleep efficiency, and subjects in the dim light group were not.
Sleep efficiency is the percentage of time in bed that subjects spent sleeping.
Lisa M. Wu, PhD, of Northwestern University in Chicago, Illinois, and her colleagues reported these results in the Journal of Clinical Sleep Medicine.
The team noted that cancer patients report sleep disturbances at a significantly higher rate than the general population. Between 23% and 44% of cancer patients experience insomnia symptoms even years after treatment.
With this in mind, the researchers studied 44 individuals who had completed cancer treatment and met criteria for clinically significant fatigue at screening.
The subjects had an average age of 53.6, and 75% percent were female. Roughly 55% (n=24) had been diagnosed with a hematologic malignancy.
The subjects were randomized to a bright white light intervention or a dim red light intervention. Subjects in both treatment arms were provided with a light box and instructed to use it every morning for 30 minutes for 4 weeks. Sleep was evaluated using wrist actigraphy and the Pittsburgh Sleep Quality Index.
At baseline, 52.6% of subjects in the dim light group and 60% in the bright light group exceeded the clinical cutoff for poor sleep efficiency (≤ 85%). The mean sleep efficiency was 81.8% and 82.8%, respectively.
During the study period, sleep efficiency improved significantly more among subjects exposed to the bright light than those exposed to the dim light (P=0.003).
The mean sleep efficiency was in the clinically normal range for subjects in the bright light group at the end of the intervention (86.06%) and 3 weeks after (85.77%).
However, the cutoff for poor sleep efficiency was not reached in the dim light group, either at the end of the intervention (mean=79.35%) or 3 weeks after (mean=80.88%).
Total sleep time tended to increase over the study period for subjects in the bright light group, but there was no significant difference in total sleep time between the bright light and dim light groups.
Likewise, there was no significant between-group difference in waking after sleep onset, although this outcome tended to decrease over the study period for subjects in the bright light group.
“Systematic light exposure using bright white light is a low-cost and easily disseminated intervention that offers a feasible and potentially effective alternative to improve sleep in cancer survivors,” Dr Wu said.
However, she and her colleagues noted that larger-scale studies are needed.
KRd improves OS in relapsed/refractory MM
Adding carfilzomib (K) to treatment with lenalidomide and dexamethasone (Rd) can improve overall survival (OS) in patients with relapsed or refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Final results from the phase 3 ASPIRE trial showed that KRd reduced the risk of death by 21% and extended OS by 7.9 months, when compared to Rd.
In patients at first relapse, KRd was associated with an OS improvement of 11.4 months.
“Results from the final analysis of the phase 3 ASPIRE trial . . . are significant, as they further validate carfilzomib, lenalidomide, and dexamethasone as a standard-of-care regimen for patients with relapsed or refractory multiple myeloma,” said study author Keith Stewart, MBChB, of Mayo Clinic in Scottsdale, Arizona.
“Furthermore, these data showed that early use of carfilzomib, lenalidomide, and dexamethasone at first relapse provided nearly 1 additional year of survival for patients, regardless of prior treatment with bortezomib or transplant.”
ASPIRE enrolled 792 MM patients who had received a median of 2 prior therapies (range, 1-3). They were randomized to receive KRd (n=396) or Rd (n=396). Baseline characteristics were well balanced between the treatment arms.
Details on patients and treatment, as well as interim results from ASPIRE, were reported at the 2014 ASH Annual Meeting and published in NEJM in January 2015.
Treatment update
In the final analysis, there were 340 patients in the KRd arm and 358 in the Rd arm who stopped study treatment.
Reasons for discontinuation (in the KRd and Rd arms, respectively) were disease progression (n=188 and 224), adverse events (AEs, n=79 and 85), other reasons (n=61 and 35), withdrawn consent (n=10 and 12), and noncompliance (n=2 and 1).
A total of 182 patients in the KRd arm and 211 in the Rd arm received subsequent treatment for MM. These treatments were generally balanced between the KRd and Rd arms.
The median time to next treatment from the time of randomization was 39.0 months in the KRd arm and 24.4 months in the Rd arm (hazard ratio [HR]=0.65 P<0.001).
Survival
Interim ASPIRE data had shown a significant improvement in progression-free survival (PFS) and a trend toward improved OS in patients who received KRd. Now, researchers have observed a significant improvement in both endpoints with KRd.
The data cutoff for the final analysis was April 28, 2017. For PFS, the median follow-up was 48.8 months in the KRd arm and 48.0 months in the Rd arm.
The median PFS was 26.1 months in the KRd arm and 16.6 months in the Rd arm (9.5-month improvement, HR=0.66; P<0.001). The 3-year PFS rates were 38.2% and 28.4%, respectively. And the 5-year PFS rates were 25.6% and 17.3%, respectively.
The median follow-up for OS was 67.1 months. The median OS was 48.3 months in the KRd arm and 40.4 months in the Rd arm (7.9-month improvement, HR=0.79, P=0.0045).
The researchers also performed subgroup analyses according to prior lines of therapy, prior bortezomib exposure at first relapse, and prior transplant at first relapse.
In patients who had received 1 prior line of therapy, the median OS was 47.3 months in the KRd arm and 35.9 months in the Rd arm (11.4-month improvement, HR=0.81). For patients with 2 or more prior lines of therapy, the median OS was 48.8 months and 42.3 months, respectively (6.5-month improvement, HR=0.79).
Among patients with prior bortezomib exposure at first relapse, the median OS was 45.9 months in the KRd arm and 33.9 months in the Rd arm (12-month improvement, HR=0.82). Among patients without prior bortezomib exposure at first relapse, the median OS was 48.3 months and 40.4 months, respectively (7.9-month improvement, HR=0.80).
Among patients with prior transplant at first relapse, the median OS was 57.2 months in the KRd arm and 38.6 months in the Rd arm (18.6-month improvement, HR=0.71).
Safety
The incidence of treatment-emergent AEs was 98% in the KRd arm and 97.9% in the Rd arm. The incidence of grade 3 or higher AEs was 87% and 83.3%, respectively. The incidence of serious AEs was 65.3% and 56.8%, respectively.
Treatment discontinuation due to an AE occurred in 19.9% of patients in the KRd arm and 21.5% of patients in the Rd arm.
AEs of interest (in the KRd and Rd arms, respectively) included acute renal failure (9.2% and 7.7%), cardiac failure (7.1% and 4.1%), ischemic heart disease (6.9% and 4.6%), hypertension (17.1% and 8.7%), hematopoietic thrombocytopenia (32.7% and 26.2%), and peripheral neuropathy (18.9% and 17.2%).
Fatal AEs were reported in 11.5% of patients in the KRd arm and 10.8% of those in the Rd arm.
Fatal AEs reported in at least 2 patients in the KRd arm included (in the KRd and Rd arms, respectively) cardiac disorders (2.6% and 2.3%), pneumonia (1.5% and 0.8%), sepsis (0.8% for both), myocardial infarction (0.8% and 0.5%), acute respiratory distress syndrome (0.8% and 0%), death (0.5% for both), and cardiac arrest (0.5% and 0.3%).
This trial was funded by Onyx Pharmaceuticals, Inc.
Adding carfilzomib (K) to treatment with lenalidomide and dexamethasone (Rd) can improve overall survival (OS) in patients with relapsed or refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Final results from the phase 3 ASPIRE trial showed that KRd reduced the risk of death by 21% and extended OS by 7.9 months, when compared to Rd.
In patients at first relapse, KRd was associated with an OS improvement of 11.4 months.
“Results from the final analysis of the phase 3 ASPIRE trial . . . are significant, as they further validate carfilzomib, lenalidomide, and dexamethasone as a standard-of-care regimen for patients with relapsed or refractory multiple myeloma,” said study author Keith Stewart, MBChB, of Mayo Clinic in Scottsdale, Arizona.
“Furthermore, these data showed that early use of carfilzomib, lenalidomide, and dexamethasone at first relapse provided nearly 1 additional year of survival for patients, regardless of prior treatment with bortezomib or transplant.”
ASPIRE enrolled 792 MM patients who had received a median of 2 prior therapies (range, 1-3). They were randomized to receive KRd (n=396) or Rd (n=396). Baseline characteristics were well balanced between the treatment arms.
Details on patients and treatment, as well as interim results from ASPIRE, were reported at the 2014 ASH Annual Meeting and published in NEJM in January 2015.
Treatment update
In the final analysis, there were 340 patients in the KRd arm and 358 in the Rd arm who stopped study treatment.
Reasons for discontinuation (in the KRd and Rd arms, respectively) were disease progression (n=188 and 224), adverse events (AEs, n=79 and 85), other reasons (n=61 and 35), withdrawn consent (n=10 and 12), and noncompliance (n=2 and 1).
A total of 182 patients in the KRd arm and 211 in the Rd arm received subsequent treatment for MM. These treatments were generally balanced between the KRd and Rd arms.
The median time to next treatment from the time of randomization was 39.0 months in the KRd arm and 24.4 months in the Rd arm (hazard ratio [HR]=0.65 P<0.001).
Survival
Interim ASPIRE data had shown a significant improvement in progression-free survival (PFS) and a trend toward improved OS in patients who received KRd. Now, researchers have observed a significant improvement in both endpoints with KRd.
The data cutoff for the final analysis was April 28, 2017. For PFS, the median follow-up was 48.8 months in the KRd arm and 48.0 months in the Rd arm.
The median PFS was 26.1 months in the KRd arm and 16.6 months in the Rd arm (9.5-month improvement, HR=0.66; P<0.001). The 3-year PFS rates were 38.2% and 28.4%, respectively. And the 5-year PFS rates were 25.6% and 17.3%, respectively.
The median follow-up for OS was 67.1 months. The median OS was 48.3 months in the KRd arm and 40.4 months in the Rd arm (7.9-month improvement, HR=0.79, P=0.0045).
The researchers also performed subgroup analyses according to prior lines of therapy, prior bortezomib exposure at first relapse, and prior transplant at first relapse.
In patients who had received 1 prior line of therapy, the median OS was 47.3 months in the KRd arm and 35.9 months in the Rd arm (11.4-month improvement, HR=0.81). For patients with 2 or more prior lines of therapy, the median OS was 48.8 months and 42.3 months, respectively (6.5-month improvement, HR=0.79).
Among patients with prior bortezomib exposure at first relapse, the median OS was 45.9 months in the KRd arm and 33.9 months in the Rd arm (12-month improvement, HR=0.82). Among patients without prior bortezomib exposure at first relapse, the median OS was 48.3 months and 40.4 months, respectively (7.9-month improvement, HR=0.80).
Among patients with prior transplant at first relapse, the median OS was 57.2 months in the KRd arm and 38.6 months in the Rd arm (18.6-month improvement, HR=0.71).
Safety
The incidence of treatment-emergent AEs was 98% in the KRd arm and 97.9% in the Rd arm. The incidence of grade 3 or higher AEs was 87% and 83.3%, respectively. The incidence of serious AEs was 65.3% and 56.8%, respectively.
Treatment discontinuation due to an AE occurred in 19.9% of patients in the KRd arm and 21.5% of patients in the Rd arm.
AEs of interest (in the KRd and Rd arms, respectively) included acute renal failure (9.2% and 7.7%), cardiac failure (7.1% and 4.1%), ischemic heart disease (6.9% and 4.6%), hypertension (17.1% and 8.7%), hematopoietic thrombocytopenia (32.7% and 26.2%), and peripheral neuropathy (18.9% and 17.2%).
Fatal AEs were reported in 11.5% of patients in the KRd arm and 10.8% of those in the Rd arm.
Fatal AEs reported in at least 2 patients in the KRd arm included (in the KRd and Rd arms, respectively) cardiac disorders (2.6% and 2.3%), pneumonia (1.5% and 0.8%), sepsis (0.8% for both), myocardial infarction (0.8% and 0.5%), acute respiratory distress syndrome (0.8% and 0%), death (0.5% for both), and cardiac arrest (0.5% and 0.3%).
This trial was funded by Onyx Pharmaceuticals, Inc.
Adding carfilzomib (K) to treatment with lenalidomide and dexamethasone (Rd) can improve overall survival (OS) in patients with relapsed or refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Final results from the phase 3 ASPIRE trial showed that KRd reduced the risk of death by 21% and extended OS by 7.9 months, when compared to Rd.
In patients at first relapse, KRd was associated with an OS improvement of 11.4 months.
“Results from the final analysis of the phase 3 ASPIRE trial . . . are significant, as they further validate carfilzomib, lenalidomide, and dexamethasone as a standard-of-care regimen for patients with relapsed or refractory multiple myeloma,” said study author Keith Stewart, MBChB, of Mayo Clinic in Scottsdale, Arizona.
“Furthermore, these data showed that early use of carfilzomib, lenalidomide, and dexamethasone at first relapse provided nearly 1 additional year of survival for patients, regardless of prior treatment with bortezomib or transplant.”
ASPIRE enrolled 792 MM patients who had received a median of 2 prior therapies (range, 1-3). They were randomized to receive KRd (n=396) or Rd (n=396). Baseline characteristics were well balanced between the treatment arms.
Details on patients and treatment, as well as interim results from ASPIRE, were reported at the 2014 ASH Annual Meeting and published in NEJM in January 2015.
Treatment update
In the final analysis, there were 340 patients in the KRd arm and 358 in the Rd arm who stopped study treatment.
Reasons for discontinuation (in the KRd and Rd arms, respectively) were disease progression (n=188 and 224), adverse events (AEs, n=79 and 85), other reasons (n=61 and 35), withdrawn consent (n=10 and 12), and noncompliance (n=2 and 1).
A total of 182 patients in the KRd arm and 211 in the Rd arm received subsequent treatment for MM. These treatments were generally balanced between the KRd and Rd arms.
The median time to next treatment from the time of randomization was 39.0 months in the KRd arm and 24.4 months in the Rd arm (hazard ratio [HR]=0.65 P<0.001).
Survival
Interim ASPIRE data had shown a significant improvement in progression-free survival (PFS) and a trend toward improved OS in patients who received KRd. Now, researchers have observed a significant improvement in both endpoints with KRd.
The data cutoff for the final analysis was April 28, 2017. For PFS, the median follow-up was 48.8 months in the KRd arm and 48.0 months in the Rd arm.
The median PFS was 26.1 months in the KRd arm and 16.6 months in the Rd arm (9.5-month improvement, HR=0.66; P<0.001). The 3-year PFS rates were 38.2% and 28.4%, respectively. And the 5-year PFS rates were 25.6% and 17.3%, respectively.
The median follow-up for OS was 67.1 months. The median OS was 48.3 months in the KRd arm and 40.4 months in the Rd arm (7.9-month improvement, HR=0.79, P=0.0045).
The researchers also performed subgroup analyses according to prior lines of therapy, prior bortezomib exposure at first relapse, and prior transplant at first relapse.
In patients who had received 1 prior line of therapy, the median OS was 47.3 months in the KRd arm and 35.9 months in the Rd arm (11.4-month improvement, HR=0.81). For patients with 2 or more prior lines of therapy, the median OS was 48.8 months and 42.3 months, respectively (6.5-month improvement, HR=0.79).
Among patients with prior bortezomib exposure at first relapse, the median OS was 45.9 months in the KRd arm and 33.9 months in the Rd arm (12-month improvement, HR=0.82). Among patients without prior bortezomib exposure at first relapse, the median OS was 48.3 months and 40.4 months, respectively (7.9-month improvement, HR=0.80).
Among patients with prior transplant at first relapse, the median OS was 57.2 months in the KRd arm and 38.6 months in the Rd arm (18.6-month improvement, HR=0.71).
Safety
The incidence of treatment-emergent AEs was 98% in the KRd arm and 97.9% in the Rd arm. The incidence of grade 3 or higher AEs was 87% and 83.3%, respectively. The incidence of serious AEs was 65.3% and 56.8%, respectively.
Treatment discontinuation due to an AE occurred in 19.9% of patients in the KRd arm and 21.5% of patients in the Rd arm.
AEs of interest (in the KRd and Rd arms, respectively) included acute renal failure (9.2% and 7.7%), cardiac failure (7.1% and 4.1%), ischemic heart disease (6.9% and 4.6%), hypertension (17.1% and 8.7%), hematopoietic thrombocytopenia (32.7% and 26.2%), and peripheral neuropathy (18.9% and 17.2%).
Fatal AEs were reported in 11.5% of patients in the KRd arm and 10.8% of those in the Rd arm.
Fatal AEs reported in at least 2 patients in the KRd arm included (in the KRd and Rd arms, respectively) cardiac disorders (2.6% and 2.3%), pneumonia (1.5% and 0.8%), sepsis (0.8% for both), myocardial infarction (0.8% and 0.5%), acute respiratory distress syndrome (0.8% and 0%), death (0.5% for both), and cardiac arrest (0.5% and 0.3%).
This trial was funded by Onyx Pharmaceuticals, Inc.
Novel JAK1 inhibitor shows promise for myeloid malignancies
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
ATLANTA – The novel Janus kinase 1 (JAK1) inhibitor INCB052793 showed encouraging activity, particularly in combination with azacitidine, in certain patients with advanced myeloid malignancies in a phase 1/2 trial.
The activity was seen even in patients who previously failed treatment with hypomethylating agents, Amer M. Zeidan, MD, reported at the annual meeting of the American Society of Hematology.
In the combination therapy dose escalation phase (phase 1b), seven patients with MM received INCB052793 at doses of 25 mg or 35 mg daily plus dexamethasone, and nine patients with acute myeloid leukemia (AML) or MDS received INCB052793 plus azacitidine. During the dose expansion, 12 patients received a daily dose of 35 mg for 28-day cycles plus azacitidine (in AML and MDS patients), according to Dr. Zeidan of Yale University, New Haven, Conn.
The study employed a 3+3 dose-escalation design until dose-limiting toxicities occurred. Patients were treated in continuous cycles until study termination, consent withdrawal, disease progression, or unacceptable toxicity.
Phase 2 of the study is evaluating INCB052793 in combination with azacitidine in nine patients with AML or high-risk MDS who failed prior therapy with hypomethylating agents. The 35-mg daily dose was selected for this phase based on pharmacodynamic effect and the presence of thrombocytopenia in solid tumor patients at higher doses, he said.
At the data cutoff for this preliminary assessment, 1 of the 11 patients who received INCB052793 monotherapy – a patient with MDS/MPN – experienced complete response (CR) and remained on study at the data cutoff. Two monotherapy patients with MDS/MPN experienced partial remission (PR).
Of seven patients with MM in the INCB052793-plus-dexamethasone group, two had a minimal response with a reduction in M protein.
In the INCB052793-plus-azacitidine group, overall response rates were 67% in 12 patients with AML and 56% in patients with MDS or MDS/MPN.
In the AML group, there was one CR, one morphologic leukemia-free state, and two PRs. In the MDS group, three of seven patients had a CR. Among the two patients in the MDS/MPN group, one had a CR and one had a PR.
Of note, none of the seven patients in the INCB052793-plus-dexamethasone group had received prior treatment with hypomethylating agents, while 10 of 21 patients in the INCB052793-plus-azacitidine phase 1b group had, as well as all of the nine phase 2 patients. The results were as of Nov. 3, 2017, Dr. Zeidan said.
The JAK/STAT pathway plays an important role in cytokine and growth factor signal transduction. Dysregulation of the JAK/STAT pathway is associated with the pathogenesis of various hematologic malignancies, Dr. Zeidan explained, noting that blocking JAK signaling can inhibit AML cell proliferation through STAT3/5 inhibition and induction of caspase-dependent apoptosis.
INCB052793 is a small molecule JAK1 inhibitor with potential as monotherapy or in combination with standard therapies for treating advanced hematologic malignancies. It could be of particular benefit for high-risk MDS patients who have failed prior therapy with hypomethylating agents, as these patients have no available standard of care and their overall survival is often less than 6 months, he said.
These preliminary data show that treatment is associated with a number of nonhematologic and hematologic adverse events. Grade 3 or greater adverse events were observed in 45% of patients receiving INCB052793 monotherapy, 86% of patients receiving INCB052793 plus dexamethasone, and 95% of those receiving INCB052793 plus azacitidine.
The most common adverse events with INCB052793 plus dexamethasone were anemia, hypercalcemia, hypophosphatemia, pneumonia, sepsis, and thrombocytopenia. With INCB052793 plus azacitidine, the most common events were febrile neutropenia, anemia, neutropenia, and thrombocytopenia.
Most patients included in the current analysis discontinued treatment, including 91% of INCB052793 monotherapy patients, 100% of INCB052793-plus-dexamethasone patients, and 90% of INCB052793-plus-azacitidine patients. The primary reasons for discontinuation were disease progression or adverse events.
Despite these events, the findings suggest that combination therapy with INCB052793 and azacitidine is promising for patients with advanced myeloid malignancies, Dr. Zeidan said. However, signals of activity were lacking in multiple myeloma or lymphoid malignancies.
The findings of encouraging activity in patients who previously failed on hypomethylating agents are of particular interest, and suggest that INCB052793 might resensitize refractory/relapsed patients to the effects of these agents, Dr. Zeidan noted, concluding that these preliminary safety and efficacy data support further evaluation of INCB052793 in this setting. Enrollment is ongoing in phase 2 of the trial.
This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
SOURCE: Zeidan A et al. ASH 2017 Abstract 640.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: Overall response rates with INCB052793 plus azacitidine were 67% in AML and 56% in MDS or MDS/MPN.
Study details: A phase 1/2 study involving 58 initial patients.
Disclosures: This study is sponsored by Incyte. Dr. Zeidan reported serving as a consultant for Incyte and Otsuka and as a member of the speakers bureau for Takeda. He also reported financial relationships with AbbVie, Pfizer, Gilead, Celgene, and Ariad.
Source: Zeidan A et al. ASH 2017 Abstract 640.
Risks of MGUS persist beyond 30 years
A long-term study showed that patients with monoclonal gammopathy of undetermined significance (MGUS) were still at risk of progressing to other plasma-cell or lymphoid disorders after more than 30 years of follow-up.
The risk of developing such disorders was nearly 7 times higher in MGUS patients than in matched control subjects.
Patients with MGUS also had a significantly shorter median survival than controls.
Researchers reported these findings in NEJM.
“Monoclonal gammopathy of undetermined significance is present in more than 3% of the general population age 50 and older,” said study author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.
“In some cases, people with monoclonal gammopathy of undetermined significance go on to develop multiple myeloma.”
With this in mind, Dr Rajkumar and his colleagues studied 1384 patients—210 with IgM MGUS and 1129 with non-IgM MGUS. Patients were diagnosed with MGUS from 1960 through 1994, and their median age at diagnosis was 72.
The median follow-up was 34.1 years (range, 0.0 to 43.6), so there were 14,130 person-years of follow-up.
During that time, 147 patients progressed to another disorder, including:
- 97 to multiple myeloma
- 19 to non-Hodgkin lymphoma
- 14 to AL amyloidosis
- 13 to Waldenstrom’s macroglobulinemia
- 3 to chronic lymphocytic leukemia
- 1 to plasmacytoma.
The rate of progression in MGUS patients—11%—represented a risk of these disorders that was 6.5 times higher than the risk observed in an age- and sex-matched control population.
The risk of progression also increased over time for MGUS patients. Without accounting for death due to competing causes, the risk of progression was 10% at 10 years, 18% at 20 years, 28% at 30 years, and 36% at both 35 and 40 years.
“We also found that patients with monoclonal gammopathy of undetermined significance had shorter survival than comparable people without the condition, which raises the possibility there may be other disorders associated with monoclonal gammopathy of undetermined significance that still need further study,” Dr Rajkumar said.
The median survival was 8.1 years in MGUS patients and 12.4 years in controls (P<0.001).
Overall, 1300 MGUS patients (94%) had died at last follow-up. Of the 84 patients who were still alive, 5 had progressed.
A long-term study showed that patients with monoclonal gammopathy of undetermined significance (MGUS) were still at risk of progressing to other plasma-cell or lymphoid disorders after more than 30 years of follow-up.
The risk of developing such disorders was nearly 7 times higher in MGUS patients than in matched control subjects.
Patients with MGUS also had a significantly shorter median survival than controls.
Researchers reported these findings in NEJM.
“Monoclonal gammopathy of undetermined significance is present in more than 3% of the general population age 50 and older,” said study author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.
“In some cases, people with monoclonal gammopathy of undetermined significance go on to develop multiple myeloma.”
With this in mind, Dr Rajkumar and his colleagues studied 1384 patients—210 with IgM MGUS and 1129 with non-IgM MGUS. Patients were diagnosed with MGUS from 1960 through 1994, and their median age at diagnosis was 72.
The median follow-up was 34.1 years (range, 0.0 to 43.6), so there were 14,130 person-years of follow-up.
During that time, 147 patients progressed to another disorder, including:
- 97 to multiple myeloma
- 19 to non-Hodgkin lymphoma
- 14 to AL amyloidosis
- 13 to Waldenstrom’s macroglobulinemia
- 3 to chronic lymphocytic leukemia
- 1 to plasmacytoma.
The rate of progression in MGUS patients—11%—represented a risk of these disorders that was 6.5 times higher than the risk observed in an age- and sex-matched control population.
The risk of progression also increased over time for MGUS patients. Without accounting for death due to competing causes, the risk of progression was 10% at 10 years, 18% at 20 years, 28% at 30 years, and 36% at both 35 and 40 years.
“We also found that patients with monoclonal gammopathy of undetermined significance had shorter survival than comparable people without the condition, which raises the possibility there may be other disorders associated with monoclonal gammopathy of undetermined significance that still need further study,” Dr Rajkumar said.
The median survival was 8.1 years in MGUS patients and 12.4 years in controls (P<0.001).
Overall, 1300 MGUS patients (94%) had died at last follow-up. Of the 84 patients who were still alive, 5 had progressed.
A long-term study showed that patients with monoclonal gammopathy of undetermined significance (MGUS) were still at risk of progressing to other plasma-cell or lymphoid disorders after more than 30 years of follow-up.
The risk of developing such disorders was nearly 7 times higher in MGUS patients than in matched control subjects.
Patients with MGUS also had a significantly shorter median survival than controls.
Researchers reported these findings in NEJM.
“Monoclonal gammopathy of undetermined significance is present in more than 3% of the general population age 50 and older,” said study author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.
“In some cases, people with monoclonal gammopathy of undetermined significance go on to develop multiple myeloma.”
With this in mind, Dr Rajkumar and his colleagues studied 1384 patients—210 with IgM MGUS and 1129 with non-IgM MGUS. Patients were diagnosed with MGUS from 1960 through 1994, and their median age at diagnosis was 72.
The median follow-up was 34.1 years (range, 0.0 to 43.6), so there were 14,130 person-years of follow-up.
During that time, 147 patients progressed to another disorder, including:
- 97 to multiple myeloma
- 19 to non-Hodgkin lymphoma
- 14 to AL amyloidosis
- 13 to Waldenstrom’s macroglobulinemia
- 3 to chronic lymphocytic leukemia
- 1 to plasmacytoma.
The rate of progression in MGUS patients—11%—represented a risk of these disorders that was 6.5 times higher than the risk observed in an age- and sex-matched control population.
The risk of progression also increased over time for MGUS patients. Without accounting for death due to competing causes, the risk of progression was 10% at 10 years, 18% at 20 years, 28% at 30 years, and 36% at both 35 and 40 years.
“We also found that patients with monoclonal gammopathy of undetermined significance had shorter survival than comparable people without the condition, which raises the possibility there may be other disorders associated with monoclonal gammopathy of undetermined significance that still need further study,” Dr Rajkumar said.
The median survival was 8.1 years in MGUS patients and 12.4 years in controls (P<0.001).
Overall, 1300 MGUS patients (94%) had died at last follow-up. Of the 84 patients who were still alive, 5 had progressed.
Drug’s label updated to include risk of allergic reactions
The US Food and Drug Administration (FDA) and Tesaro, Inc., have updated the prescribing information for Varubi® (rolapitant) injectable emulsion to include a new warning about the risk of allergic reactions.
Varubi injectable emulsion is a substance P/neurokinin receptor antagonist approved to prevent delayed nausea and vomiting associated with chemotherapy in adults.
Since Varubi injectable emulsion gained FDA approval, there have been reports of anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions to the drug, some of which required hospitalization.
Now, the labeling for Varubi injectable emulsion has been changed to include information about these events. The changes include modifications to the CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, and ADVERSE REACTIONS sections of the label.
Since Varubi injectable emulsion was introduced to the US market in late November 2017, at least 7000 doses of the drug have been administered to patients receiving emetogenic chemotherapy in the US, according to Tesaro.
Anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have occurred during or soon after the infusion of Varubi. Most reactions have occurred within the first few minutes of administration.
The FDA has advised that patients who are hypersensitive to any component of Varubi injectable emulsion (including soybean oil) do not receive the drug. And patients with known allergies to legumes or other related allergens should be monitored closely.
The FDA said healthcare professionals should be vigilant for signs of hypersensitivity or anaphylaxis in all patients receiving Varubi injectable emulsion, both during administration and afterward.
Symptoms of anaphylaxis can include wheezing, difficulty breathing, swelling of the face or throat, hives, flushing, itching, abdominal cramping, abdominal pain, vomiting, back pain, chest pain, hypotension, and shock.
If anaphylaxis or any other serious hypersensitivity/infusion reaction occurs, Varubi injectable emulsion should be stopped immediately and permanently. The patient should receive appropriate medical management, including epinephrine and/or antihistamines.
To ensure patients and healthcare professionals are aware of the label update to Varubi injectable emulsion, Tesaro has issued a Dear Healthcare Professional letter. In addition, the updated prescribing information has been posted on the Varubi website.
For any questions about the use of Varubi injectable emulsion or to report adverse events related to the drug, contact Tesaro’s medical information department at 1-844-4-TESARO (1-844-483-7276).
Adverse events related to Varubi should also be reported to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
The US Food and Drug Administration (FDA) and Tesaro, Inc., have updated the prescribing information for Varubi® (rolapitant) injectable emulsion to include a new warning about the risk of allergic reactions.
Varubi injectable emulsion is a substance P/neurokinin receptor antagonist approved to prevent delayed nausea and vomiting associated with chemotherapy in adults.
Since Varubi injectable emulsion gained FDA approval, there have been reports of anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions to the drug, some of which required hospitalization.
Now, the labeling for Varubi injectable emulsion has been changed to include information about these events. The changes include modifications to the CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, and ADVERSE REACTIONS sections of the label.
Since Varubi injectable emulsion was introduced to the US market in late November 2017, at least 7000 doses of the drug have been administered to patients receiving emetogenic chemotherapy in the US, according to Tesaro.
Anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have occurred during or soon after the infusion of Varubi. Most reactions have occurred within the first few minutes of administration.
The FDA has advised that patients who are hypersensitive to any component of Varubi injectable emulsion (including soybean oil) do not receive the drug. And patients with known allergies to legumes or other related allergens should be monitored closely.
The FDA said healthcare professionals should be vigilant for signs of hypersensitivity or anaphylaxis in all patients receiving Varubi injectable emulsion, both during administration and afterward.
Symptoms of anaphylaxis can include wheezing, difficulty breathing, swelling of the face or throat, hives, flushing, itching, abdominal cramping, abdominal pain, vomiting, back pain, chest pain, hypotension, and shock.
If anaphylaxis or any other serious hypersensitivity/infusion reaction occurs, Varubi injectable emulsion should be stopped immediately and permanently. The patient should receive appropriate medical management, including epinephrine and/or antihistamines.
To ensure patients and healthcare professionals are aware of the label update to Varubi injectable emulsion, Tesaro has issued a Dear Healthcare Professional letter. In addition, the updated prescribing information has been posted on the Varubi website.
For any questions about the use of Varubi injectable emulsion or to report adverse events related to the drug, contact Tesaro’s medical information department at 1-844-4-TESARO (1-844-483-7276).
Adverse events related to Varubi should also be reported to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
The US Food and Drug Administration (FDA) and Tesaro, Inc., have updated the prescribing information for Varubi® (rolapitant) injectable emulsion to include a new warning about the risk of allergic reactions.
Varubi injectable emulsion is a substance P/neurokinin receptor antagonist approved to prevent delayed nausea and vomiting associated with chemotherapy in adults.
Since Varubi injectable emulsion gained FDA approval, there have been reports of anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions to the drug, some of which required hospitalization.
Now, the labeling for Varubi injectable emulsion has been changed to include information about these events. The changes include modifications to the CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, and ADVERSE REACTIONS sections of the label.
Since Varubi injectable emulsion was introduced to the US market in late November 2017, at least 7000 doses of the drug have been administered to patients receiving emetogenic chemotherapy in the US, according to Tesaro.
Anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have occurred during or soon after the infusion of Varubi. Most reactions have occurred within the first few minutes of administration.
The FDA has advised that patients who are hypersensitive to any component of Varubi injectable emulsion (including soybean oil) do not receive the drug. And patients with known allergies to legumes or other related allergens should be monitored closely.
The FDA said healthcare professionals should be vigilant for signs of hypersensitivity or anaphylaxis in all patients receiving Varubi injectable emulsion, both during administration and afterward.
Symptoms of anaphylaxis can include wheezing, difficulty breathing, swelling of the face or throat, hives, flushing, itching, abdominal cramping, abdominal pain, vomiting, back pain, chest pain, hypotension, and shock.
If anaphylaxis or any other serious hypersensitivity/infusion reaction occurs, Varubi injectable emulsion should be stopped immediately and permanently. The patient should receive appropriate medical management, including epinephrine and/or antihistamines.
To ensure patients and healthcare professionals are aware of the label update to Varubi injectable emulsion, Tesaro has issued a Dear Healthcare Professional letter. In addition, the updated prescribing information has been posted on the Varubi website.
For any questions about the use of Varubi injectable emulsion or to report adverse events related to the drug, contact Tesaro’s medical information department at 1-844-4-TESARO (1-844-483-7276).
Adverse events related to Varubi should also be reported to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
Generic bortezomib available in US
Fresenius Kabi has introduced its generic version of Velcade, Bortezomib for Injection, to the US market.
This is the first intravenous alternative to Velcade available in the US.
Bortezomib for Injection is available as a single dose vial containing 3.5 mg of lyophilized powder.
The product is approved to treat patients with multiple myeloma and patients with mantle cell lymphoma who have received at least 1 prior therapy.
For details, see the prescribing information for Bortezomib for Injection.
Velcade is a registered trademark of Millennium Pharmaceuticals, Inc.
Fresenius Kabi has introduced its generic version of Velcade, Bortezomib for Injection, to the US market.
This is the first intravenous alternative to Velcade available in the US.
Bortezomib for Injection is available as a single dose vial containing 3.5 mg of lyophilized powder.
The product is approved to treat patients with multiple myeloma and patients with mantle cell lymphoma who have received at least 1 prior therapy.
For details, see the prescribing information for Bortezomib for Injection.
Velcade is a registered trademark of Millennium Pharmaceuticals, Inc.
Fresenius Kabi has introduced its generic version of Velcade, Bortezomib for Injection, to the US market.
This is the first intravenous alternative to Velcade available in the US.
Bortezomib for Injection is available as a single dose vial containing 3.5 mg of lyophilized powder.
The product is approved to treat patients with multiple myeloma and patients with mantle cell lymphoma who have received at least 1 prior therapy.
For details, see the prescribing information for Bortezomib for Injection.
Velcade is a registered trademark of Millennium Pharmaceuticals, Inc.
FDA approves denosumab for MM patients
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
Denosumab indication now includes multiple myeloma, Amgen announces
The Food and Drug Administration has expanded the indications for denosumab (Xgeva), previously indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, to include patients with multiple myeloma, according to a press release from Amgen, the manufacturer of Xgeva.
“Up to 40% of [multiple myeloma] patients remain untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis. Denosumab, which is not cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, providing patients with a novel treatment option,” Dr. Noopur Raje, director of the Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, said in the press release.
Adverse events in multiple myeloma patients were broadly similar to the known safety profile of denosumab. The most common adverse events were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common adverse event resulting in discontinuation of treatment was osteonecrosis of the jaw.
Find the full press release on the Amgen website.
The Food and Drug Administration has expanded the indications for denosumab (Xgeva), previously indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, to include patients with multiple myeloma, according to a press release from Amgen, the manufacturer of Xgeva.
“Up to 40% of [multiple myeloma] patients remain untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis. Denosumab, which is not cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, providing patients with a novel treatment option,” Dr. Noopur Raje, director of the Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, said in the press release.
Adverse events in multiple myeloma patients were broadly similar to the known safety profile of denosumab. The most common adverse events were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common adverse event resulting in discontinuation of treatment was osteonecrosis of the jaw.
Find the full press release on the Amgen website.
The Food and Drug Administration has expanded the indications for denosumab (Xgeva), previously indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, to include patients with multiple myeloma, according to a press release from Amgen, the manufacturer of Xgeva.
“Up to 40% of [multiple myeloma] patients remain untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis. Denosumab, which is not cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, providing patients with a novel treatment option,” Dr. Noopur Raje, director of the Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, said in the press release.
Adverse events in multiple myeloma patients were broadly similar to the known safety profile of denosumab. The most common adverse events were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common adverse event resulting in discontinuation of treatment was osteonecrosis of the jaw.
Find the full press release on the Amgen website.
Continue to opt for HDT/ASCT for multiple myeloma
High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents, according to a recent systematic review and two meta-analyses.
Given the “unprecedented efficacy” of “modern induction therapy with immunomodulatory drugs and proteasome inhibitors (also called ‘novel agents’),” investigators “have sought to reevaluate the role of HDT/ASCT,” wrote Binod Dhakal, MD, of the Medical College of Wisconsin, and his colleagues. The report is in JAMA Oncology.
To solve the issue, they analyzed five randomized controlled trials conducted since 2000 and concluded that HDT/ASCT is still the preferred treatment approach.
Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma, the researchers noted.
The combined odds for complete response were 1.27 (95% confidence interval, 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT). The combined hazard ratio (HR) for PFS was 0.55 (95% CI, 0.41-0.7, P less than .001) and 0.76 for overall survival (95% CI, 0.42-1.36, P = .20) in favor of HDT.
PFS was best with tandem HDT/ASCT (HR, 0.49, 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation (HR, 0.53, 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68, 95% CI, 0.53-0.87), compared with SDT. However, none of the HDT/ASCT approaches had a significant impact on overall survival.
Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.
“The achievement of high [minimal residual disease] rates with HDT/ASCT may render this approach the ideal platform for testing novel approaches (e.g., immunotherapy) aiming at disease eradication and cures,” the researchers wrote.
The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.
SOURCE: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.
High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents, according to a recent systematic review and two meta-analyses.
Given the “unprecedented efficacy” of “modern induction therapy with immunomodulatory drugs and proteasome inhibitors (also called ‘novel agents’),” investigators “have sought to reevaluate the role of HDT/ASCT,” wrote Binod Dhakal, MD, of the Medical College of Wisconsin, and his colleagues. The report is in JAMA Oncology.
To solve the issue, they analyzed five randomized controlled trials conducted since 2000 and concluded that HDT/ASCT is still the preferred treatment approach.
Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma, the researchers noted.
The combined odds for complete response were 1.27 (95% confidence interval, 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT). The combined hazard ratio (HR) for PFS was 0.55 (95% CI, 0.41-0.7, P less than .001) and 0.76 for overall survival (95% CI, 0.42-1.36, P = .20) in favor of HDT.
PFS was best with tandem HDT/ASCT (HR, 0.49, 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation (HR, 0.53, 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68, 95% CI, 0.53-0.87), compared with SDT. However, none of the HDT/ASCT approaches had a significant impact on overall survival.
Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.
“The achievement of high [minimal residual disease] rates with HDT/ASCT may render this approach the ideal platform for testing novel approaches (e.g., immunotherapy) aiming at disease eradication and cures,” the researchers wrote.
The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.
SOURCE: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.
High-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) is still the best option for multiple myeloma even after almost 2 decades with newer and highly effective induction agents, according to a recent systematic review and two meta-analyses.
Given the “unprecedented efficacy” of “modern induction therapy with immunomodulatory drugs and proteasome inhibitors (also called ‘novel agents’),” investigators “have sought to reevaluate the role of HDT/ASCT,” wrote Binod Dhakal, MD, of the Medical College of Wisconsin, and his colleagues. The report is in JAMA Oncology.
To solve the issue, they analyzed five randomized controlled trials conducted since 2000 and concluded that HDT/ASCT is still the preferred treatment approach.
Despite a lack of demonstrable overall survival benefit, there is a significant progression-free survival (PFS) benefit, low treatment-related mortality, and potential high minimal residual disease-negative rates conferred by HDT/ASCT in newly-diagnosed multiple myeloma, the researchers noted.
The combined odds for complete response were 1.27 (95% confidence interval, 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT). The combined hazard ratio (HR) for PFS was 0.55 (95% CI, 0.41-0.7, P less than .001) and 0.76 for overall survival (95% CI, 0.42-1.36, P = .20) in favor of HDT.
PFS was best with tandem HDT/ASCT (HR, 0.49, 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation (HR, 0.53, 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68, 95% CI, 0.53-0.87), compared with SDT. However, none of the HDT/ASCT approaches had a significant impact on overall survival.
Meanwhile, treatment-related mortality with HDT/ASCT was minimal, at less than 1%.
“The achievement of high [minimal residual disease] rates with HDT/ASCT may render this approach the ideal platform for testing novel approaches (e.g., immunotherapy) aiming at disease eradication and cures,” the researchers wrote.
The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.
SOURCE: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.
FROM JAMA ONCOLOGY
Key clinical point:
Major finding: The combined odds for complete response were 1.27 (95% CI 0.97-1.65, P = .07) with HDT/ASCT, compared with standard-dose therapy (SDT).
Study details: A systematic review and two meta-analyses examining five phase 3 clinical trials reported since 2000.
Disclosures: The researchers reported relationships with a number of companies, including Takeda, Celgene, and Amgen, that make novel induction agents.
Source: Dhakal B et al. JAMA Oncol. 2018 Jan 4. doi: 10.1001/jamaoncol.2017.4600.
Daratumumab looks good in light chain amyloidosis
ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.
So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”
“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.
In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.
Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.
Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.
At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.
Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.
At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.
Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”
The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.
Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).
Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.
At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.
There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.
First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.
“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”
Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.
Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.
SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.
So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”
“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.
In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.
Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.
Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.
At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.
Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.
At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.
Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”
The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.
Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).
Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.
At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.
There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.
First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.
“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”
Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.
Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.
SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.
So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”
“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.
In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.
Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.
Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.
At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.
Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.
At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.
Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”
The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.
Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).
Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.
At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.
There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.
First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.
“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”
Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.
Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.
SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.
REPORTING FROM ASH 2017
Key clinical point: Major finding: Rates of very good partial response or complete response were 44% and 33%, respectively, at 6 months.
Data source: Two phase 2 trials of daratumumab monotherapy in patients with previously treated light chain amyloidosis (NCT02816476 [36 patients] and NCT02841033 [12 patients]).
Disclosures: Janssen makes daratumumab and provided partial funding for both studies. Dr. Roussel disclosed honoraria and research funding from Janssen. Dr. Sanchorawala had no conflicts of interest.
Sources: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.