Multiple Myeloma

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Micrograph showing

multiple myeloma

Combining a calcineurin inhibitor and a histone deacetylase (HDAC) inhibitor could improve the treatment of multiple myeloma (MM), according to researchers.

The team found that MM cells express high levels of the protein phosphatase PPP3CA, a subunit of calcineurin.

And combining the calcineurin inhibitor FK506 with the HDAC inhibitor panobinostat suppressed MM cell growth in vitro and decreased tumor growth in mouse models of MM.

Yoichi Imai, MD, PhD, of Tokyo Women’s Medical University in Japan, and colleagues conducted this research and reported the results in JCI Insight.

First, the team observed increased PPP3CA expression in MM cell lines and MM cells isolated from patients with advanced disease.

Then, the researchers found that panobinostat reduced PPP3CA expression in MM cell lines. And further investigation revealed that the drug induced degradation of PPP3CA through HSP90 inhibition.

When the team knocked down PPP3CA in MM cells, they observed a reduction in cell growth. And when they overexpressed PPP3CA, they observed enhanced MM cell growth.

The researchers noted that FK506 inhibits the association between PPP3CA and calcineurin B. Unfortunately, FK506 alone did not suppress the growth of MM cells in vitro.

However, when FK506 was given with panobinostat or the HDAC inhibitor ACY-1215, the researchers observed a greater reduction in MM cell growth than with either HDAC inhibitor alone.

Panobinostat and FK506 reduced the growth of MM cells that were t(4;14)-positive (KMS-11, KMS-18, and KMS-26) and t(4;14)-negative (U266 and KMS-12PE) more effectively than panobinostat alone.

In mice with MM, those treated with FK506 alone had tumor sizes similar to control mice. However, mice treated with panobinostat saw a decrease in tumor size. And this effect was enhanced by the addition of FK506.

The researchers observed reduced PPP3CA expression, enhanced histone H3 acetylation, and cleavage of caspase-3 in samples from panobinostat-treated mice. And FK506 augmented panobinostat-induced apoptosis.

The team said these results suggest that FK506 enhances the antimyeloma effect of panobinostat through PPP3CA reduction, which supports the importance of calcineurin in the pathogenesis of MM.

Daratumumab monotherapy was associated with an overall response rate of 29.2% and was well tolerated in 106 heavily treated patients with multiple myeloma, based on results from the SIRIUS trial.

Of 106 patients who received daratumumab at 16 mg/kg, 3% achieved a stringent complete response, 9% had a very good partial response, and 17% had a partial response. The median progression-free survival was 3.7 months and median duration of response was 7.4 months. The 12-month overall survival was 64·8%, and, at a subsequent cutoff, median overall survival was 17.5 months.

All of the study patients had been treated with proteasome inhibitors and immunomodulatory drugs, with a median of five previous therapies. Most patients (80%) had received autologous stem cell transplantation, and 97% were refractory to the last line of therapy before study enrollment.

Courtesy Wikimedia Commons/KGH/Creative Commons License

“Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies,” wrote Dr. Sagar Lonial of Emory University, Atlanta, and colleagues (Lancet 2016;387:1551-60). Response rates were similar for patients with moderate renal impairment, those over age 75, and those with extramedullary disease or high-risk baseline cytogenetic characteristics.

Daratumumab was well tolerated, and none of the patients discontinued treatment because of treatment-related adverse events. The most common adverse events of any grade were anemia (33%), thrombocytopenia (25%), and neutropenia (23%). Additional supportive care in the form of red blood cell transfusions was received by 38% of patients, platelet transfusions by 13%, and granulocyte colony-stimulating factor by 8%. Fatigue (40%) and nausea (29%) were the most common nonhematologic adverse events. Serious adverse events were observed in 30% of patients.

Daratumumab compares favorably with other regimens such as pomalidomide alone or with dexamethasone or carfilzomib monotherapy, according to the investigators.

The favorable safety profile of daratumumab makes it an attractive candidate for combination regimens, the authors noted, and daratumumab combined with other backbone agents are currently under investigation.

This study was sponsored by Janssen, maker of daratumumab (Darzalex). Dr. Lonial reported consulting or advisory roles with Janssen and several other drug companies.

Daratumumab monotherapy was associated with an overall response rate of 29.2% and was well tolerated in 106 heavily treated patients with multiple myeloma, based on results from the SIRIUS trial.

Of 106 patients who received daratumumab at 16 mg/kg, 3% achieved a stringent complete response, 9% had a very good partial response, and 17% had a partial response. The median progression-free survival was 3.7 months and median duration of response was 7.4 months. The 12-month overall survival was 64·8%, and, at a subsequent cutoff, median overall survival was 17.5 months.

All of the study patients had been treated with proteasome inhibitors and immunomodulatory drugs, with a median of five previous therapies. Most patients (80%) had received autologous stem cell transplantation, and 97% were refractory to the last line of therapy before study enrollment.

Courtesy Wikimedia Commons/KGH/Creative Commons License

“Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies,” wrote Dr. Sagar Lonial of Emory University, Atlanta, and colleagues (Lancet 2016;387:1551-60). Response rates were similar for patients with moderate renal impairment, those over age 75, and those with extramedullary disease or high-risk baseline cytogenetic characteristics.

Daratumumab was well tolerated, and none of the patients discontinued treatment because of treatment-related adverse events. The most common adverse events of any grade were anemia (33%), thrombocytopenia (25%), and neutropenia (23%). Additional supportive care in the form of red blood cell transfusions was received by 38% of patients, platelet transfusions by 13%, and granulocyte colony-stimulating factor by 8%. Fatigue (40%) and nausea (29%) were the most common nonhematologic adverse events. Serious adverse events were observed in 30% of patients.

Daratumumab compares favorably with other regimens such as pomalidomide alone or with dexamethasone or carfilzomib monotherapy, according to the investigators.

The favorable safety profile of daratumumab makes it an attractive candidate for combination regimens, the authors noted, and daratumumab combined with other backbone agents are currently under investigation.

This study was sponsored by Janssen, maker of daratumumab (Darzalex). Dr. Lonial reported consulting or advisory roles with Janssen and several other drug companies.

Daratumumab monotherapy was associated with an overall response rate of 29.2% and was well tolerated in 106 heavily treated patients with multiple myeloma, based on results from the SIRIUS trial.

Of 106 patients who received daratumumab at 16 mg/kg, 3% achieved a stringent complete response, 9% had a very good partial response, and 17% had a partial response. The median progression-free survival was 3.7 months and median duration of response was 7.4 months. The 12-month overall survival was 64·8%, and, at a subsequent cutoff, median overall survival was 17.5 months.

All of the study patients had been treated with proteasome inhibitors and immunomodulatory drugs, with a median of five previous therapies. Most patients (80%) had received autologous stem cell transplantation, and 97% were refractory to the last line of therapy before study enrollment.

Courtesy Wikimedia Commons/KGH/Creative Commons License

“Resistance to any previous therapy had no effect on the activity of daratumumab, lending support to a novel mechanism of action, but these findings need to be confirmed in larger studies,” wrote Dr. Sagar Lonial of Emory University, Atlanta, and colleagues (Lancet 2016;387:1551-60). Response rates were similar for patients with moderate renal impairment, those over age 75, and those with extramedullary disease or high-risk baseline cytogenetic characteristics.

Daratumumab was well tolerated, and none of the patients discontinued treatment because of treatment-related adverse events. The most common adverse events of any grade were anemia (33%), thrombocytopenia (25%), and neutropenia (23%). Additional supportive care in the form of red blood cell transfusions was received by 38% of patients, platelet transfusions by 13%, and granulocyte colony-stimulating factor by 8%. Fatigue (40%) and nausea (29%) were the most common nonhematologic adverse events. Serious adverse events were observed in 30% of patients.

Daratumumab compares favorably with other regimens such as pomalidomide alone or with dexamethasone or carfilzomib monotherapy, according to the investigators.

The favorable safety profile of daratumumab makes it an attractive candidate for combination regimens, the authors noted, and daratumumab combined with other backbone agents are currently under investigation.

This study was sponsored by Janssen, maker of daratumumab (Darzalex). Dr. Lonial reported consulting or advisory roles with Janssen and several other drug companies.

Monoclonal antibodies

Photo by Linda Bartlett

NEW ORLEANS—A small study suggests that treatment with lenalidomide and dexamethasone (len-dex) prompts an increase in cancer stem cells (CSCs) for patients with newly diagnosed multiple myeloma (MM).

However, adding an anti-CD19 monoclonal antibody (mAb) to the regimen can reduce CSCs.

Most patients who received the mAb, MEDI-551, experienced a decrease in CSCs, but the cells rebounded after the patients stopped receiving  MEDI-551.

And those patients who did not see a decrease in CSCs progressed. However, some patients are still in response and remain on treatment with len-dex.

The investigators believe these early results suggest prolonged treatment with len-dex and MED-551 may be safe and clinically beneficial for MM patients.

The results were presented at the 2016 AACR Annual Meeting (abstract CT102).

The study included 17 patients with newly diagnosed MM. They had a median age of 65 (range, 34-73). Most had ISS stage I (n=11), 2 had stage II, and 4 had stage III. Seven patients had t(4;14).

“We chose to carry out this clinical trial in newly diagnosed patients because our original data showed that CD19 was almost always expressed by myeloma stem cells in these patients, whereas we don’t know if that is the case in more advanced patients,” said investigator William Matsui, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

The patients received 28-day cycles of len-dex (len at 25 mg PO, days 1-21, and dex at 40 mg PO, weekly). Patients received MEDI-551 (at 4 mg/kg IV) in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding patients continued on len-dex.

The investigators measured MM CSCs by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates at baseline and at the end of cycles 2 and 4.

The team quantified peripheral blood CSCs by flow cytometry (CD19+CD27+ALDH+) at baseline and the end of cycles 2, 4, 5, and 7.

“We wanted to see if these 2 assays gave similar results, and, in this clinical trial, they were almost identical,” said investigator Carol Ann Huff, MD, also of Johns Hopkins.

“Since it is much easier to draw blood than bone marrow from our patients, we think that we can primarily use blood to track multiple myeloma stem cells in the future.”

Response

Two patients did not receive MEDI-551 due to progressive disease and noncompliance. So the investigators assessed responses in 15 patients.

After cycle 2 (len-dex alone), there were 3 very good partial responses (VGPRs), 10 partial responses (PRs), 1 molecular response, and 1 case of stable disease.

After cycle 4 (len-dex plus MEDI-551), there were 6 VGPRs, 8 PRs, and 1 molecular response.

Ten patients who completed treatment with MED-551 remain on len-dex. At the end of cycle 7, there was 1 complete response, 8 VGPRs, and 1 PR.

CFU-MM

When compared to baseline, bone-marrow-derived CFU-MM increased a median of 2.5-fold (range, 0.4-7.4) after cycle 2 but decreased a median of 0.48-fold (range, 0.14-0.85) in 14 patients after cycle 4.

The investigators compared these results to 5 newly diagnosed MM patients who only received standard treatment with len-dex.

In these patients, CFU-MM increased a median of 9.3-fold (range, 4-14) at a median of 4 months (range, 2-4). This is in spite of the fact that all of these patients had a PR or better.

Circulating CSCs

Compared to baseline, circulating MM CSCs increased a median of 1.6-fold (range, 0.4-8.6) in 14 patients after cycle 2 but decreased a median of 0.6-fold (range, 0.01-7.4) in 13 patients after cycle 4.

At the end of cycle 5, MM CSCs had increased in 4 of the 10 patients who were still on len-dex. By the end of cycle 7, MM CSCs had increased in 8 of the patients.

Circulating MM CSCs increased by the end of cycle 4 in 2 patients, and both had progressed by end of cycle 7.

Safety and next steps

The investigators said there were no serious adverse events in this trial, but 2 patients experienced grade 2 infusion reactions after the first MEDI-551 dose.

The team plans to conduct further studies to assess the long-term impact of MED-551 in MM patients and determine how the mAb might work in combination with other treatments, particularly transplant.

“In other studies at Johns Hopkins, we have found that antibody therapies can work much better after a bone marrow transplant, especially allogeneic transplants,” Dr Matsui said.

Funding and drugs for this study were provided by MedImmune Inc., the developers of MEDI-551. Drs Huff and Matsui served as a paid scientific advisory board member and a consultant to MedImmune Inc., respectively.

Monoclonal antibodies

Photo by Linda Bartlett

NEW ORLEANS—A small study suggests that treatment with lenalidomide and dexamethasone (len-dex) prompts an increase in cancer stem cells (CSCs) for patients with newly diagnosed multiple myeloma (MM).

However, adding an anti-CD19 monoclonal antibody (mAb) to the regimen can reduce CSCs.

Most patients who received the mAb, MEDI-551, experienced a decrease in CSCs, but the cells rebounded after the patients stopped receiving  MEDI-551.

And those patients who did not see a decrease in CSCs progressed. However, some patients are still in response and remain on treatment with len-dex.

The investigators believe these early results suggest prolonged treatment with len-dex and MED-551 may be safe and clinically beneficial for MM patients.

The results were presented at the 2016 AACR Annual Meeting (abstract CT102).

The study included 17 patients with newly diagnosed MM. They had a median age of 65 (range, 34-73). Most had ISS stage I (n=11), 2 had stage II, and 4 had stage III. Seven patients had t(4;14).

“We chose to carry out this clinical trial in newly diagnosed patients because our original data showed that CD19 was almost always expressed by myeloma stem cells in these patients, whereas we don’t know if that is the case in more advanced patients,” said investigator William Matsui, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

The patients received 28-day cycles of len-dex (len at 25 mg PO, days 1-21, and dex at 40 mg PO, weekly). Patients received MEDI-551 (at 4 mg/kg IV) in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding patients continued on len-dex.

The investigators measured MM CSCs by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates at baseline and at the end of cycles 2 and 4.

The team quantified peripheral blood CSCs by flow cytometry (CD19+CD27+ALDH+) at baseline and the end of cycles 2, 4, 5, and 7.

“We wanted to see if these 2 assays gave similar results, and, in this clinical trial, they were almost identical,” said investigator Carol Ann Huff, MD, also of Johns Hopkins.

“Since it is much easier to draw blood than bone marrow from our patients, we think that we can primarily use blood to track multiple myeloma stem cells in the future.”

Response

Two patients did not receive MEDI-551 due to progressive disease and noncompliance. So the investigators assessed responses in 15 patients.

After cycle 2 (len-dex alone), there were 3 very good partial responses (VGPRs), 10 partial responses (PRs), 1 molecular response, and 1 case of stable disease.

After cycle 4 (len-dex plus MEDI-551), there were 6 VGPRs, 8 PRs, and 1 molecular response.

Ten patients who completed treatment with MED-551 remain on len-dex. At the end of cycle 7, there was 1 complete response, 8 VGPRs, and 1 PR.

CFU-MM

When compared to baseline, bone-marrow-derived CFU-MM increased a median of 2.5-fold (range, 0.4-7.4) after cycle 2 but decreased a median of 0.48-fold (range, 0.14-0.85) in 14 patients after cycle 4.

The investigators compared these results to 5 newly diagnosed MM patients who only received standard treatment with len-dex.

In these patients, CFU-MM increased a median of 9.3-fold (range, 4-14) at a median of 4 months (range, 2-4). This is in spite of the fact that all of these patients had a PR or better.

Circulating CSCs

Compared to baseline, circulating MM CSCs increased a median of 1.6-fold (range, 0.4-8.6) in 14 patients after cycle 2 but decreased a median of 0.6-fold (range, 0.01-7.4) in 13 patients after cycle 4.

At the end of cycle 5, MM CSCs had increased in 4 of the 10 patients who were still on len-dex. By the end of cycle 7, MM CSCs had increased in 8 of the patients.

Circulating MM CSCs increased by the end of cycle 4 in 2 patients, and both had progressed by end of cycle 7.

Safety and next steps

The investigators said there were no serious adverse events in this trial, but 2 patients experienced grade 2 infusion reactions after the first MEDI-551 dose.

The team plans to conduct further studies to assess the long-term impact of MED-551 in MM patients and determine how the mAb might work in combination with other treatments, particularly transplant.

“In other studies at Johns Hopkins, we have found that antibody therapies can work much better after a bone marrow transplant, especially allogeneic transplants,” Dr Matsui said.

Funding and drugs for this study were provided by MedImmune Inc., the developers of MEDI-551. Drs Huff and Matsui served as a paid scientific advisory board member and a consultant to MedImmune Inc., respectively.

Monoclonal antibodies

Photo by Linda Bartlett

NEW ORLEANS—A small study suggests that treatment with lenalidomide and dexamethasone (len-dex) prompts an increase in cancer stem cells (CSCs) for patients with newly diagnosed multiple myeloma (MM).

However, adding an anti-CD19 monoclonal antibody (mAb) to the regimen can reduce CSCs.

Most patients who received the mAb, MEDI-551, experienced a decrease in CSCs, but the cells rebounded after the patients stopped receiving  MEDI-551.

And those patients who did not see a decrease in CSCs progressed. However, some patients are still in response and remain on treatment with len-dex.

The investigators believe these early results suggest prolonged treatment with len-dex and MED-551 may be safe and clinically beneficial for MM patients.

The results were presented at the 2016 AACR Annual Meeting (abstract CT102).

The study included 17 patients with newly diagnosed MM. They had a median age of 65 (range, 34-73). Most had ISS stage I (n=11), 2 had stage II, and 4 had stage III. Seven patients had t(4;14).

“We chose to carry out this clinical trial in newly diagnosed patients because our original data showed that CD19 was almost always expressed by myeloma stem cells in these patients, whereas we don’t know if that is the case in more advanced patients,” said investigator William Matsui, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.

The patients received 28-day cycles of len-dex (len at 25 mg PO, days 1-21, and dex at 40 mg PO, weekly). Patients received MEDI-551 (at 4 mg/kg IV) in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding patients continued on len-dex.

The investigators measured MM CSCs by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates at baseline and at the end of cycles 2 and 4.

The team quantified peripheral blood CSCs by flow cytometry (CD19+CD27+ALDH+) at baseline and the end of cycles 2, 4, 5, and 7.

“We wanted to see if these 2 assays gave similar results, and, in this clinical trial, they were almost identical,” said investigator Carol Ann Huff, MD, also of Johns Hopkins.

“Since it is much easier to draw blood than bone marrow from our patients, we think that we can primarily use blood to track multiple myeloma stem cells in the future.”

Response

Two patients did not receive MEDI-551 due to progressive disease and noncompliance. So the investigators assessed responses in 15 patients.

After cycle 2 (len-dex alone), there were 3 very good partial responses (VGPRs), 10 partial responses (PRs), 1 molecular response, and 1 case of stable disease.

After cycle 4 (len-dex plus MEDI-551), there were 6 VGPRs, 8 PRs, and 1 molecular response.

Ten patients who completed treatment with MED-551 remain on len-dex. At the end of cycle 7, there was 1 complete response, 8 VGPRs, and 1 PR.

CFU-MM

When compared to baseline, bone-marrow-derived CFU-MM increased a median of 2.5-fold (range, 0.4-7.4) after cycle 2 but decreased a median of 0.48-fold (range, 0.14-0.85) in 14 patients after cycle 4.

The investigators compared these results to 5 newly diagnosed MM patients who only received standard treatment with len-dex.

In these patients, CFU-MM increased a median of 9.3-fold (range, 4-14) at a median of 4 months (range, 2-4). This is in spite of the fact that all of these patients had a PR or better.

Circulating CSCs

Compared to baseline, circulating MM CSCs increased a median of 1.6-fold (range, 0.4-8.6) in 14 patients after cycle 2 but decreased a median of 0.6-fold (range, 0.01-7.4) in 13 patients after cycle 4.

At the end of cycle 5, MM CSCs had increased in 4 of the 10 patients who were still on len-dex. By the end of cycle 7, MM CSCs had increased in 8 of the patients.

Circulating MM CSCs increased by the end of cycle 4 in 2 patients, and both had progressed by end of cycle 7.

Safety and next steps

The investigators said there were no serious adverse events in this trial, but 2 patients experienced grade 2 infusion reactions after the first MEDI-551 dose.

The team plans to conduct further studies to assess the long-term impact of MED-551 in MM patients and determine how the mAb might work in combination with other treatments, particularly transplant.

“In other studies at Johns Hopkins, we have found that antibody therapies can work much better after a bone marrow transplant, especially allogeneic transplants,” Dr Matsui said.

Funding and drugs for this study were provided by MedImmune Inc., the developers of MEDI-551. Drs Huff and Matsui served as a paid scientific advisory board member and a consultant to MedImmune Inc., respectively.

Short-term low-dose corticosteroid prophylaxis reduces the incidence of graft-vs.-host disease in patients who undergo allogeneic haploidentical stem-cell transplantation to treat hematologic neoplasms, according to a report published online April 18 in the Journal of Clinical Oncology.

The key to selecting patients most likely to benefit from the corticosteroid therapy is to identify those at high risk for graft-vs.-host disease (GVHD) using two biomarkers: high levels of CD56bright natural killer cells in allogeneic grafts or high CD4:CD8 ratios in bone marrow grafts, according to Dr. Ying-Jun Chang of Peking University People’s Hospital, Beijing, and associates.

The investigators performed an open-label trial involving 228 patients aged 15-60 years treated at a single medical center during an 18-month period for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or other hematologic neoplasms. Using the two biomarkers, the patients were categorized as either high or low risk for developing GVHD. They were randomly assigned to three study groups: 72 high-risk patients who received short-term low-dose corticosteroids, 73 high-risk patients who received usual care, and 83 low-risk patients who received usual care.

The cumulative 100-day incidence of acute grade-II to grade-IV GVHD was significantly lower in the high-risk patients who received prophylaxis (21%) than in the high-risk patients who did not receive prophylaxis (48%). In fact, corticosteroids decreased the rate of GVHD so that it was comparable with that in the low-risk patients (26%), Dr. Chang and associates said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.63l.8817).

Moreover, in the high-risk patients the median interval until GVHD developed was 25 days for those who took corticosteroids, compared with only 15 days for those who did not. Median times to myeloid recovery and platelet recovery were significantly shorter for high-risk patients who received corticosteroids than for either of the other study groups. However, 3-year overall survival and leukemia-free survival were comparable among the three study groups.

The short-term low-dose regimen of corticosteroids did not raise the rate of adverse events, including infection, which suggests that it is preferable to standard corticosteroid regimens in this patient population. The incidences of cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia, and invasive fungal infections were comparable among the three study groups. Of note, the incidences of osteonecrosis of the femoral head and secondary hypertension were significantly lower among high-risk patients who received corticosteroid prophylaxis than among those who did not.

“These results provide the first test, to our knowledge, of a novel risk-stratification-directed prophylaxis strategy that effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents,” Dr. Chang and associates said.

Short-term low-dose corticosteroid prophylaxis reduces the incidence of graft-vs.-host disease in patients who undergo allogeneic haploidentical stem-cell transplantation to treat hematologic neoplasms, according to a report published online April 18 in the Journal of Clinical Oncology.

The key to selecting patients most likely to benefit from the corticosteroid therapy is to identify those at high risk for graft-vs.-host disease (GVHD) using two biomarkers: high levels of CD56bright natural killer cells in allogeneic grafts or high CD4:CD8 ratios in bone marrow grafts, according to Dr. Ying-Jun Chang of Peking University People’s Hospital, Beijing, and associates.

The investigators performed an open-label trial involving 228 patients aged 15-60 years treated at a single medical center during an 18-month period for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or other hematologic neoplasms. Using the two biomarkers, the patients were categorized as either high or low risk for developing GVHD. They were randomly assigned to three study groups: 72 high-risk patients who received short-term low-dose corticosteroids, 73 high-risk patients who received usual care, and 83 low-risk patients who received usual care.

The cumulative 100-day incidence of acute grade-II to grade-IV GVHD was significantly lower in the high-risk patients who received prophylaxis (21%) than in the high-risk patients who did not receive prophylaxis (48%). In fact, corticosteroids decreased the rate of GVHD so that it was comparable with that in the low-risk patients (26%), Dr. Chang and associates said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.63l.8817).

Moreover, in the high-risk patients the median interval until GVHD developed was 25 days for those who took corticosteroids, compared with only 15 days for those who did not. Median times to myeloid recovery and platelet recovery were significantly shorter for high-risk patients who received corticosteroids than for either of the other study groups. However, 3-year overall survival and leukemia-free survival were comparable among the three study groups.

The short-term low-dose regimen of corticosteroids did not raise the rate of adverse events, including infection, which suggests that it is preferable to standard corticosteroid regimens in this patient population. The incidences of cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia, and invasive fungal infections were comparable among the three study groups. Of note, the incidences of osteonecrosis of the femoral head and secondary hypertension were significantly lower among high-risk patients who received corticosteroid prophylaxis than among those who did not.

“These results provide the first test, to our knowledge, of a novel risk-stratification-directed prophylaxis strategy that effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents,” Dr. Chang and associates said.

Short-term low-dose corticosteroid prophylaxis reduces the incidence of graft-vs.-host disease in patients who undergo allogeneic haploidentical stem-cell transplantation to treat hematologic neoplasms, according to a report published online April 18 in the Journal of Clinical Oncology.

The key to selecting patients most likely to benefit from the corticosteroid therapy is to identify those at high risk for graft-vs.-host disease (GVHD) using two biomarkers: high levels of CD56bright natural killer cells in allogeneic grafts or high CD4:CD8 ratios in bone marrow grafts, according to Dr. Ying-Jun Chang of Peking University People’s Hospital, Beijing, and associates.

The investigators performed an open-label trial involving 228 patients aged 15-60 years treated at a single medical center during an 18-month period for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or other hematologic neoplasms. Using the two biomarkers, the patients were categorized as either high or low risk for developing GVHD. They were randomly assigned to three study groups: 72 high-risk patients who received short-term low-dose corticosteroids, 73 high-risk patients who received usual care, and 83 low-risk patients who received usual care.

The cumulative 100-day incidence of acute grade-II to grade-IV GVHD was significantly lower in the high-risk patients who received prophylaxis (21%) than in the high-risk patients who did not receive prophylaxis (48%). In fact, corticosteroids decreased the rate of GVHD so that it was comparable with that in the low-risk patients (26%), Dr. Chang and associates said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.63l.8817).

Moreover, in the high-risk patients the median interval until GVHD developed was 25 days for those who took corticosteroids, compared with only 15 days for those who did not. Median times to myeloid recovery and platelet recovery were significantly shorter for high-risk patients who received corticosteroids than for either of the other study groups. However, 3-year overall survival and leukemia-free survival were comparable among the three study groups.

The short-term low-dose regimen of corticosteroids did not raise the rate of adverse events, including infection, which suggests that it is preferable to standard corticosteroid regimens in this patient population. The incidences of cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia, and invasive fungal infections were comparable among the three study groups. Of note, the incidences of osteonecrosis of the femoral head and secondary hypertension were significantly lower among high-risk patients who received corticosteroid prophylaxis than among those who did not.

“These results provide the first test, to our knowledge, of a novel risk-stratification-directed prophylaxis strategy that effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents,” Dr. Chang and associates said.

As a single agent for use in patients with lymphoma, an acceptable once-daily dose of OTX015 appears to be 80 mg on a 14 days on, 7 days off schedule, the results of a phase 1 study indicate.

The small-molecule inhibitor, which inhibits binding of bromodomain and exterminal proteins to acetylated histones, was associated with acceptable toxicity and efficacy in this regimen. The investigational drug is now being tested in expansion cohorts on a schedule of 14 days every 3 weeks, a regimen projected to allow for recovery from the drug’s toxic effects, Dr. Sandy Amorin of Hôpital Saint Louis, Paris, and associates reported.

The drug also is being evaluated in patients with acute leukemias.

Adults with nonleukemia hematologic malignancies that progressed on standard therapies participated in the open-label study, which was conducted at seven university hospital centers in Europe. Oral OTX015 was given once a day at one of five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg). The 3 + 3 study design permitted evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

The study included 33 patients with lymphoma and 12 with myeloma; patients’ median age was 66 years, and they had received a median of four lines of prior therapy. No dose-limiting toxicities were seen in three patients given doses as high as 80 mg once a day. However, grade 4 thrombocytopenia occurred in five of six patients on a 21-day schedule of 40 mg twice a day. No patient tolerated various schedules of 120 mg once a day (Lancet Haematol. 2016;3[4]:e196-204).

The researchers then examined the 80 mg once a day dose on a continuous basis in four patients, two of whom developed grade 4 thrombocytopenia. In light of these and other toxicities, a regimen was proposed of 80 mg once a day on a schedule of 14 days on, 7 days off.

Thrombocytopenia affected 43 of 45 patients, and 26 of them had grade 3-4 events. Other grade 3-4 events were infrequent. Anemia was seen in 41, and neutropenia in 23.

Of three patients with diffuse large B-cell lymphoma, two had complete responses at 120 mg once a day, and one had a partial response at 80 mg once a day. Six additional patients, two with diffuse large B-cell lymphoma and four with indolent lymphomas, had evidence of clinical activity, but did not meet the criteria for an objective response.

The study was funded by the developers of OTX015, Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme.

[email protected]

On Twitter @maryjodales

As a single agent for use in patients with lymphoma, an acceptable once-daily dose of OTX015 appears to be 80 mg on a 14 days on, 7 days off schedule, the results of a phase 1 study indicate.

The small-molecule inhibitor, which inhibits binding of bromodomain and exterminal proteins to acetylated histones, was associated with acceptable toxicity and efficacy in this regimen. The investigational drug is now being tested in expansion cohorts on a schedule of 14 days every 3 weeks, a regimen projected to allow for recovery from the drug’s toxic effects, Dr. Sandy Amorin of Hôpital Saint Louis, Paris, and associates reported.

The drug also is being evaluated in patients with acute leukemias.

Adults with nonleukemia hematologic malignancies that progressed on standard therapies participated in the open-label study, which was conducted at seven university hospital centers in Europe. Oral OTX015 was given once a day at one of five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg). The 3 + 3 study design permitted evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

The study included 33 patients with lymphoma and 12 with myeloma; patients’ median age was 66 years, and they had received a median of four lines of prior therapy. No dose-limiting toxicities were seen in three patients given doses as high as 80 mg once a day. However, grade 4 thrombocytopenia occurred in five of six patients on a 21-day schedule of 40 mg twice a day. No patient tolerated various schedules of 120 mg once a day (Lancet Haematol. 2016;3[4]:e196-204).

The researchers then examined the 80 mg once a day dose on a continuous basis in four patients, two of whom developed grade 4 thrombocytopenia. In light of these and other toxicities, a regimen was proposed of 80 mg once a day on a schedule of 14 days on, 7 days off.

Thrombocytopenia affected 43 of 45 patients, and 26 of them had grade 3-4 events. Other grade 3-4 events were infrequent. Anemia was seen in 41, and neutropenia in 23.

Of three patients with diffuse large B-cell lymphoma, two had complete responses at 120 mg once a day, and one had a partial response at 80 mg once a day. Six additional patients, two with diffuse large B-cell lymphoma and four with indolent lymphomas, had evidence of clinical activity, but did not meet the criteria for an objective response.

The study was funded by the developers of OTX015, Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme.

[email protected]

On Twitter @maryjodales

As a single agent for use in patients with lymphoma, an acceptable once-daily dose of OTX015 appears to be 80 mg on a 14 days on, 7 days off schedule, the results of a phase 1 study indicate.

The small-molecule inhibitor, which inhibits binding of bromodomain and exterminal proteins to acetylated histones, was associated with acceptable toxicity and efficacy in this regimen. The investigational drug is now being tested in expansion cohorts on a schedule of 14 days every 3 weeks, a regimen projected to allow for recovery from the drug’s toxic effects, Dr. Sandy Amorin of Hôpital Saint Louis, Paris, and associates reported.

The drug also is being evaluated in patients with acute leukemias.

Adults with nonleukemia hematologic malignancies that progressed on standard therapies participated in the open-label study, which was conducted at seven university hospital centers in Europe. Oral OTX015 was given once a day at one of five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg). The 3 + 3 study design permitted evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

The study included 33 patients with lymphoma and 12 with myeloma; patients’ median age was 66 years, and they had received a median of four lines of prior therapy. No dose-limiting toxicities were seen in three patients given doses as high as 80 mg once a day. However, grade 4 thrombocytopenia occurred in five of six patients on a 21-day schedule of 40 mg twice a day. No patient tolerated various schedules of 120 mg once a day (Lancet Haematol. 2016;3[4]:e196-204).

The researchers then examined the 80 mg once a day dose on a continuous basis in four patients, two of whom developed grade 4 thrombocytopenia. In light of these and other toxicities, a regimen was proposed of 80 mg once a day on a schedule of 14 days on, 7 days off.

Thrombocytopenia affected 43 of 45 patients, and 26 of them had grade 3-4 events. Other grade 3-4 events were infrequent. Anemia was seen in 41, and neutropenia in 23.

Of three patients with diffuse large B-cell lymphoma, two had complete responses at 120 mg once a day, and one had a partial response at 80 mg once a day. Six additional patients, two with diffuse large B-cell lymphoma and four with indolent lymphomas, had evidence of clinical activity, but did not meet the criteria for an objective response.

The study was funded by the developers of OTX015, Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme.

[email protected]

On Twitter @maryjodales

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Renal status should be evaluated at diagnosis and follow-up in all myeloma patients, according to new guidance from the International Myeloma Working Group published online in the Journal of Clinical Oncology.

Renal impairment (RI) affects up to half of patients with multiple myeloma, and severe RI predicts early death, noted Dr. Meletios Dimopoulos of National and Kapodistrian University of Athens and his associates. Novel therapies have substantially increased survival for myeloma with less severe kidney disease, underscoring the importance of early treatment. To develop the guidelines, the authors reviewed all evidence from randomized trials, systematic reviews, meta-analyses, and prospective and observational studies published through December 2015 (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).

Grade A recommendations (evidence obtained from meta-analysis of multiple well-designed, randomized controlled trials) include the following:

Evaluate serum creatinine, estimated glomerular filtration rate, and electrolytes at initial diagnosis and follow-up assessments. Also perform the serum free light chain test, if available, and electrophoresis of a 24-hour urine specimen.

In patients with stabilized serum creatinine, evaluate GFR using the Chronic Kidney Disease Epidemiology Collaboration (preferred) or the Modification of Diet in Renal Disease formulas.

Based on GFR, determine stage of chronic kidney disease (ranging from 1, kidney damage with normal or elevated GFR, to 5, renal failure).

Bortezomib remains the foundational treatment for myeloma-related renal impairment, the authors emphasized. This 26S proteasome inhibitor should be started at the standard dose of 1.3 mg/m² on days 1, 4, 8, and 11 of a 3-week cycle.

Another option for patients with creatinine clearance above 15 mL/min is carfilzomib, which needs no dose modification and yields similar results regardless of RI status. However, more data are needed on its renal safety, the authors said.

Patients with creatinine clearance above 30 mL/min can safely receive ixazomib in combination with lenalidomide and dexamethasone.

Those with creatinine clearance above 45 mL/min should receive pomalidomide at a dose of 4 mg/day; it is not yet clear whether the dose should be cut for more severe renal impairment.

Hypercalcemia can be treated with bisphosphonates, but patients with creatinine clearance below 30 mL/min should not receive pamidronate or zoledronic acid.

Avoid nephrotoxic agents, such as as aminoglycosides, furosemide, and contrast agents, in all patients with multiple myeloma and RI.

Dr. Dimopoulos reported receiving honoraria or financial support related to travel, accommodations, or expenses from Amgen, Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Bristol-Myers Squibb, Novartis, and Genesis Pharmaceuticals. Seventeen coauthors also reported financial relationships with a number of pharmaceutical companies. The remaining three coauthors had no disclosures.

Renal status should be evaluated at diagnosis and follow-up in all myeloma patients, according to new guidance from the International Myeloma Working Group published online in the Journal of Clinical Oncology.

Renal impairment (RI) affects up to half of patients with multiple myeloma, and severe RI predicts early death, noted Dr. Meletios Dimopoulos of National and Kapodistrian University of Athens and his associates. Novel therapies have substantially increased survival for myeloma with less severe kidney disease, underscoring the importance of early treatment. To develop the guidelines, the authors reviewed all evidence from randomized trials, systematic reviews, meta-analyses, and prospective and observational studies published through December 2015 (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).

Grade A recommendations (evidence obtained from meta-analysis of multiple well-designed, randomized controlled trials) include the following:

Evaluate serum creatinine, estimated glomerular filtration rate, and electrolytes at initial diagnosis and follow-up assessments. Also perform the serum free light chain test, if available, and electrophoresis of a 24-hour urine specimen.

In patients with stabilized serum creatinine, evaluate GFR using the Chronic Kidney Disease Epidemiology Collaboration (preferred) or the Modification of Diet in Renal Disease formulas.

Based on GFR, determine stage of chronic kidney disease (ranging from 1, kidney damage with normal or elevated GFR, to 5, renal failure).

Bortezomib remains the foundational treatment for myeloma-related renal impairment, the authors emphasized. This 26S proteasome inhibitor should be started at the standard dose of 1.3 mg/m² on days 1, 4, 8, and 11 of a 3-week cycle.

Another option for patients with creatinine clearance above 15 mL/min is carfilzomib, which needs no dose modification and yields similar results regardless of RI status. However, more data are needed on its renal safety, the authors said.

Patients with creatinine clearance above 30 mL/min can safely receive ixazomib in combination with lenalidomide and dexamethasone.

Those with creatinine clearance above 45 mL/min should receive pomalidomide at a dose of 4 mg/day; it is not yet clear whether the dose should be cut for more severe renal impairment.

Hypercalcemia can be treated with bisphosphonates, but patients with creatinine clearance below 30 mL/min should not receive pamidronate or zoledronic acid.

Avoid nephrotoxic agents, such as as aminoglycosides, furosemide, and contrast agents, in all patients with multiple myeloma and RI.

Dr. Dimopoulos reported receiving honoraria or financial support related to travel, accommodations, or expenses from Amgen, Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Bristol-Myers Squibb, Novartis, and Genesis Pharmaceuticals. Seventeen coauthors also reported financial relationships with a number of pharmaceutical companies. The remaining three coauthors had no disclosures.

Renal status should be evaluated at diagnosis and follow-up in all myeloma patients, according to new guidance from the International Myeloma Working Group published online in the Journal of Clinical Oncology.

Renal impairment (RI) affects up to half of patients with multiple myeloma, and severe RI predicts early death, noted Dr. Meletios Dimopoulos of National and Kapodistrian University of Athens and his associates. Novel therapies have substantially increased survival for myeloma with less severe kidney disease, underscoring the importance of early treatment. To develop the guidelines, the authors reviewed all evidence from randomized trials, systematic reviews, meta-analyses, and prospective and observational studies published through December 2015 (J Clin Oncol. 2016 Mar 14. doi: 10.1200/JCO.2015.65.0044).

Grade A recommendations (evidence obtained from meta-analysis of multiple well-designed, randomized controlled trials) include the following:

Evaluate serum creatinine, estimated glomerular filtration rate, and electrolytes at initial diagnosis and follow-up assessments. Also perform the serum free light chain test, if available, and electrophoresis of a 24-hour urine specimen.

In patients with stabilized serum creatinine, evaluate GFR using the Chronic Kidney Disease Epidemiology Collaboration (preferred) or the Modification of Diet in Renal Disease formulas.

Based on GFR, determine stage of chronic kidney disease (ranging from 1, kidney damage with normal or elevated GFR, to 5, renal failure).

Bortezomib remains the foundational treatment for myeloma-related renal impairment, the authors emphasized. This 26S proteasome inhibitor should be started at the standard dose of 1.3 mg/m² on days 1, 4, 8, and 11 of a 3-week cycle.

Another option for patients with creatinine clearance above 15 mL/min is carfilzomib, which needs no dose modification and yields similar results regardless of RI status. However, more data are needed on its renal safety, the authors said.

Patients with creatinine clearance above 30 mL/min can safely receive ixazomib in combination with lenalidomide and dexamethasone.

Those with creatinine clearance above 45 mL/min should receive pomalidomide at a dose of 4 mg/day; it is not yet clear whether the dose should be cut for more severe renal impairment.

Hypercalcemia can be treated with bisphosphonates, but patients with creatinine clearance below 30 mL/min should not receive pamidronate or zoledronic acid.

Avoid nephrotoxic agents, such as as aminoglycosides, furosemide, and contrast agents, in all patients with multiple myeloma and RI.

Dr. Dimopoulos reported receiving honoraria or financial support related to travel, accommodations, or expenses from Amgen, Celgene, Onyx Pharmaceuticals, Janssen-Cilag, Bristol-Myers Squibb, Novartis, and Genesis Pharmaceuticals. Seventeen coauthors also reported financial relationships with a number of pharmaceutical companies. The remaining three coauthors had no disclosures.

 

 

Micrograph showing DLBCL

 

The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.

In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).

And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.

However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.

These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.

“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.

CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.

Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).

Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).

Treatment

CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.

Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.

Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).

Safety

Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.

The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).

Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.

AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).

Efficacy

Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.

Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.

The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.

Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.

Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.

 

 

Micrograph showing DLBCL

 

The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.

In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).

And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.

However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.

These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.

“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.

CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.

Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).

Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).

Treatment

CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.

Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.

Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).

Safety

Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.

The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).

Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.

AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).

Efficacy

Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.

Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.

The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.

Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.

Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.

 

 

Micrograph showing DLBCL

 

The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.

In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).

And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.

However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.

These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.

“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.

CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.

Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).

Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).

Treatment

CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.

Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.

Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).

Safety

Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.

The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).

Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.

AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).

Efficacy

Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.

Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.

The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.

Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.

Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.

Daratumumab (Darzalex)

Photo courtesy of Janssen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for daratumumab (Darzalex), a first-in-class monoclonal antibody targeting CD38.

The recommended indication for daratumumab is as monotherapy for adults with relapsed and refractory multiple myeloma (MM).

The patients must have progressed on their last therapy and have received treatment with both a proteasome inhibitor and an immunomodulatory agent.

The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for medicines in the European Economic Area.

The European Commission’s final decision on daratumumab is anticipated in the coming months.

About conditional authorization

A product may receive conditional marketing authorization if the CHMP finds that, although comprehensive clinical data on the safety and efficacy of the product are not available, all of the following requirements are met:

• The risk-benefit balance of the product is positive
• The company developing the product will likely be in a position to provide comprehensive clinical data in the future
• Unmet medical needs will be fulfilled
• The benefit to public health of the immediate availability of the product outweighs the risk inherent in the fact that additional data are still required.

Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance of a product is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.

About daratumumab

Daratumumab is the first CD38-directed monoclonal antibody recommended for approval in Europe. It works by binding to CD38, a signaling molecule highly expressed on the surface of MM cells regardless of stage of disease.

In binding to CD38, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple, immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death via apoptosis.

The CHMP’s positive opinion of daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. Janssen licensed daratumumab from Genmab A/S in August 2012.

Daratumumab (Darzalex)

Photo courtesy of Janssen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for daratumumab (Darzalex), a first-in-class monoclonal antibody targeting CD38.

The recommended indication for daratumumab is as monotherapy for adults with relapsed and refractory multiple myeloma (MM).

The patients must have progressed on their last therapy and have received treatment with both a proteasome inhibitor and an immunomodulatory agent.

The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for medicines in the European Economic Area.

The European Commission’s final decision on daratumumab is anticipated in the coming months.

About conditional authorization

A product may receive conditional marketing authorization if the CHMP finds that, although comprehensive clinical data on the safety and efficacy of the product are not available, all of the following requirements are met:

• The risk-benefit balance of the product is positive
• The company developing the product will likely be in a position to provide comprehensive clinical data in the future
• Unmet medical needs will be fulfilled
• The benefit to public health of the immediate availability of the product outweighs the risk inherent in the fact that additional data are still required.

Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance of a product is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.

About daratumumab

Daratumumab is the first CD38-directed monoclonal antibody recommended for approval in Europe. It works by binding to CD38, a signaling molecule highly expressed on the surface of MM cells regardless of stage of disease.

In binding to CD38, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple, immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death via apoptosis.

The CHMP’s positive opinion of daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. Janssen licensed daratumumab from Genmab A/S in August 2012.

Daratumumab (Darzalex)

Photo courtesy of Janssen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for daratumumab (Darzalex), a first-in-class monoclonal antibody targeting CD38.

The recommended indication for daratumumab is as monotherapy for adults with relapsed and refractory multiple myeloma (MM).

The patients must have progressed on their last therapy and have received treatment with both a proteasome inhibitor and an immunomodulatory agent.

The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for medicines in the European Economic Area.

The European Commission’s final decision on daratumumab is anticipated in the coming months.

About conditional authorization

A product may receive conditional marketing authorization if the CHMP finds that, although comprehensive clinical data on the safety and efficacy of the product are not available, all of the following requirements are met:

• The risk-benefit balance of the product is positive
• The company developing the product will likely be in a position to provide comprehensive clinical data in the future
• Unmet medical needs will be fulfilled
• The benefit to public health of the immediate availability of the product outweighs the risk inherent in the fact that additional data are still required.

Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance of a product is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.

About daratumumab

Daratumumab is the first CD38-directed monoclonal antibody recommended for approval in Europe. It works by binding to CD38, a signaling molecule highly expressed on the surface of MM cells regardless of stage of disease.

In binding to CD38, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple, immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death via apoptosis.

The CHMP’s positive opinion of daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. Janssen licensed daratumumab from Genmab A/S in August 2012.

Micrograph showing amyloidosis

A novel molecular probe can detect amyloidosis at least as well as—and perhaps even better than—traditional methods, according to research published in Amyloid: The Journal of Protein Folding Disorders.

Investigators found that a luminescent conjugated oligothiophene, h-FTAA, allowed them to correctly identify amyloidosis in every sample tested.

But results also suggested h-FTAA may be more sensitive than traditional methods used to diagnose amyloidosis, as h-FTAA detected small amyloid deposits in samples that were previously determined to be amyloid-free.

The investigators said this suggests h-FTAA could be used to detect amyloidosis before symptoms present, leading to faster treatment.

“Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement,” said study author Per Hammarström, PhD, of Linköping University in Sweden.

Dr Hammarström and his colleagues screened amyloid-containing tissues from 107 patients who had their amyloidosis verified by Congo red staining and/or immunohistochemistry, as well as tissues from 32 negative control cases.

The results showed that h-FTAA could detect amyloidosis with 100% sensitivity, identifying amyloid deposits in all 107 patients.

However, h-FTAA also detected microdeposits of amyloid-like protein aggregates in 5 of the control samples that were negative according to Congo red.

The investigators said they don’t know the clinical significance of these “false-positive” lesions. However, because h-FTAA fluorescence is 1 magnitude brighter than Congo red and because the staining is performed 4 magnitudes lower than the concentration of dye, the team believes these 5 cases may have been beyond detection by Congo red and h-FTAA may be a more sensitive technique.

They therefore concluded that h-FTAA could potentially be used as a complementary technique for accurate detection of amyloid in routine surgical pathology settings, for the detection of prodromal amyloidosis, and for the discovery of new amyloid-like protein aggregates.

Micrograph showing amyloidosis

A novel molecular probe can detect amyloidosis at least as well as—and perhaps even better than—traditional methods, according to research published in Amyloid: The Journal of Protein Folding Disorders.

Investigators found that a luminescent conjugated oligothiophene, h-FTAA, allowed them to correctly identify amyloidosis in every sample tested.

But results also suggested h-FTAA may be more sensitive than traditional methods used to diagnose amyloidosis, as h-FTAA detected small amyloid deposits in samples that were previously determined to be amyloid-free.

The investigators said this suggests h-FTAA could be used to detect amyloidosis before symptoms present, leading to faster treatment.

“Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement,” said study author Per Hammarström, PhD, of Linköping University in Sweden.

Dr Hammarström and his colleagues screened amyloid-containing tissues from 107 patients who had their amyloidosis verified by Congo red staining and/or immunohistochemistry, as well as tissues from 32 negative control cases.

The results showed that h-FTAA could detect amyloidosis with 100% sensitivity, identifying amyloid deposits in all 107 patients.

However, h-FTAA also detected microdeposits of amyloid-like protein aggregates in 5 of the control samples that were negative according to Congo red.

The investigators said they don’t know the clinical significance of these “false-positive” lesions. However, because h-FTAA fluorescence is 1 magnitude brighter than Congo red and because the staining is performed 4 magnitudes lower than the concentration of dye, the team believes these 5 cases may have been beyond detection by Congo red and h-FTAA may be a more sensitive technique.

They therefore concluded that h-FTAA could potentially be used as a complementary technique for accurate detection of amyloid in routine surgical pathology settings, for the detection of prodromal amyloidosis, and for the discovery of new amyloid-like protein aggregates.

Micrograph showing amyloidosis

A novel molecular probe can detect amyloidosis at least as well as—and perhaps even better than—traditional methods, according to research published in Amyloid: The Journal of Protein Folding Disorders.

Investigators found that a luminescent conjugated oligothiophene, h-FTAA, allowed them to correctly identify amyloidosis in every sample tested.

But results also suggested h-FTAA may be more sensitive than traditional methods used to diagnose amyloidosis, as h-FTAA detected small amyloid deposits in samples that were previously determined to be amyloid-free.

The investigators said this suggests h-FTAA could be used to detect amyloidosis before symptoms present, leading to faster treatment.

“Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement,” said study author Per Hammarström, PhD, of Linköping University in Sweden.

Dr Hammarström and his colleagues screened amyloid-containing tissues from 107 patients who had their amyloidosis verified by Congo red staining and/or immunohistochemistry, as well as tissues from 32 negative control cases.

The results showed that h-FTAA could detect amyloidosis with 100% sensitivity, identifying amyloid deposits in all 107 patients.

However, h-FTAA also detected microdeposits of amyloid-like protein aggregates in 5 of the control samples that were negative according to Congo red.

The investigators said they don’t know the clinical significance of these “false-positive” lesions. However, because h-FTAA fluorescence is 1 magnitude brighter than Congo red and because the staining is performed 4 magnitudes lower than the concentration of dye, the team believes these 5 cases may have been beyond detection by Congo red and h-FTAA may be a more sensitive technique.

They therefore concluded that h-FTAA could potentially be used as a complementary technique for accurate detection of amyloid in routine surgical pathology settings, for the detection of prodromal amyloidosis, and for the discovery of new amyloid-like protein aggregates.