Lymphoma & Plasma Cell Disorders

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

To listen to a podcast concerning the brentuximab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

To listen to a podcast concerning the brentuximab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

To listen to a podcast concerning the brentuximab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.

Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.

All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).

The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.

Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.

Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.

"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.

Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.

Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.

He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.

Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).

Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.

The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).

A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).

Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.

All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.

Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.

"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.

Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.

Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.

There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.

One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.

Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.

The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.

Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.

The study was funded by the participating centers. The authors reported no relevant conflicts of interest.

SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.

Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.

All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).

The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.

Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.

Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.

"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.

Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.

Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.

He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.

Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).

Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.

The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).

A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).

Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.

All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.

Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.

"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.

Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.

Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.

There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.

One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.

Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.

The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.

Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.

The study was funded by the participating centers. The authors reported no relevant conflicts of interest.

SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.

Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.

All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).

The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.

Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.

Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.

"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.

Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.

Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.

He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.

Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).

Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.

The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).

A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).

Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.

All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.

Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.

"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.

Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.

Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.

There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.

One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.

Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.

The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.

Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.

The study was funded by the participating centers. The authors reported no relevant conflicts of interest.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – The potent, next-generation immunomodulatory inhibitor pomalidomide works in at least one-third of patients with relapsed and/or refractory multiple myeloma when nothing else does, a series of studies shows.

MM-002: With Dexamethasone or Alone. One of the most closely watched presentations at the recent American Society of Hematology annual meeting was the one showing phase II results from the phase I/II MM-002 study of pomalidomide with or without low-dose dexamethasone in relapsed and refractory myeloma. The heavily pretreated 221-patient cohort had received a median of five prior regimens (range 2-13), 60% were refractory to lenalidomide (Revlimid) and bortezomib (Velcade), and 99% had received prior dexamethasone.

In all, 34% of patients given pomalidomide plus dexamethasone achieved at least a partial response, compared with 13% of those given pomalidomide alone, said Dr. Paul G. Richardson, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute in Boston. Complete responses were observed in 1% of both groups.

The responses were rapid and the duration of response appeared durable at a median of 8.5 months with single-agent pomalidomide and 7.9 months with the combination. Importantly, stable disease or better was observed in 81% of patients overall, he said.

As observed in the phase I portion of the study, pomalidomide plus dexamethasone was active in the vulnerable population of lenalidomide-refractory patients, with 29% achieving at least a partial response vs. 15% on single-agent pomalidomide. Equally encouraging were similar rates of response in patients refractory to lenalidomide and bortezomib (30% vs. 16%), Dr. Richardson said.

The median time to progression for patients on both drugs was 4.7 months, compared with 2.7 months for those on pomalidomide monotherapy.

Median overall survival reached 16.9 months with both drugs, compared with 14 months with pomalidomide alone. Dr. Richardson pointed out that median overall survival was just 5.4 months for patients with progressive disease as their best response.

Among patients refractory to lenalidomide and bortezomib, the use of pomalidomide and dexamethasone increased the median time to progression from 2.0 months with pomalidomide alone to 3.9 months, and median overall survival from 12.7 months to 13.7 months.

Oral pomalidomide 4 mg/day was administered on a 3-week on, 1-week off schedule with or without dexamethasone 40 mg/week. All patients received daily low-dose aspirin. Notably, 56% of the 108 patients given pomalidomide alone went on to receive dexamethasone due to progression, as per protocol.

During a discussion of the study, Dr. Richardson said the contribution of dexamethasone is critical to the pomalidomide backbone, but that investigators have been struck with how well both regimens are tolerated.

"I’m impressed that it doesn’t have the same muscle cramping and so forth that lenalidomide can sometimes be associated with, and it’s not associated with the diarrhea that can sometimes be a challenge with thalidomide," he said.

Neutropenia was the dominant grade 3-4 adverse event, occurring in 45% of those on single-agent pomalidomide and in 38% on both drugs. Thrombocytopenia was observed in 21% and 19% of patients, respectively. Both adverse events were manageable and required dose reduction in a minimum of patients, Dr. Richardson said.

Importantly, there was no grade 3/4 peripheral neuropathy, an important side effect of treatment with bortezomib, thalidomide, and cisplatin.

On the basis of the findings, pomalidomide is being investigated in phase III trials in the United States and Europe as part of combination treatments including low- and high-dose dexamethasone and bortezomib, he noted.

With Cyclophosphamide and Prednisone. Dr. Antonio Palumbo presented phase II results from a phase I/II study of relapsed or refractory myeloma evaluating continuous pomalidomide 2.5 mg daily in combination with cyclophosphamide 50 mg every other day and prednisone 50 mg every other day. Maintenance therapy with pomalidomide 2.5 mg/day and prednisone 25 mg every other day was given until disease progression.

The 29 evaluable patients had received a median of three prior therapies, and 62% were refractory to lenalidomide.

The most striking findings were the response rates and toxicity, said Dr. Palumbo, chief of the myeloma unit at the University of Torino (Italy).

After a median of four cycles, a partial response or better was observed in 65.5% of patients, at least a very good partial response in 28%, and a complete response in 7%. In the 11 lenalidomide-refractory patients, these response rates reached 81%, 27%, and 9%, respectively, he said.

Responses in the refractory population were described as amazing by an attendee, who asked for a possible explanation. Dr. Palumbo responded that the first explanation is "caution" and that experience shows that a three-drug combination increases efficacy. He went on to say that pomalidomide plus cyclophosphamide and prednisone is a "nice combination with a good risk-benefit ratio."

Key grade 4 hematologic adverse events were neutropenia (17%) and thrombocytopenia (7%). Grade 3 rash occurred in 10% of patients and grade 3/4 neurologic events in 7%. Despite the use of daily low-dose aspirin, 3% of patients experienced grade 3/4 thromboembolism.

Continuous pomalidomide 2.5 mg/day was identified as the maximum tolerated dose in the phase I portion of the study, and is roughly equivalent to the 4-mg dose given on the 3-week on, 1 week-off schedule, Dr. Palumbo said.

Progression-free and overall survival data are immature after a median follow-up of only 4 months, but appear "interesting," he added.

Final Analysis of IFM 2009-02. The French-led Intergroupe Francophone du Myélome (IFM) 2009-02 trial tested the combination of pomalidomide 4 mg/day on days 1-21 or given continuously throughout the 28-day cycle, with dexamethasone 40 mg/week in patients with relapsed multiple myeloma who were resistant or refractory to lenalidomide and bortezomib. The 84 patients had a median of five previous lines of therapy, and three-fourths were refractory to lenalidomide and bortezomib.

Considering the duration of response, treatment duration, and similar safety profile, the 3-week on, 1-week off regimen appears superior to the continuous pomalidomide regimen, said Dr. Xavier Leleu of Hospital Huriez, CHRU, in Lille (France).

The median treatment duration was slightly longer at 7.2 months with the 21-day schedule vs. 5.2 months with continuous pomalidomide. The median number of cycles was 8 and 6, respectively.

A partial response or better was observed in 35% of the 21-day group and in 34% of the 28-day group, including very good partial responses in 1% of both groups and stable disease in 44% and 51%, respectively.

The median duration of response was 10.5 months with the 21-day schedule and 7.2 with the continuous schedule, resulting in more patients on the 21-day schedule being responsive at 1 year or more (47.5% vs. 36%), Dr. Leleu said.

Median progression-free survival (PFS) in the entire study was 5.7 months. This compares favorably with a median of 3.8 months in patients refractory to lenalidomide and bortezomib, and a median of 5.7 months in those refractory to lenalidomide as their last line of therapy, he said.

Notably, median PFS was just 3.8 months in patients with stable disease vs. 11.3 months for responders. "Apparently, it [PFS] is significantly lower in patients with stable disease, but if you have patients who are responders, clearly their outcome is really, really good," Dr. Leleu said.

Subgroup analyses revealed poorer PFS in patients with adverse cytogenetics compared with others (2.8 vs. 9.9 months). PFS was also lower in elderly patients than in those under age 65 (4.0 months vs. 6.8 months), although Dr. Leleu said the numbers were small and it was hard to know whether the elderly received all their medication.

Serious adverse events were reported in 33% of patients in the 3-week on, 1-week off regimen and in 41.5% of those on the continuous regimen.

A study is underway evaluating pomalidomide 2 mg daily, but Dr. Leleu said such a regimen would have to be administered carefully. "There is no room for mistakes, because if you don’t treat them in an optimized way, they can escape treatment very quickly," he said. "So if you can manage 4 mg, it is probably better."

Long-Term Outcomes. Finally, Dr. Joseph R. Mikhael and his colleagues evaluated outcomes 4 years after the first Mayo Clinic cohort of relapsed or refractory myeloma patients was treated with continuous pomalidomide 2 mg/day and weekly dexamethasone 40 mg. The patients also received prophylaxis for deep vein thrombosis (DVT) with aspirin, heparin, or warfarin.

The 60 patients were enrolled from November 2007 to August 2008, and had received one to three prior therapies. Those therapies included stem cell transplantation (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%), immunomodulatory drugs (60%), and radiation (38%).

In all, 32% were high risk according to mSMART criteria, and 78% had International Staging System 2-3 disease.

A median of 11.5 treatment cycles were administered (range 1-47 cycles). All patients also received DVT prophylaxis with aspirin, heparin, or warfarin.

With a median follow-up of 33.6 months, the overall response was 65% (39/60 patients), including 4 stringent complete responses, 4 complete responses, 15 very good partial responses, and 16 partial responses.

Response was no less in patients with high-risk disease at 74% (14/19 patients), according to Dr. Mikhael, a hematologist at the Mayo Clinic in Scottsdale, Ariz.

The responses were durable, with a median duration of 21.3 months. At the time of the analysis, 12 patients (20%) remained on therapy. "Pomalidomide and dexamethasone provides a long-term benefit with median progression-free survival of 13 months and a 2-year survival rate of 76%," the authors wrote.

Overall survival in the whole cohort has not yet been reached.

In patients with high-risk myeloma, PFS was 9.2 months and overall survival 40.4 months. In the 36 patients with prior immunomodulatory drug use, PFS was 11.6 months; overall survival had not yet been reached, but was 23% at 24 months.

Grades 3-4 nonhematologic toxicities occurred in 50% of patients. The most common grade 3 event was fatigue (18%), followed by pneumonia (8%), hyperglycemia (5%), and constipation (5%). One patient had grade 3 neuropathy, and 2% of patients experienced grade 4 pneumonia.

Celgene provided support for the trials. Dr. Richardson and his coauthors reported financial relationships with several pharmaceutical companies, including Celgene and Millennium Pharmaceuticals. Dr. Palumbo and his coauthors reported relationships with several firms, including Celgene. Dr. Leleu and his coauthors reported financial relationships with Celgene and others. Dr. Mikhael reported no conflicts of interest; his coauthors reported research funding and consultancy with several firms, including Celgene, Millennium, and Onyx Pharmaceuticals.

SAN DIEGO – A simple scoring system identified a subset of young patients with Hodgkin’s lymphoma who are predicted to have an event-free survival rate of less than 80%.

The system, known as the Childhood Hodgkin International Prognostic Score (CHIPS), found that four factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever, Dr. Cindy L. Schwartz reported during a poster session at the annual meeting of the American Society of Hematology.

She and her associates with the Children’s Oncology Group evaluated 1,721 patients with intermediate risk Hodgkin’s lymphoma who were younger than age 21 and treated on AHOD0031: a phase III study of dose-intensive therapy.

The current study involved tailoring treatment by early response in 770 patients who were randomized or assigned to receive the same treatment (four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) and 21 Gy involved field radiotherapy (IFRT).

According to Dr. Schwartz, director of the division of pediatric hematology/oncology at Hasbro Children’s Hospital, Providence, R.I., rapid early response was defined as a two-dimensional tumor reduction of greater than 60% on CT after two cycles of ABVE-PC. Complete response was defined as a greater than 80% two-dimensional reduction by CT, and resolution of nuclear imaging abnormalities.

Rapid responders who achieved complete response after two additional ABVE-PC treatments were randomized to receive 21 Gy radiation. Slow early responders were randomized to receive dexamethasone, etoposide, cisplatin, and cytarabine (DECA) in addition to the four ABVE-PC treatments and 21 Gy radiation treatment.

Using Cox regression analysis and multivariable predictive modeling, the researchers identified four predictors of event-free survival: stage IV disease (hazard ratio, 1.6), mediastinal adenopathy (HR 1.7), albumin of less than 3.5 g/dL (HR 1.8), and fever (HR 2.5).

Because the hazard ratios were similar, the researchers devised the CHIPS score, which gave one point for each of the four adverse predictors. Using this approach, they determined that the event-free survival rate was 90% for patients with a CHIPS score of 0 or 1, 78% for those with a CHIPS score of 2, and 62% for those with a CHIPS score of 3. (Because the study enrolled only patients with intermediate-risk disease, no one had a CHIPS score of 4.) From this they determined that 22% of an intermediate-risk population can be predicted to have an event-free survival rate of less than 80%.

"Now that we know who’s a good responder to initial chemotherapy, we’re going to try and change their treatment much earlier than we have been able to previously," Dr. Schwartz said in an interview. "The next thing to do is analyze some of the biologic factors that contribute to their response rate."

Studies of CHIPS in additional cohorts of newly diagnosed patients are also planned, she said.

Dr. Schwartz said that she had no relevant financial disclosures to make.

SAN DIEGO – A simple scoring system identified a subset of young patients with Hodgkin’s lymphoma who are predicted to have an event-free survival rate of less than 80%.

The system, known as the Childhood Hodgkin International Prognostic Score (CHIPS), found that four factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever, Dr. Cindy L. Schwartz reported during a poster session at the annual meeting of the American Society of Hematology.

She and her associates with the Children’s Oncology Group evaluated 1,721 patients with intermediate risk Hodgkin’s lymphoma who were younger than age 21 and treated on AHOD0031: a phase III study of dose-intensive therapy.

The current study involved tailoring treatment by early response in 770 patients who were randomized or assigned to receive the same treatment (four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) and 21 Gy involved field radiotherapy (IFRT).

According to Dr. Schwartz, director of the division of pediatric hematology/oncology at Hasbro Children’s Hospital, Providence, R.I., rapid early response was defined as a two-dimensional tumor reduction of greater than 60% on CT after two cycles of ABVE-PC. Complete response was defined as a greater than 80% two-dimensional reduction by CT, and resolution of nuclear imaging abnormalities.

Rapid responders who achieved complete response after two additional ABVE-PC treatments were randomized to receive 21 Gy radiation. Slow early responders were randomized to receive dexamethasone, etoposide, cisplatin, and cytarabine (DECA) in addition to the four ABVE-PC treatments and 21 Gy radiation treatment.

Using Cox regression analysis and multivariable predictive modeling, the researchers identified four predictors of event-free survival: stage IV disease (hazard ratio, 1.6), mediastinal adenopathy (HR 1.7), albumin of less than 3.5 g/dL (HR 1.8), and fever (HR 2.5).

Because the hazard ratios were similar, the researchers devised the CHIPS score, which gave one point for each of the four adverse predictors. Using this approach, they determined that the event-free survival rate was 90% for patients with a CHIPS score of 0 or 1, 78% for those with a CHIPS score of 2, and 62% for those with a CHIPS score of 3. (Because the study enrolled only patients with intermediate-risk disease, no one had a CHIPS score of 4.) From this they determined that 22% of an intermediate-risk population can be predicted to have an event-free survival rate of less than 80%.

"Now that we know who’s a good responder to initial chemotherapy, we’re going to try and change their treatment much earlier than we have been able to previously," Dr. Schwartz said in an interview. "The next thing to do is analyze some of the biologic factors that contribute to their response rate."

Studies of CHIPS in additional cohorts of newly diagnosed patients are also planned, she said.

Dr. Schwartz said that she had no relevant financial disclosures to make.

SAN DIEGO – A simple scoring system identified a subset of young patients with Hodgkin’s lymphoma who are predicted to have an event-free survival rate of less than 80%.

The system, known as the Childhood Hodgkin International Prognostic Score (CHIPS), found that four factors were predictive of worse event-free survival: stage IV disease, large mediastinal adenopathy, albumin level of less than 3.5 g/dL, and fever, Dr. Cindy L. Schwartz reported during a poster session at the annual meeting of the American Society of Hematology.

She and her associates with the Children’s Oncology Group evaluated 1,721 patients with intermediate risk Hodgkin’s lymphoma who were younger than age 21 and treated on AHOD0031: a phase III study of dose-intensive therapy.

The current study involved tailoring treatment by early response in 770 patients who were randomized or assigned to receive the same treatment (four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) and 21 Gy involved field radiotherapy (IFRT).

According to Dr. Schwartz, director of the division of pediatric hematology/oncology at Hasbro Children’s Hospital, Providence, R.I., rapid early response was defined as a two-dimensional tumor reduction of greater than 60% on CT after two cycles of ABVE-PC. Complete response was defined as a greater than 80% two-dimensional reduction by CT, and resolution of nuclear imaging abnormalities.

Rapid responders who achieved complete response after two additional ABVE-PC treatments were randomized to receive 21 Gy radiation. Slow early responders were randomized to receive dexamethasone, etoposide, cisplatin, and cytarabine (DECA) in addition to the four ABVE-PC treatments and 21 Gy radiation treatment.

Using Cox regression analysis and multivariable predictive modeling, the researchers identified four predictors of event-free survival: stage IV disease (hazard ratio, 1.6), mediastinal adenopathy (HR 1.7), albumin of less than 3.5 g/dL (HR 1.8), and fever (HR 2.5).

Because the hazard ratios were similar, the researchers devised the CHIPS score, which gave one point for each of the four adverse predictors. Using this approach, they determined that the event-free survival rate was 90% for patients with a CHIPS score of 0 or 1, 78% for those with a CHIPS score of 2, and 62% for those with a CHIPS score of 3. (Because the study enrolled only patients with intermediate-risk disease, no one had a CHIPS score of 4.) From this they determined that 22% of an intermediate-risk population can be predicted to have an event-free survival rate of less than 80%.

"Now that we know who’s a good responder to initial chemotherapy, we’re going to try and change their treatment much earlier than we have been able to previously," Dr. Schwartz said in an interview. "The next thing to do is analyze some of the biologic factors that contribute to their response rate."

Studies of CHIPS in additional cohorts of newly diagnosed patients are also planned, she said.

Dr. Schwartz said that she had no relevant financial disclosures to make.

Catch up with what you missed as we count down the 10 most-read stories on OncologyReport.com last year.

10. Everolimus Posts Big Win in ER-Positive Breast Cancer By Patrice Wendling
This first report of the BOLERO-2 trial -- a potential practice changer -- came out of the European Multidisciplinary Cancer Congress in Stockholm.

Courtesy flickr user woodleywonderworks (Creative Commons)

9. Multimodal DCIS Therapy, Tamoxifen Cuts Breast Cancer Deaths By Neil Osterweil
A meta-analysis from Australia found that adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ. It was presented at the American Society of Radiation Oncology (ASTRO) meeitng in Miami Beach.

8. Crizotinib Approval Personalizes Lung Cancer Therapy By Miriam E. Tucker
The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represented another milestone in biomarker-driven, personalized medicine. Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets.

7. Clinicians Slow to Embrace Sipuleucel-T for Prostate Cancer By Diana Mahoney
Most physicians have strong opinions on sipuleucel-T, including dubbing its approval "a milestone in the history of oncology," but many of them refused to speak about it on the record. Our persistent reporter found the reasons for their reluctance to use the first cancer vaccine went beyond reimbursement issues belabored in the financial press.

6. Drug Shortages Increasingly Take Toll on Care By Elizabeth Mechcatie
With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

5. Practice Changers Expected at San Antonio Breast Cancer Symposium By Jane Salodof MacNeil
The 2011 San Antonio Breast Cancer Symposium featured a hefty number of studies that could change clinical practice. One of the most exciting SABCS meetings in recent years, it featured the phase III BOLERO-2 and CLEOPATRA trials, a new Oncotype DX assay for ductal carcinoma in situ, reports from four bisphosphonate trials, and a controversial brachytherapy study.

4. FDA Approves Brentuximab for Two Lymphomas By Elizabeth Mechcatie
The Food and Drug Administration on Aug. 19 gave an accelerated approval to brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

3. FDA Approves Vemurafenib for Advanced Melanoma By Jane Salodof MacNeil
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients. It also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine whether a patient’s melanoma cells carry the BRAF V600E mutation.

2. Novel Therapies Put Multiple Myeloma 'On the Ropes' By Susan London
A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco. Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress in San Francisco. Others come from classes not previously used in this disease.

1. NICE Rejects Ipilimumab by Jennie Smith
A drug considered a breakthrough treatment for advanced melanoma was turned down by England’s clinical and cost-effectiveness agency. The National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy). The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab.

Did you miss any of last year's top reads in oncology? Click here to receive our weekly e-newsletter.

Catch up with what you missed as we count down the 10 most-read stories on OncologyReport.com last year.

10. Everolimus Posts Big Win in ER-Positive Breast Cancer By Patrice Wendling
This first report of the BOLERO-2 trial -- a potential practice changer -- came out of the European Multidisciplinary Cancer Congress in Stockholm.

Courtesy flickr user woodleywonderworks (Creative Commons)

9. Multimodal DCIS Therapy, Tamoxifen Cuts Breast Cancer Deaths By Neil Osterweil
A meta-analysis from Australia found that adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ. It was presented at the American Society of Radiation Oncology (ASTRO) meeitng in Miami Beach.

8. Crizotinib Approval Personalizes Lung Cancer Therapy By Miriam E. Tucker
The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represented another milestone in biomarker-driven, personalized medicine. Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets.

7. Clinicians Slow to Embrace Sipuleucel-T for Prostate Cancer By Diana Mahoney
Most physicians have strong opinions on sipuleucel-T, including dubbing its approval "a milestone in the history of oncology," but many of them refused to speak about it on the record. Our persistent reporter found the reasons for their reluctance to use the first cancer vaccine went beyond reimbursement issues belabored in the financial press.

6. Drug Shortages Increasingly Take Toll on Care By Elizabeth Mechcatie
With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

5. Practice Changers Expected at San Antonio Breast Cancer Symposium By Jane Salodof MacNeil
The 2011 San Antonio Breast Cancer Symposium featured a hefty number of studies that could change clinical practice. One of the most exciting SABCS meetings in recent years, it featured the phase III BOLERO-2 and CLEOPATRA trials, a new Oncotype DX assay for ductal carcinoma in situ, reports from four bisphosphonate trials, and a controversial brachytherapy study.

4. FDA Approves Brentuximab for Two Lymphomas By Elizabeth Mechcatie
The Food and Drug Administration on Aug. 19 gave an accelerated approval to brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

3. FDA Approves Vemurafenib for Advanced Melanoma By Jane Salodof MacNeil
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients. It also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine whether a patient’s melanoma cells carry the BRAF V600E mutation.

2. Novel Therapies Put Multiple Myeloma 'On the Ropes' By Susan London
A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco. Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress in San Francisco. Others come from classes not previously used in this disease.

1. NICE Rejects Ipilimumab by Jennie Smith
A drug considered a breakthrough treatment for advanced melanoma was turned down by England’s clinical and cost-effectiveness agency. The National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy). The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab.

Did you miss any of last year's top reads in oncology? Click here to receive our weekly e-newsletter.

Catch up with what you missed as we count down the 10 most-read stories on OncologyReport.com last year.

10. Everolimus Posts Big Win in ER-Positive Breast Cancer By Patrice Wendling
This first report of the BOLERO-2 trial -- a potential practice changer -- came out of the European Multidisciplinary Cancer Congress in Stockholm.

Courtesy flickr user woodleywonderworks (Creative Commons)

9. Multimodal DCIS Therapy, Tamoxifen Cuts Breast Cancer Deaths By Neil Osterweil
A meta-analysis from Australia found that adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ. It was presented at the American Society of Radiation Oncology (ASTRO) meeitng in Miami Beach.

8. Crizotinib Approval Personalizes Lung Cancer Therapy By Miriam E. Tucker
The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represented another milestone in biomarker-driven, personalized medicine. Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets.

7. Clinicians Slow to Embrace Sipuleucel-T for Prostate Cancer By Diana Mahoney
Most physicians have strong opinions on sipuleucel-T, including dubbing its approval "a milestone in the history of oncology," but many of them refused to speak about it on the record. Our persistent reporter found the reasons for their reluctance to use the first cancer vaccine went beyond reimbursement issues belabored in the financial press.

6. Drug Shortages Increasingly Take Toll on Care By Elizabeth Mechcatie
With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

5. Practice Changers Expected at San Antonio Breast Cancer Symposium By Jane Salodof MacNeil
The 2011 San Antonio Breast Cancer Symposium featured a hefty number of studies that could change clinical practice. One of the most exciting SABCS meetings in recent years, it featured the phase III BOLERO-2 and CLEOPATRA trials, a new Oncotype DX assay for ductal carcinoma in situ, reports from four bisphosphonate trials, and a controversial brachytherapy study.

4. FDA Approves Brentuximab for Two Lymphomas By Elizabeth Mechcatie
The Food and Drug Administration on Aug. 19 gave an accelerated approval to brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

3. FDA Approves Vemurafenib for Advanced Melanoma By Jane Salodof MacNeil
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients. It also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine whether a patient’s melanoma cells carry the BRAF V600E mutation.

2. Novel Therapies Put Multiple Myeloma 'On the Ropes' By Susan London
A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco. Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress in San Francisco. Others come from classes not previously used in this disease.

1. NICE Rejects Ipilimumab by Jennie Smith
A drug considered a breakthrough treatment for advanced melanoma was turned down by England’s clinical and cost-effectiveness agency. The National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy). The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab.

Did you miss any of last year's top reads in oncology? Click here to receive our weekly e-newsletter.

SAN DIEGO – Dr. Kenneth C. Anderson, associate editor of The Oncology Report, discusses new therapies for multiple myeloma and changing risk factors in presentations at the 2011 annual meeting of the American Society of Hematology (ASH).

SAN DIEGO – Dr. Kenneth C. Anderson, associate editor of The Oncology Report, discusses new therapies for multiple myeloma and changing risk factors in presentations at the 2011 annual meeting of the American Society of Hematology (ASH).

SAN DIEGO – Dr. Kenneth C. Anderson, associate editor of The Oncology Report, discusses new therapies for multiple myeloma and changing risk factors in presentations at the 2011 annual meeting of the American Society of Hematology (ASH).

SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.

SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.

SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.