ASH News Daily 2012 - Saturday, December 8, 2012 - (Page A-12)
Page A–12
®
Myeloma
«« From Page A-8
Next S. Vincent Rajkumar, MD,
A vendor waits for the forklift traffic jam to clear before crossing aisles during
set-up on the Exhibit Hall floor.
from the Mayo Clinic in Rochester,
MN, is given the task of updating
the audience on the treatment for
newly diagnosed myeloma. He routinely
classifies patients into “standard-,
intermediate-, and high-risk
disease using the Mayo stratification
and risk-adapted therapy classification.”
He will navigate through the
myriads of two-, three-, and fourdrug
regimens and will highlight
features of each that are clinically
relevant. For those who were not
eligible for ASCT, lenalidomide
and low-dose dexamethasone are a
starting point because they are well
tolerated and can result in threeyear
OS of 70 percent, and may be
better than melphalan-containing
triplets. For those treated with the
intent of ASCT, bortezomib-based,
three-drug induction regimens appear
to be superior over four-drug
regimens.
Lastly, Antonio Palumbo, MD, of
the University of Torino, Italy, will
pose a provocative question: “Have
new drug combinations supplanted
stem cell transplantation?” Historically,
melphalan-based
induction
Brief Summary
(bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.
VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received
at least 1 prior therapy.
INDICATIONS:
VELCADE®
CONTRAINDICATIONS:
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
VELCADE is contraindicated for intrathecal administration.
WARNINGS AND PRECAUTIONS:
VELCADE should be administered under the supervision of a physician experienced in the use
of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during
treatment with VELCADE.
Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly
sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported.
Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or
signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3)
during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such
as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or
weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs.
intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous
and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the
subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting
VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of
peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may
benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3
relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments,
improvement in or resolution of peripheral neuropathy was reported in 51% of patients with
≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or
resolution of peripheral neuropathy was reported in 73% of patients who discontinued due
to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple
myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle
cell lymphoma.
Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was
13%. These events are observed throughout therapy. Caution should be used when treating
patients with a history of syncope, patients receiving medications known to be associated with
hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension
may include adjustment of antihypertensive medications, hydration, and administration of
mineralocorticoids and/or sympathomimetics.
Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset
of decreased left ventricular ejection fraction have been reported, including reports in patients
with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for,
or existing heart disease should be closely monitored. In the relapsed multiple myeloma study
of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was
15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart
failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic
shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and
4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies;
causality has not been established.
Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease
of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute
Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have
been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2
per day) by
continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia
died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension
associated with VELCADE administration in the absence of left heart failure or significant
pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt
comprehensive diagnostic evaluation should be conducted.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of
RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can
present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and
neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to
confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating
VELCADE therapy in patients previously experiencing RPLS is not known.
Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation,
and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can
occur. Fluid and electrolyte replacement should be administered to prevent dehydration.
Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and
neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each
cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of
platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice
weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia.
The mean platelet count nadir measured was approximately 40% of baseline. The severity of
thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma
study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3)
was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be
monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require
change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and
intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The
incidence of febrile neutropenia was <1%.
Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant
cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis
syndrome are those with high tumor burden prior to treatment. These patients should be
monitored closely and appropriate precautions taken.
Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple
concomitant medications and with serious underlying medical conditions. Other reported hepatic events
include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible
upon discontinuation of VELCADE. There is limited re-challenge information in these patients.
Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is
increased in patients with moderate or severe hepatic impairment; these patients should be
treated with VELCADE at reduced starting doses and closely monitored for toxicities.
Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid
becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during
organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2
surface area caused post-implantation loss and a decreased number of live fetuses.
based on body
ADVERSE EVENT DATA:
Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2
/dose
[doxorubicin HCI liposome injection] study) and previously treated mantle
cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of
VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.
administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in
1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3,
VELCADE plus DOXIL®
In the integrated analysis, the most commonly reported adverse events were asthenic
conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%),
constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and
peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including
anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache,
paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%),
rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%),
pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension
(each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and
pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%).
Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most
commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced
serious adverse events (SAEs) during the studies. The most commonly reported SAEs included
pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea
and thrombocytopenia (each 3%).
In the phase 3 VELCADE + melphalan and prednisone study in previously untreated
multiple myeloma, the safety profile of VELCADE administered intravenously in combination
with melphalan/prednisone is consistent with the known safety profiles of both VELCADE
and melphalan/prednisone. The most commonly reported adverse events in this
study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia
(52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy
(47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%),
neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia
(29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia
(21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral
(20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness
(16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%),
abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis
(13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper
(12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%),
bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).
In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma,
safety data were similar between the two treatment groups. The most commonly reported
adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia
(36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea
(24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%),
nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation
(14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%),
insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%),
hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal
pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence
of serious adverse events was similar for the subcutaneous treatment group (36%) and the
intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%)
and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%),
peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.
DRUG INTERACTIONS:
Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration
of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in
12 patients. Therefore, patients should be closely monitored when given bortezomib in
combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration
of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in
17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease
the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not
designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than
45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong
CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in
patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib
exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak
CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration
of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients.
However, this increase is unlikely to be clinically relevant.
USE IN SPECIFIC POPULATIONS:
Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reactions in
nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.
Geriatric Use: No overall differences in safety or effectiveness were observed between patients
≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals
cannot be ruled out.
Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the
degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for
patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE
should be administered after the dialysis procedure. For information concerning dosing of
melphalan in patients with renal impairment, see manufacturer’s prescribing information.
Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with
moderate and severe hepatic impairment. Starting dose should be reduced in those patients.
Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported
in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving
VELCADE treatment may require close monitoring of their blood glucose levels and adjustment
of the dose of their antidiabetic medication.
Please see full Prescribing Information for VELCADE at VELCADEHCP.com.
plus ASCT was superior over melphalan
alone. While consolidation
with bortezomib or IMiDs after
ASCT is currently under evaluation,
several studies have shown
that maintenance (after ASCT) with
either bortezomib or IMiDs delays
progression. Thus “the role of ASCT
in the era of novel agents,” Dr. Palumbo
stated, needs to be re-defined.
There are two large studies testing
this directly: IFM/DFCI2009 will
evaluate bortezomib, lenalidomide,
dexamethasone (BLD) induction
and BLD maintenance versus BLD
induction, ASCT, and BLD consolidation
and the EMN02 study will
compare BCD induction, then BMP
continuation versus ASCT, and then
with or without BLD consolidation.
Both studies include maintenance
with lenalidomide.
Induction, consolidation, and
maintenance will remain the treatment
paradigm for myeloma.
ASCT, proteosome inhibitors, and
IMiDs are here to stay. Indeed three
is a wonderful number.
Dr. Hsieh indicated no relevant conflicts
of interest.
ASH NEWS DAILY
Saturday, December 8, 2012
VELCADE, MILLENNIUM and
Other trademarks are property of their respective owners.
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139
Copyright © 2012, Millennium Pharmaceuticals, Inc.
All rights reserved.
Printed in USA
are registered trademarks of Millennium Pharmaceuticals, Inc.
V-12-0256
12/12
Alaeddin Raafat (left), Monklands
Hospital, Airdrie, United Kingdom,
and Dr. Carlos Conzalez, Academia
Nac. de Medicina, Caba, Argentina,
take advantage of the nice weather
to review the meeting program
outside the Georgia World Congress
Center.
3921_milpro_fa2_hilda_ashdn.indd 2
10/5/12 11:44 AM
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