On Location 2018 ASH Annual Meeting
Eric Seifter, MD
Associate Professor,
Johns Hopkins University
School of Medicine
Hematologist, Park
Medical Associates
Baltimore, MD
Myeloma Therapy:
From Diagnosis to Relapse
This year’s Education Program takes a new approach to disease-specific
content: In two Special Education Sessions, “Approach to the Treatment
of the Young, Fit Patient With Myeloma” and “Approach to the Treat-
ment of the Older, Unfit Patient With Myeloma,” experts will engage in
a back-and-forth exchange about the optimal management.
This debate will begin with each
participant stating his or her rec-
ommendations and rationales for
induction therapy, transplantation/
consolidation therapy, and main-
tenance therapy, followed by a
discussion about the therapeutic
choices and resulting outcomes.
Here, we speak with Eric Seifter,
MD, chair of the session on the
REVLIMID [lenalidomide] capsules, for oral use
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
REVLIMID is a thalidomide analogue and is contraindicated for use
during pregnancy. Thalidomide is a known human teratogen that causes
life-threatening human birth defects or embryo-fetal death [see Use in
Specific Populations (8.1)]. An embryo-fetal development study in
monkeys indicates that lenalidomide produced malformations in the
offspring of female monkeys who received the drug during pregnancy,
similar to birth defects observed in humans following exposure to
thalidomide during pregnancy.
REVLIMID is only available through the REVLIMID REMS program [see
Warnings and Precautions (5.2)].
Females of Reproductive Potential
Females of reproductive potential must avoid pregnancy for at least
4 weeks before beginning REVLIMID therapy, during therapy, during
dose interruptions and for at least 4 weeks after completing therapy.
Females must commit either to abstain continuously from heterosexual
sexual intercourse or to use two methods of reliable birth control,
beginning 4 weeks prior to initiating treatment with REVLIMID, during
therapy, during dose interruptions and continuing for 4 weeks following
discontinuation of REVLIMID therapy.
Two negative pregnancy tests must be obtained prior to initiating therapy.
The first test should be performed within 10-14 days and the second test
within 24 hours prior to prescribing REVLIMID therapy and then weekly
during the first month, then monthly thereafter in females with regular
menstrual cycles or every 2 weeks in females with irregular menstrual
cycles [see Use in Specific Populations (8.3)].
Males
Lenalidomide is present in the semen of patients receiving the drug.
Therefore, males must always use a latex or synthetic condom during
any sexual contact with females of reproductive potential while taking
REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if
they have undergone a successful vasectomy. Male patients taking
REVLIMID must not donate sperm [see Use in Specific Populations (8.3)].
Blood Donation
Patients must not donate blood during treatment with REVLIMID and for
4 weeks following discontinuation of the drug because the blood might
be given to a pregnant female patient whose fetus must not be exposed
to REVLIMID.
5.2 REVLIMID REMS Program
Because of the embryo-fetal risk [see Warnings and Precautions (5.1)],
REVLIMID is available only through a restricted program under a Risk
Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS
program.
Required components of the REVLIMID REMS program include the
following:
• Prescribers must be certified with the REVLIMID REMS program by
enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician agreement form and comply
with the REMS requirements. In particular, female patients of
reproductive potential who are not pregnant must comply with the
pregnancy testing and contraception requirements [see Use in Specific
Populations (8.3)] and males must comply with contraception
requirements [see Use in Specific Populations (8.3)].
• Pharmacies must be certified with the REVLIMID REMS program, must
only dispense to patients who are authorized to receive REVLIMID and
comply with REMS requirements.
Further information about the REVLIMID REMS program is available at
www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.
5.3 Hematologic Toxicity
REVLIMID can cause significant neutropenia and thrombocytopenia.
Monitor patients with neutropenia for signs of infection. Advise patients
to observe for bleeding or bruising, especially with use of concomitant
medication that may increase risk of bleeding. Patients taking REVLIMID
should have their complete blood counts assessed periodically as
described below [see Dosage and Administration (2.1)].
Patients taking REVLIMID in combination with dexamethasone or as
REVLIMID maintenance therapy for MM should have their complete
blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles,
on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A
dose interruption and/or dose reduction may be required [see Dosage
and Administration (2.1)]. In the MM maintenance therapy trials, Grade 3
or 4 neutropenia was reported in up to 59% of REVLIMID-treated
patients and Grade 3 or 4 thrombocytopenia in up to 38% of REVLIMID-
treated patients [see Adverse Reactions (6.1)].
5.4 Venous and Arterial Thromboembolism
Venous thromboembolic events (VTE [DVT and PE]) and arterial
thromboembolic events (ATE, myocardial infarction and stroke) are
increased in patients treated with REVLIMID.
A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in
patients with MM after at least one prior therapy who were treated with
REVLIMID and dexamethasone therapy compared to patients treated in
the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials
with varying use of anticoagulant therapies. In the newly diagnosed
multiple myeloma (NDMM) study in which nearly all patients received
antithrombotic prophylaxis, DVT was reported as a serious adverse
reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT
Arms, respectively. The frequency of serious adverse reactions of PE was
similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%,
and 3.7%, respectively) [see Boxed Warning and Adverse Reactions
(6.1)].
Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in
patients with MM after at least one prior therapy who were treated with
REVLIMID and dexamethasone therapy compared to patients treated with
placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the
NDMM study, myocardial infarction (including acute) was reported as a
serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous,
Rd18, and MPT Arms, respectively. The frequency of serious adverse
reactions of CVA was similar between the Rd Continuous, Rd18, and
MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse
Reactions (6.1)].
Patients with known risk factors, including prior thrombosis, may be at
greater risk and actions should be taken to try to minimize all modifiable
factors (e.g. hyperlipidemia, hypertension, smoking).
In controlled clinical trials that did not use concomitant
thromboprophylaxis, 21.5% overall thrombotic events (Standardized
MedDRA Query Embolic and Thrombotic events) occurred in patients
with refractory and relapsed MM who were treated with REVLIMID and
dexamethasone compared to 8.3% thrombosis in patients treated with
placebo and dexamethasone. The median time to first thrombosis event
was 2.8 months. In the NDMM study in which nearly all patients received
antithrombotic prophylaxis, the overall frequency of thrombotic events
was 17.4% in patients in the combined Rd Continuous and Rd18 Arms,
and was 11.6% in the MPT Arm. The median time to first thrombosis
event was 4.3 months in the combined Rd Continuous and Rd18 Arms.
Thromboprophylaxis is recommended. The regimen of
thromboprophylaxis should be based on an assessment of the patient’s
underlying risks. Instruct patients to report immediately any signs and
symptoms suggestive of thrombotic events. ESAs and estrogens may
further increase the risk of thrombosis and their use should be based on
a benefit-risk decision in patients receiving REVLIMID [see Drug
Interactions (7.2)].
5.5 Increased Mortality in Patients with CLL
In a prospective randomized (1:1) clinical trial in the first line treatment
of patients with chronic lymphocytic leukemia, single agent REVLIMID
therapy increased the risk of death as compared to single agent
chlorambucil. In an interim analysis, there were 34 deaths among
210 patients on the REVLIMID treatment arm compared to 18 deaths
among 211 patients in the chlorambucil treatment arm, and hazard ratio
for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a
92% increase in the risk of death. The trial was halted for safety in
July 2013.
Serious adverse cardiovascular reactions, including atrial fibrillation,
myocardial infarction, and cardiac failure occurred more frequently in
the REVLIMID treatment arm. REVLIMID is not indicated and not
recommended for use in CLL outside of controlled clinical trials.
5.6 Second Primary Malignancies
In clinical trials in patients with MM receiving REVLIMID, an increase
of hematologic plus solid tumor second primary malignancies (SPM)
notably AML and MDS have been observed. An increase in hematologic
SPM including AML and MDS occurred in 5.3% of patients with NDMM
receiving REVLIMID in combination with oral melphalan compared with
1.3% of patients receiving melphalan without REVLIMID. The frequency
of AML and MDS cases in patients with NDMM treated with REVLIMID in
combination with dexamethasone without melphalan was 0.4%.
In patients receiving REVLIMID maintenance therapy following high dose
intravenous melphalan and auto-HSCT, hematologic SPM occurred in
7.5% of patients compared to 3.3% in patients receiving placebo. The
incidence of hematologic plus solid tumor (excluding squamous cell
carcinoma and basal cell carcinoma) SPM was 14.9%, compared to 8.8%
in patients receiving placebo with a median follow-up of 91.5 months.
Non-melanoma skin cancer SPM, including squamous cell carcinoma
and basal cell carcinoma, occurred in 3.9% of patients receiving
REVLIMID maintenance, compared to 2.6% in the placebo arm.
In patients with relapsed or refractory MM treated with REVLIMID/
dexamethasone, the incidence of hematologic plus solid tumor (excluding
squamous cell carcinoma and basal cell carcinoma) SPM was 2.3%
versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer