On Location 2018 ASH Annual Meeting
Algorithm Built on Big Data Improves Prognostic
Accuracy Over Existing MDS Models
Using machine learning, researchers were
able to develop a prognostic model that
predicted survival among patients with
myelodysplastic syndromes (MDS) and
was more accurate than existing, “gold-
standard” prognostic tools, according to a
study presented at the 2018 ASH Annual
Meeting.
“All treatment guidelines are driven
by risk, which means that if we get the
risk wrong, we get the treatment wrong,”
said lead study author Aziz Nazha, MD,
of the Cleveland Clinic. “Improving and
personalizing our prognostic models is
extremely important and can help patients
understand their disease and what they
can expect during their journey.”
The survival estimates provided by
the International Prognostic Scoring
System (IPSS) and IPSS-Revised (IPPS-
R) systems “are all over the place … and
underestimate the heterogeneity of MDS,”
Dr. Nazha said. “So, for us, the question
became, ‘Can we build a model that can
provide a personalized prediction specific
for a given patient?’”
To develop this tool, a collaborative
team from Cleveland Clinic and Mu-
nich Leukemia Laboratory developed a
REVLIMID [lenalidomide] capsules, for oral use
Other Toxicities in MM
For other Grade 3/4 toxicities judged to be related to REVLIMID, hold
treatment and restart at the physician’s discretion at next lower dose level
when toxicity has resolved to ≤ Grade 2.
Starting Dose Adjustment for Renal Impairment in MM:
[See Dosage and Administration (2.4)].
2.4 Starting Dose for Renal Impairment in MM
The recommendations for starting doses for patients with renal impairment
are shown in the following
Table 3: Starting Dose Adjustments for Patients with Renal Impairment
Renal Function
Dose in REVLIMID
Dose in REVLIMID
(Cockcroft-Gault)
Combination Therapy
Maintenance Therapy
for MM
Following Auto-HSCT
CLcr 30 to 60 mL/min 10 mg once daily
5 mg once daily
CLcr < 30 mL/min
15 mg every other day
2.5 mg once daily
(not requiring dialysis)
5 mg once daily. On
2.5 mg once daily. On
CLcr < 30 mL/min
(requiring dialysis)
dialysis days, administer dialysis days, administer
the dose following dialysis. the dose following dialysis.
REVLIMID Combination Therapy for MM: For CLcr of 30 to 60 mL/min,
consider escalating the dose to 15 mg after 2 cycles if the patient
tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.
REVLIMID Maintenance Therapy Following Auto-HSCT for MM: Base
subsequent REVLIMID dose increase or decrease on individual patient
treatment tolerance [see Dosage and Administration (2.1)].
4 CONTRAINDICATIONS
4.1 Pregnancy
REVLIMID can cause fetal harm when administered to a pregnant female.
Limb abnormalities were seen in the offspring of monkeys that were
dosed with lenalidomide during organogenesis. This effect was seen at
all doses tested. Due to the results of this developmental monkey study,
and lenalidomide’s structural similarities to thalidomide, a known human
teratogen, lenalidomide is contraindicated in females who are pregnant
[see Boxed Warning]. If this drug is used during pregnancy or if the
patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus [see Warnings and
Precautions (5.1, 5.2), Use in Special Populations (8.1,8.3)].
4.2 Severe Hypersensitivity Reactions
REVLIMID is contraindicated in patients who have demonstrated severe
hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic
epidermal necrolysis) to lenalidomide [see Warnings and Precautions
(5.8)].
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
Cosmos Communications
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
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