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REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of adult patients with multiple myeloma (MM). REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

REVLIMID is a FOUNDATION in
NDMM post auto-HSCT.1

REVLIMID is the #1 prescribed
maintenance therapy post auto-HSCT.3

ONLY NCCN
CATEGORY 1

Lenalidomide (REVLIMID): the ONLY preferred NCCN Category 1 maintenance therapy post
auto-HSCT.9*

*See full NCCN Guidelines® for further detail about recommended therapies.

Multiple Myeloma Maintenance Therapy

ONLY FDA-APPROVED
MAINTENANCE THERAPY

The ONLY FDA-approved maintenance therapy post auto-HSCT.1

Multiple Myeloma Maintenance Treatment

#1 PRESCRIBED

#1 prescribed maintenance therapy post auto-HSCT.3†

Claims data 02/2016-05/2019. Source: IntrinsiQ Data © 2019, IntrinsiQ Specialty Solutions, Inc.

Multiple Myeloma Maintenance Therapy Post Transplant

An expert perspective.

Dr. Brion Randolph—a hematologist/oncologist specializing in high-risk multiple myeloma—discusses the importance of maintenance therapy.

Vimeo ID: 356723066

Maintenance Therapy.


View Video Transcript

MODERATOR: Hi…I’m Drew Moore.

MODERATOR: Today I’m joined by Dr Brion Randolph to discuss the importance of maintenance therapy for multiple myeloma patients post autologous hematopoietic stem cell transplant—or auto-HSCT.

MODERATOR: Thanks for being here today, Dr Randolph.

DR RANDOLPH: Thanks for having me.

MODERATOR: To get started, I’d just like to ask a little bit about why you got into the field of multiple myeloma treatment?

DR RANDOLPH: Well, there are a few reasons. One, I find the biology of this disease complex and challenging. But also, there are still populations where an unmet need exists—such as among African Americans, and being African American myself, this really struck a chord with me. So I have made it my mission to try to make an impact for patients with multiple myeloma.

MODERATOR: Great background, Dr Randolph. Now we’ll specifically discuss auto-HSCT in multiple myeloma. We know that this type of transplant may be a good option for eligible patients. If these patients achieve a good response, what’s typically your next step?

DR RANDOLPH: I remind patients that a good response doesn’t mean “disease free.” So, even after receiving a transplant, there’s still the concern that patients may relapse due to residual disease.

DR RANDOLPH: We know that patients may still have approximately 100 million residual myeloma cells even if they achieve a complete response.

That’s why in my practice I believe maintenance therapy is a great strategy after transplant—and there’s an abundance of data out there that supports this.

MODERATOR: For these patients, how do you typically set expectations after transplant?

DR RANDOLPH: Well, Drew, I believe in setting expectations with patients immediately—especially when it comes to the duration of treatment.

On day one, I outline their full treatment plan so that they understand what’s ahead of them—with the caveat that we may need to modify along the way.

As a physician, I make sure that they understand that multiple myeloma is currently not curable, while also instilling a sense of hope. That’s why I remind patients that there are efficacious options to help manage their disease.

MODERATOR: I see—that can be a difficult balance. Well, when choosing a maintenance therapy post-transplant, what factors are important to you?

DR RANDOLPH: Well, for me, data is key. I always look to ensure that the therapy I choose has strong phase III data—like REVLIMID®, or lenalidomide.

I’ve been using REVLIMID as a FOUNDATION in newly diagnosed multiple myeloma, or NDMM, post autologous stem cell transplant. REVLIMID is the only FDA approved and number one prescribed maintenance therapy post autologous stem cell transplant.

Additionally, lenalidomide is also the only preferred NCCN Category 1 maintenance therapy post autologous stem cell transplant. So, I think REVLIMID has really become a standard of practice in the multiple myeloma community.

NARRATOR: REVLIMID® (lenalidomide) is indicated as maintenance therapy in adult patients with multiple myeloma (MM) following autologous hematopoietic stem cell transplantation (auto-HSCT).

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

The REVLIMID Prescribing Information contains Boxed Warnings for the following: Embryo-Fetal Toxicity, a Restricted Distribution Program—the REVLIMID REMS®, Hematologic Toxicity, and Venous and Arterial Thromboembolism.

Embryo-Fetal Toxicity

• Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.

• Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception.

REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program.

Hematologic Toxicity

• REVLIMID can cause significant neutropenia and thrombocytopenia.

Venous and Arterial Thromboembolism

• Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone. Anti-thrombotic prophylaxis is recommended.

Please see Important Safety Information at the end of this video and accompanying full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

MODERATOR: How important is REVLIMID maintenance therapy?

DR RANDOLPH: From my perspective, it’s important. The REVLIMID data shows that response following autologous stem cell transplant is significantly longer with REVLIMID maintenance therapy. These results are consistent with my experience, and I’m a firm believer that maintenance therapy is a key factor for prolonged progression-free survival.

It’s also important to remember the Boxed WARNINGS and the common adverse events, which include cytopenias and diarrhea.

MODERATOR: You mentioned the pivotal trials for REVLIMID. Let’s take a look at these in more detail. CALGB (Study 1) and IFM (Study 2) were two phase 3 cooperative group trials that were conducted in the US and EU, respectively.

MODERATOR: The 2 studies evaluated REVLIMID versus placebo and included more than 1,000 patients.

MODERATOR: The primary endpoint in both studies was progression-free survival, or PFS, while the secondary endpoint was overall survival, or OS.

MODERATOR: Study 1 and Study 2 randomized patients after transplant…

MODERATOR: …to either placebo

MODERATOR: …or REVLIMID maintenance therapy.

MODERATOR: Differences between the two studies included: location, consolidation therapy, and whether patients were allowed to cross over.

Both studies required that, at diagnosis, patients between 18 and 70 years in CALGB and less than 65 years in IFM received induction therapy within 12 months of diagnosis and then went on to receive an auto-HSCT. Patients then had to achieve at least a stable disease response following hematologic recovery and their creatinine clearance had to be at least 30 mL per minute before randomization.

At a pre-planned interim analysis the primary endpoint was met and both studies were unblinded.

MODERATOR: Patients received 10 mg of REVLIMID once daily on days 1 through 28 of repeated 28-day cycles until progression.

MODERATOR: Treatment with REVLIMID in both studies was to be continued until disease progression, unacceptable toxicity, or patient withdrawal for another reason. Dose was reduced, interrupted, or discontinued as needed to manage toxicities.

MODERATOR: Let’s take a closer look at the PFS data for REVLIMID.

MODERATOR: During CALGB (Study 1), the updated data from March 2015 showed continued improvement in PFS…

MODERATOR: …with a median PFS of 5.7 years with REVLIMID Maintenance therapy versus 1.9 years with placebo.

MODERATOR: This represents a 3.8-year PFS advantage in favor of REVLIMID Maintenance therapy compared to placebo.

MODERATOR: Meanwhile, IFM (Study 2) demonstrated a median PFS of 3.9 years with REVLIMID Maintenance and 2.0 years with placebo.

This resulted in a 1.9-year advantage in median PFS versus placebo.

MODERATOR: How do you typically discuss the PFS data in these studies with patients?

DR RANDOLPH: I think the data is very impactful. In my own practice I definitely make sure to go over the PFS data with patients. I remind them that the data is an average of all patients studied, but that it clearly shows the advantage of maintenance therapy.

MODERATOR: When assessing efficacy, what other factors are important besides PFS?

DR RANDOLPH: As physicians, we tend to look at progression-free survival because we haven’t seen many therapies that have OS data, so it’s something I look for.

MODERATOR: That’s a great point. Let’s look at the OS data for REVLIMID.

MODERATOR: CALGB and IFM also assessed overall survival in a descriptive analysis.

MODERATOR: The data showed that in CALGB, patients receiving REVLIMID maintenance therapy lived a median of 9.3 years…versus 7 years without maintenance therapy.

MODERATOR: In IFM, patients on REVLIMID maintenance therapy lived a median of 8.8 years…versus 7.3 years for patients without maintenance therapy. The median follow -up time was 81.6 months for CALGB and 96.7 months for IFM.

It’s important to note that neither study was powered to evaluate overall survival.

MODERATOR: Additionally, it’s important to consider the risk of adverse events.

The most frequently reported Grade 3 or 4 adverse reactions–classified as greater than 20% in the REVLIMID arm, included: neutropenia, thrombocytopenia, and leukopenia.

MODERATOR: Clinical trials demonstrated that in MM patients receiving REVLIMID, an increase of hematologic plus solid tumor SPM, notable AML and MDS was observed—which is why it’s important to monitor patients for the development of SPM.

MODERATOR: What’s your approach to handling adverse events?

DR RANDOLPH: It’s important for my team to keep a frequent dialogue with patients to understand what they are experiencing. I counsel my patients about boxed warnings, which include embryo-fetal toxicity, hematologic toxicity, and thromboembolism, as well as the REMS program. I typically look out for and manage common adverse events such as cytopenias and diarrhea. However, I closely monitor all patients for any adverse events.

Because my goal is to treat patients until progression or unacceptable toxicity, I try to help patients stay on REVLIMID maintenance therapy with dose modifications as needed.

MODERATOR: What’s your overall impression of the data demonstrated in these REVLIMID maintenance studies?

DR RANDOLPH: I think the data play a big role in my decision-making.

Through both CALGB and IFM, we see that patients who received REVLIMID maintenance therapy achieved a better PFS than those who did not.

MODERATOR: Throughout our discussion, you emphasized the importance of maintenance therapy. Generally, what are your goals for these patients post-transplant?

DR RANDOLPH: My goal is to continue treatment for as long as possible. I think this can sometimes be difficult for a patient to comprehend, but I remind them that they need to think of this as any other chronic illness that would necessitate continuous treatment.

You know, with the advancements that are being made, it’s an exciting time at the forefront of treating multiple myeloma, and together with REVLIMID, there’s the potential to help multiple myeloma patients truly achieve long-term goals.

MODERATOR: Thank you for your time today, Dr Randolph. It’s been wonderful to hear your perspective on multiple myeloma and how you treat patients post auto-HSCT with REVLIMID.

Indications

REVLIMID® (lenalidomide) is indicated as maintenance therapy in adult patients with multiple myeloma (MM) following autologous hematopoietic stem cell transplantation (auto-HSCT).

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program.

Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

 

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. 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 risk to the fetus.

Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS.

Males: Lenalidomide is present in the semen of patients receiving the drug. 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.

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.

REVLIMID REMS® Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.

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 medications that may increase risk of bleeding. Patients may require a dose interruption and/or dose reduction. MM: Monitor complete blood counts in patients taking REVLIMID + dexamethasone or REVLIMID as maintenance therapy, every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter.

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. 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). Thromboprophylaxis is recommended and the regimen should be based on the patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision.

Increased Mortality in Patients With CLL: In a clinical trial in the first-line treatment of patients with CLL, single-agent REVLIMID therapy increased the risk of death as compared to single-agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID and in patients with FL or MZL receiving REVLIMID + rituximab therapy, an increase of hematologic plus solid tumor SPM, notably AML, have been observed. In patients with MM, MDS was also observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment.

Increased Mortality With Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID + dexamethasone. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or DRESS is suspected and should not be resumed following discontinuation for these reactions.

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treatment. Closely monitor patients at risk and take appropriate preventive approaches.

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection.

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting REVLIMID treatment and during therapy.

Early Mortality in Patients With MCL: In another MCL study, there was an increase in early deaths (within 20 weeks); 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L).

ADVERSE REACTIONS

Multiple Myeloma

Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm.

The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin-stimulating agents or estrogencontaining therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.

USE IN SPECIFIC POPULATIONS

• PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

• LACTATION: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID.

• RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on the creatinine clearance value and for patients on dialysis.

REFERENCES: 1. Poon ML, Chng WJ. Is complete remission an important therapeutic aim in multiple myeloma? Cancer Ther. 2008;6:275-284. 2. Data on file. Celgene Corp; 2019. 3. REVLIMID [package insert]. Summit, NJ: Celgene Corp; 2019.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

NARRATOR: To learn more about REVLIMID maintenance therapy, please visit: www.REVLIMID.com

REVLIMID® and REVLIMID REMS® are registered trademarks of Celgene Corporation.

© 2019 Celgene Corporation

US-REV-19-0339


auto-HSCT, autologous hematopoietic stem cell transplantation; NCCN, National Comprehensive Cancer Network; NDMM, newly diagnosed multiple myeloma.

See results of REVLIMID maintenance
in 2 pivotal trials.

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program.

Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. 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 risk to the fetus

Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

CONTRAINDICATIONS FOR DARATUMUMAB

Daratumumab is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

  • Females of Reproductive PotentialSee Boxed WARNINGS
  • Males: Lenalidomide is present in the semen of patients receiving the drug. 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
  • 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 REVLIMID REMS® Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

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 medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex or REVLIMID as maintenance therapy should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. FL/MZL: Monitor CBC in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then monthly thereafter.

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. 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). Thromboprophylaxis is recommended and the regimen should be based on patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients with CLL: In a clinical trial in the first-line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor SPM, notably AML and MDS, have been observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment

Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or DRESS is suspected and should not be resumed following discontinuation for these reactions.

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treatment. Closely monitor patients at risk and take appropriate preventive approaches.

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection.

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting REVLIMID treatment and during therapy.

Early Mortality in Patients With MCL: In another MCL study, there was an increase in early deaths (within 20 weeks); 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L).

WARNINGS AND PRECAUTIONS FOR DARATUMUMAB

Infusion reactions: Interrupt daratumumab infusion for infusion reactions of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening infusion reactions and institute appropriate emergency care.

Interference with cross-matching and red blood cell antibody screening: Type and screen patients prior to starting treatment. Inform blood banks that a patient has received daratumumab.

Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Dose delay may be required to allow recovery of neutrophils.

Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets.

Interference with Determination of Complete Response: Daratumumab can interfere with the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

ADVERSE REACTIONS

Multiple Myeloma

  • In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18
  • The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
  • Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm
  • The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
  • After at least one prior therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)

ADVERSE REACTIONS FOR REVLIMID + DEXAMETHASONE + DARATUMUMAB (DRd)

The most frequent (≥20%) adverse reactions (DRd arm) were: infusion reactions (41%), diarrhea (57%), constipation (41%), nausea (32%), peripheral edema (41%), fatigue (40%), back pain (34%), asthenia (32%), pyrexia (23%), upper respiratory tract

infection (52%), bronchitis (29%), pneumonia (26%), decreased appetite (22%), muscle spasms (29%), peripheral sensory neuropathy (24%), dyspnea (32%), and cough (30%).

Grade 3 or 4 hematology laboratory abnormalities (DRd arm) included: neutropenia (56%), lymphopenia (52%), leukopenia (35%), anemia (13%), thrombocytopenia (9%).

Follicular Lymphoma/Marginal Zone Lymphoma

Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID + rituximab across both trials. Fatal adverse reactions (1 each) included: cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. The most frequent serious adverse reaction that occurred in the REVLIMID + rituximab arm was febrile neutropenia (3.0%).

Grade 3 and 4 adverse reactions reported in ≥5% of patients treated in the FL/MZL trial with REVLIMID + rituximab were: neutropenia (50%) and leukopenia (7%)

Adverse reactions reported in ≥15% of patients with FL/MZL treated with REVLIMID + rituximab were: neutropenia (58%),

diarrhea (31%), constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leukopenia (20%), pruritus (20%), upper respiratory tract infections (18%), abdominal pain (18%), anemia (16%), headache (15%), thrombocytopenia (15%)

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin

USE IN SPECIFIC POPULATIONS

  • PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436
  • LACTATIONThere is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID PEDIATRIC USE: Safety and effectiveness have not been established in pediatric patients
  • RENAL IMPAIRMENTAdjust the starting dose of REVLIMID based on creatinine clearance value and in patients on dialysis.

Please see full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalex.com.

Please see the rituximab full Prescribing Information for Important Safety Information at www.rituxan.com.