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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.

The importance of continuous
treatment in multiple myeloma.

Patients may still have ~100 million
residual myeloma cells, even in CR.13

Importance of Continuous Treatment in Multiple Myeloma
Image adapted from: Poon ML, et al. Cancer Ther. 2008;6:275-284.

Without continuous treatment, patients may relapse sooner.14

The absence of treatment post-transplant may allow residual cells to proliferate, possibly leading to a shorter response.7,15,16

  • Patients typically relapse within 3 years post auto-HSCT without maintenance therapy17
Multiple Myeloma Treatment Continuous vs Fixed
Illustration is a hypothetical benefit of maintenance therapy post auto-HSCT.
Image adapted from: Moreau P, Giralt A. Leuk Res. 2012;36:S13-S18.

The importance of continuous treatment.

Play the video below and get an expert’s perspective on how continuous treatment may improve patient outcomes.

Vimeo ID: 356714250

Continuous Treatment.


View Video Transcript

MODERATOR: Hello, I’m Drew Moore. Today I’m joined by Dr Daniel Landau to discuss the importance of continuous treatment until disease progression or unacceptable toxicity in multiple myeloma.

MODERATOR: Thanks for being here today, Dr Landau.

DR LANDAU: Thank you for having me.

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

DR LANDAU: Well, it was one area of hematology where I expected to have all kinds of really exciting developments through the course of my career. That has proven to be the case, and we are at the forefront of new therapies that are extending survival.

MODERATOR: Great background, Dr Landau. Now we will specifically discuss how continuous therapy fits into the multiple myeloma landscape. Is continuous treatment an important consideration for you?

DR LANDAU: Yes, absolutely. I discuss the risks and benefits of continuous therapy with my patients to help maintain a response to their treatment.

DR LANDAU: I explain that the first response is typically the longest, so I aim to optimize first-line therapy by treating until progression or unacceptable toxicity.

MODERATOR: For these patients, how do you typically set expectations about continuous treatment?

DR LANDAU: I’m very upfront with my patients about treatment. While there is no cure, we’re pretty good about getting their disease under control, but they’re going to have to be treated and monitored long term because the disease does have the ability to return due to residual myeloma cells. Even in a complete 5 response, patients may have up to approximately 100 million residual myeloma cells. Without continuous treatment, patients may relapse sooner.

DR LANDAU: I describe it relative to a chronic illness—most chronic illnesses typically require long-term therapies.

MODERATOR: That seems like a helpful way to discuss continuous treatment so patients can understand. When choosing a therapy for non-transplant candidates, what factors are important to you?

DR LANDAU: I first look at the individual needs of the patient and then the safety and efficacy data of potential treatments. PFS has become a standard endpoint, so one of the first things I look at is the Kaplan-Meier curve for separation in progression-free survival.

It’s also important to me that the drug has an acceptable safety profile.

When considering REVLIMID®, or lenalidomide, as an option until disease progression or unacceptable toxicity, I look at the data in the FIRST trial, which studied REVLIMID with dexamethasone in newly diagnosed nontransplant candidates.

NARRATOR: REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of adult patients with multiple myeloma (MM).

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: Dr Landau, when the FIRST trial was read out, what was your reaction to the published data?

DR LANDAU: The most important take-away from this trial was seeing the results from continuous versus fixed-cycle treatment. The FIRST trial demonstrated significant improvement in median PFS with Rd Continuous versus fixed-cycle MPT.

MODERATOR: Let’s take a look at the trial design in more detail.

The FIRST trial is one of the largest Phase 3 trials in multiple myeloma. It evaluated more than 1,000 patients with multiple myeloma who did not receive a stem cell transplant.

MODERATOR: The primary endpoint was progression-free survival, or PFS.

MODERATOR: The FIRST trial randomized patients into 3 arms: Rd Continuous… Rd18… or MPT.

The primary comparison for efficacy was between REVLIMID and dexamethasone Continuous, or Rd, and melphalan, prednisone, and thalidomide, or MPT. A secondary efficacy comparison was between Rd Continuous and fixed-cycle Rd, or Rd18.

MODERATOR: Patients received 25 mg of REVLIMID once daily on days 1 through 21 of 28-day cycles.

MODERATOR: In the Rd Continuous arm, treatment was continued until disease progression, unacceptable toxicity, or patient withdrawal for another reason. The dose was reduced, interrupted, or discontinued as needed to manage toxicities.

MODERATOR: Let’s take a closer look into the data for Rd Continuous.

MODERATOR: Rd Continuous extended the PFS versus Rd18 and MPT…

MODERATOR: …with a median PFS of 25.5 months with Rd Continuous versus 21.2 months with MPT and 20.7 months with Rd18.

MODERATOR: Patients also achieved PFS at 3 and 4 years with Rd Continuous…

MODERATOR: …with 42.1% of patients treated with Rd Continuous achieving PFS at 3 years, and 34.6% at 4 years.

MODERATOR: Now that we’ve reviewed the data for Rd Continuous vs Rd18 and MPT, how does this data inform your clinical decision-making?

DR LANDAU: It provides insight into the importance of duration of therapy. The separation in the PFS curves showed the benefit of Rd Continuous versus fixed-cycle Rd and fixed-cycle MPT.

Based on the results from this trial, I treat my patients with REVLIMID until progression or unacceptable toxicity.

MODERATOR: How does the median PFS for Rd Continuous affect your view of REVLIMID plus dexamethasone?

DR LANDAU: As far as a two-drug regimen goes, 25.5 months median PFS means you may be able to treat patients continuously and get them to a longer PFS with an established safety profile.

MODERATOR: You bring up the safety profile. It’s important to consider the risk of adverse events, or AEs.

MODERATOR: The most frequently reported Grade 3 or 4 adverse reactions in the FIRST trial included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia.

MODERATOR: How do you typically discuss dosing and adverse events with your patients, especially considering that these patients may be on therapy continuously until disease progression or unacceptable toxicity?

DR LANDAU: For continuous dosing, patients typically prefer oral medications because they can take it at home and that’s convenient for them.

DR LANDAU: I tell them we will monitor side effects and if high-grade ones develop, whether it’s neutropenia or thrombocytopenia, or other unacceptable toxicities, there are dose modification guidelines in the Prescribing Information.

DR LANDAU: I think it’s important to closely monitor patients for AEs over time, as REVLIMID has safety data showing a decrease in common adverse reactions over time with continuous treatment.

MODERATOR: The frequency of adverse reactions was generally highest in the first 6 months in both Rd arms, and decreased or remained stable over time, except for cataracts.

MODERATOR: Clinical trials demonstrated that multiple myeloma patients who received REVLIMID until disease progression did not show a higher incidence of invasive second primary malignancy, or SPM, than those in the fixed duration, REVLIMID-containing arm.

MODERATOR: Throughout our discussion, you’ve discussed the importance of treating patients until disease progression or unacceptable toxicity. How would you summarize your thoughts on this topic?

DR LANDAU: My goal is to continue treatment for as long as possible and hopefully give my patients a long and lasting response. A therapy like REVLIMID helps achieve treatment goals by providing proven efficacy with a well-established safety profile.

While I have my own 20 way of approaching things, I really just want to keep it patient friendly and accessible—it’s important to keep my conversations at a more basic level with my patients to ensure they really understand their treatment and what to expect with REVLIMID.

MODERATOR: It was wonderful to get to hear your perspective on multiple myeloma and how you manage treatment with REVLIMID.

Indications

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of adult patients with multiple myeloma (MM).

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

• 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%).

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. Hajek R. Strategies for the treatment of multiple myeloma in 2013: moving toward the cure. In: Hajek R, ed. Multiple Myeloma. IntechOpen; 2013. doi:10.5772/55366. 2. Poon ML, Chng WJ. Is complete remission an important therapeutic aim in multiple myeloma? Cancer Ther. 2008;6:275-284. 3. Data on file. Celgene Corp; 2019. 4. National Institutes of Health. Search Results: Multiple Myeloma Clinical Trial. Available at: Clinicaltrials.gov. Accessed March 28, 2019. 5. 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-19-0357

 

 


auto-HSCT, autologous hematopoietic stem cell transplantation; CR, complete response; NDMM, newly diagnosed multiple myeloma, NSCT, non-stem cell transplant; PFS, progression-free survival, PR, partial response; Rd, REVLIMID + dexamethasone.

Rd Continuous was studied vs fixed-cycle
treatments in NSCT NDMM.1

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.