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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 in combination with daratumumab and dexamethasone (DRd)

An FDA-approved triplet with REVLIMID
for patients with NSCT NDMM.2,10

Watch Dr. Faith Davies share her thoughts on the DRd regimen for patients with NDMM ineligible for stem cell transplant.


MAIA was a Phase 3, open-label, randomized, multicenter trial of DRd (n=368) vs Rd (n=369) in adult patients with NDMM who were ineligible for an auto-SCT.1

Indication for REVLIMID + dexamethasone + daratumumab (DRd)
DRd is indicated for the treatment of adult patients with newly diagnosed MM who are ineligible for an autologous stem cell transplant.

Information about DRd does not appear in the REVLIMID full Prescribing Information. Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalex.com.

An expert perspective.

Dr. Faith Davies—a multiple myeloma specialist—discusses why she considers DRd an effective and viable treatment option for appropriate patients with NDMM not eligible for a stem cell transplant.

Dr. Faith Davies Multiple Myeloma Specialist

A Combination with REVLIMID for NSCT NDMM.


View Video Transcript

MODERATOR: Hello everyone, I’m Drew Moore, and I’m here with Dr. Faith Davies, a multiple myeloma specialist at the Perlmutter Cancer Center.

MODERATOR: Today we’ll be discussing treatment options for patients who have newly diagnosed multiple myeloma and are ineligible for stem cell transplant, or SCT.

MODERATOR: Thank you for joining me, Dr. Davies.

DAVIES: Pleasure to be here.

MODERATOR: I’d like to start by asking what drew you to multiple myeloma?

DAVIES: My interest in multiple myeloma developed over 20 years ago now. At that time immunomodulatory drugs, and proteasome inhibitors, were not available, and stem cell transplant and bisphosphonate therapy were just being introduced. The median survival was less than three years, and patients developed many symptoms related to both the disease and the side effects of treatment. I felt that, in hematology, multiple myeloma was like the forgotten family member, and so I was drawn to it as I thought I could make a difference for patients; as so much needed to be done, and as so little was known about it scientifically, I thought it would be interesting to study.

MODERATOR: Thanks for sharing. That background will be relevant to the rest of our conversation. The focus of today’s conversation will be the treatment of patients with newly diagnosed multiple myeloma who are ineligible for SCT. In your experience, approximately what percentage of MM patients in your practice are ineligible for SCT?

DAVIES: Multiple myeloma is generally thought of as a disease of the elderly, with a median age of diagnosis of approximately 69 years. I work in an academic setting, and so a disproportionate number of my patients are transplant eligible. I would therefore say, in my opinion, approximately 30%-40% of my patients would be considered stem cell transplant ineligible.

MODERATOR: I see. In your experience, what are the unique challenges of treating this patient population?

DAVIES: Every patient with multiple myeloma is different and has unique challenges—that’s what makes it interesting as a physician to treat. For stem cell transplant ineligible patients, I think managing existing comorbidities and identifying emerging side effects are probably the biggest challenges.

DAVIES: I might add that weighing the risks and benefits to the patient is crucial to initiating any treatment. Choosing a regimen that can be taken until disease progression or unacceptable toxicity is especially critical for older patients who are ineligible for SCT.

MODERATOR: Since we’re talking about patients with NDMM who are ineligible for SCT, I understand that there’s some excitement in the field about a REVLIMID-dexamethasone-daratumumab, or lenalidomide-dexamethasone-daratumumab, combination, also known as DRd. But before we get to that, I’d like to discuss REVLIMID and dexamethasone data from the FIRST trial.

NARRATOR:
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.

Indication for REVLIMID + dexamethasone + daratumumab (DRd)

DRd is indicated for the treatment of adult patients with newly diagnosed MM who are ineligible for an autologous stem cell transplant.

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

Information about DRd does not appear in the REVLIMID full Prescribing Information. Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalex.com.

REVLIMID has Boxed WARNINGS for Embryo-Fetal Toxicity, 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: The FIRST trial was a large, randomized, multicenter, open-label, Phase 3 study that evaluated REVLIMID + dex until progression or unacceptable toxicity (Rd Continuous) compared to Rd fixed-cycle therapy (Rd18) or MPT, in over 1600 patients with newly diagnosed multiple myeloma who did not receive a stem cell transplant. The dose of Rd Continuous and Rd18 in the clinical trial was 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles with low-dose oral dex on Days 1, 8, 15, and 22. The dose for dex was 40 mg orally for patients ≤75 years or 20 mg orally for patients >75 years. Initial dose and regimens for Rd Continuous and Rd18 were adjusted by age and renal function.

MODERATOR: Progression-free survival was the primary endpoint. Overall survival and response rates were assessed as secondary endpoints.

MODERATOR: The median PFS in the Rd Continuous arm was 25.5 months vs 21.2 months in the MPT arm.

MODERATOR: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, deep vein thrombosis, hyperglycemia, and leukopenia. The highest frequency of infections occurred in the Rd Continuous arm (75%), compared to MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in the Rd Continuous arm than in either the MPT or Rd18 arms.

MODERATOR: How did the results from the FIRST trial affect decisions in your practice?

DAVIES: I think the FIRST trial was an important milestone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for SCT. Rd Continuous showed better PFS than MPT, and now it is the number 1 prescribed therapy in newly diagnosed multiple myeloma. The learnings about Rd Continuous from the FIRST trial were applied through the protocol amendment in the MAIA trial. I feel this is another important study for the treatment of patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant.

MODERATOR: Continuing off that thought, let’s discuss the MAIA trial, in this particular patient setting.

MODERATOR: MAIA was a Phase 3, open-label, randomized, multicenter trial of DRd vs Rd in adult patients with NDMM who were ineligible for an auto-SCT. Patients were stratified by the International Staging System, region, and age (<75 vs ≥75 years). The primary endpoint was PFS according to IMWG criteria. PFS was defined as the time from randomization to either disease progression or death. Secondary endpoints included overall response rate, minimal residual disease, and safety, among others. Information about DRd does not appear in the REVLIMID full Prescribing Information. Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalex.com.

MODERATOR: The original protocol in the MAIA trial provided for Rd dosing in the DRd arm for a maximum of 2 years. Dexamethasone was continued as a premedication for daratumumab even after Rd treatment was discontinued. The MAIA trial protocol was amended to continue Rd in the DRd arm until disease progression or unacceptable toxicity. Dose adjustments due to toxicity for REVLIMID and dexamethasone were applied according to the REVLIMID Prescribing Information.

MODERATOR: In this study, the median PFS for DRd was not reached while the median PFS for Rd was 31.9 months. The median follow-up was 28 months. The data reported a hazard ratio of 0.56, which amounts to a 44% reduction in the risk of disease progression or death with DRd vs Rd.

MODERATOR: The overall response rate was 93% for DRd and 81% for Rd. Complete response or greater was achieved for 48% of patients treated with DRd, compared to 25% of patients who received Rd. 24% of patients in the DRd arm achieved MRD-negative status, compared to 7% treated with Rd.

MODERATOR: I’d like to switch gears and discuss the safety profile of DRd.

DAVIES: Let’s do it.

MODERATOR: Shown here are the most frequent (≥20%) adverse reactions of any grade. Grade 3 or 4 hematology laboratory abnormalities in the DRd arm compared to the Rd arm included: neutropenia (DRd 56% vs Rd 39%), lymphopenia (DRd 52% vs Rd 42%), leukopenia (DRd 35% vs Rd 24%), anemia (DRd 13% vs Rd 24%), and thrombocytopenia (DRd 9% vs Rd 11%). Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%), and dehydration (DRd 2% vs Rd <1%).

MODERATOR: What’s your impression of the DRd data as observed in the MAIA trial?

DAVIES: As I mentioned earlier, it’s always important to understand the risks and benefits of any regimen when considering a treatment option for my patients. Having reviewed the data, this is a regimen I would consider for an appropriate patient with newly diagnosed multiple myeloma who was ineligible for autologous stem cell transplant. In addition, it’s important to consider regimens that can be taken until disease progression or unacceptable toxicity.

MODERATOR: Considering the results of this trial, how relevant is this to your clinical practice?

DAVIES: I find the data from the MAIA trial to be very compelling. Viewed in its totality—the PFS data, complete response rates, overall response rates, MRD negativity, and the adverse event profile from the trial—I feel that this regimen offers another treatment option with a depth of response that I would consider for my appropriate patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

MODERATOR: Following up on that thought, the percentage of patients who achieved MRD negativity in the DRd arm was 24% and was 7% in patients who received Rd. What are your thoughts for patients who achieve MRD negativity?

DAVIES: According to the amended protocol of the MAIA trial, patients were to receive a DRd or Rd regimen until disease progression or unacceptable toxicity, and that’s how I would proceed with my patients who achieve MRD negativity. Consistent with what we saw in the FIRST trial was increased PFS among patients who received continuous treatment vs fixed-cycle of REVLIMID + dexamethasone.

MODERATOR: Thank you, Doctor. Now… thinking about everything we’ve talked about in regard to DRd—the duration and depth of response, the safety profile—how do you see this regimen within the current treatment realm of options?

DAVIES: DRd offers another treatment option for adult patients with newly diagnosed MM who are ineligible for autologous stem cell transplant. Data from the MAIA and FIRST trials demonstrate that REVLIMID and dexamethasone form an effective treatment option with a known safety profile in patients with newly diagnosed multiple myeloma ineligible for SCT.

MODERATOR: Thank you for your time, Dr. Davies.

DAVIES: Thanks for having me.

MODERATOR: Here’s safety information that should be taken into consideration when evaluating this treatment regimen.

NARRATOR:
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.

Indication for REVLIMID + dexamethasone + daratumumab (DRd)

DRd is indicated for the treatment of adult patients with newly diagnosed MM who are ineligible for an autologous stem cell transplant.

Information about DRd does not appear in the REVLIMID full Prescribing Information. Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalex.com.

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.

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

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. Erythropoietin-stimulating agents (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: 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. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.

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).

Hypersensitivity: Hypersensitivity including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for these reactions. 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 (45%), 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 (20%), muscle spasms (20%), and thrombocytopenia (20%).

ADVERSE REACTIONS FOR REVLIMID + DEXAMETHASONE + DARATUMUMAB
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%).

DRUG INTERACTIONS
Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as ESAs or estrogen-containing 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.

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

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

To learn more about REVLIMID in patients with NSCT NDMM, please visit REVLIMIDHCP.com.

REVLIMID®, REVLIMID REMS®, and associated logos are trademarks of Celgene Corporation, a Bristol-Myers Squibb company.

Other trademarks are property of their respective owners.

© 2020 Bristol-Myers Squibb Company. 02/20 US-REV-19-0665

44% reduction in the risk of disease progression or death with DRd.1,2

MEDIAN PFS

REVLIMID® + dexamethasone + daratumumab Median Progression-Free Survival
DRd and Rd were continued until disease
progression or unacceptable toxicity.1

PFS was defined as the time from randomization to either disease progression or death.

The primary endpoint was PFS according to IMWG criteria.


Selected Safety Information.

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 FOR DARATUMUMAB  

  • Infusion-related reactions: Interrupt daratumumab infusion for infusion-related 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. Consider withholding daratumumab until recovery of neutrophils.
  • Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Consider withholding daratumumab until 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.
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception.

48% of patients achieved ≥CR with DRd.1

RESPONSE AND MRD-NEGATIVE RATES

REVLIMID® + dexamethasone + daratumumab Response Rate
  • ≥CR = CR + sCR
  • DRd ORR = sCR (30.4%) + CR (17.1%) + VGPR (31.8%) + PR (13.6%)
  • Rd ORR = sCR (12.5%) + CR (12.5%) + VGPR (28.2%) + PR (28.2%)
  • MRD was measured by next-generation sequencing (NGS) to 10-5
DRd and Rd were continued until disease
progression or unacceptable toxicity.1

MAIA STUDY DESIGN (N-737)1,2

REVLIMID® + dexamethasone + daratumumab Trial

MAIA was a Phase 3, open-label, randomized, multicenter trial of DRd (n=368) vs Rd (n=369) in adult patients with NDMM who were ineligible for auto-SCT. Patients were stratified by ISS stage, region, and age (<75 vs ≥75 years). The primary endpoint was PFS according to IMWG criteria. Secondary endpoints included ORR (PR, VGPR, CR, sCR), MRD, and safety, among others. The original protocol provided Rd dosing in the DRd arm for a maximum of 2 years. Dex was continued as a premedication for dara administration even after Rd treatment was discontinued.

The MAIA trial protocol was amended to continue REVLIMID in the DRd arm until disease progression or unacceptable toxicity.1,2

Dose adjustments due to toxicity for REVLIMID and dexamethasone were applied according to the REVLIMID Prescribing Information.

*The starting dose of REVLIMID was adjusted for patients with renal impairment.
Or reduced dose of 20 mg/week for patients >75 years or BMI <18.5. On daratumumab infusion days, the dexamethasone dose was given as a pre-infusion medication.

PFS was defined as the time from randomization to either disease progression or death.


auto-SCT, autologous stem cell transplantation; BMI, body mass index; CR, complete response; DRd, daratumumab + REVLIMID + dexamethasone; IMWG, International Working Group; MM, multiple myeloma; MRD, median residual response; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PFS, progression-free survival; PR, partial response; Rd, REVLIMID + dexamethasone; sCR, stringent complete response; VGPR, very good partial response.

References: 1. Daratumumab [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2019. 2. Facon T, Kumar S, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Presented at: 60th ASH Annual Meeting and Exposition; December 4, 2018; San Diego, CA.

Safety profile.

INDICATIONS

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.

 

INDICATION FOR REVLIMID + DEXAMETHASONE + DARATUMUMAB (DRd)

DRd is indicated for the treatment of adult patients with newly diagnosed MM who are ineligible for an autologous stem cell transplant. Information about DRd does not appear in the REVLIMID full Prescribing Information. Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalexhcp.com.

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. 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. Erythropoietin-stimulating agents (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: 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. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.

 

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).

 

Hypersensitivity: Hypersensitivity including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for these reactions.

 

WARNINGS AND PRECAUTIONS FOR DARATUMUMAB

  • Infusion-related reactions: Interrupt daratumumab infusion for infusion-related 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. Consider withholding daratumumab until recovery of neutrophils.
  • Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Consider withholding daratumumab until 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.
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception.

 

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 (45%), 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 (20%), 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 (4%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (54%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 20%).
  • 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 (27% 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: DRd

  • The most frequent (≥20%) adverse reactions (DRd arm) were: diarrhea (57%), upper respiratory tract infection (52%), infusion reactions (41%), constipation (41%), peripheral edema (41%), fatigue (40%), back pain (34%), nausea (32%), asthenia (32%), dyspnea (32%), cough (30%), bronchitis (29%), muscle spasms (29%), pneumonia (26%), peripheral sensory neuropathy (24%), pyrexia (23%), decreased appetite (22%).
  • Grade 3 or 4 hematology laboratory abnormalities (DRd arm) included: neutropenia (56%), lymphopenia (52%), leukopenia (35%), anemia (13%), thrombocytopenia (9%).

DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as ESAs or estrogen-containing 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, a Bristol Myers Squibb company, 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 creatinine clearance value and for 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.darzalexhcp.com.

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