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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.

DR. DAVIES: Pleasure to be here.

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

DR. 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?

DR. 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?

DR. 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.

DR. 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:

INDICATION:

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 only available through a restricted distribution program, Lenalidomide REMS.

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.darzalexhcp.com/iv.

Selected Safety Information: Boxed WARNINGS

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?

DR. 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.darzalexhcp.com/iv.

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.

DR. 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?

DR. 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?

DR. 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?

DR. 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?

DR. 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.

DR. DAVIES: Thanks for having me.

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

NARRATOR:

INDICATION:

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 only available through a restricted distribution program, Lenalidomide REMS.

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/iv.

Important Safety Information

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 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 while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID.
• 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.

Lenalidomide REMS Program: See Boxed WARNINGS. Prescribers and pharmacies must be certified with the Lenalidomide 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 (CBC) 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, including fatal reactions, have 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 angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONS FOR DARATUMUMAB

• Infusion-related reactions: Daratumumab can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported. 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%).
• 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 FOR DRd

• In newly diagnosed: 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 C_max 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 REMS Call Center 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 women 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 full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalexhcp.com/iv.

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

REVLIMID^® and its associated logo are registered trademarks of Celgene Corporation, a Bristol-Myers Squibb Company.

Other trademarks are property of their respective owners.

© 2022 Bristol-Myers Squibb Company. 07/22 2003-US-2200188

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:

INDICATION:

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 only available through a restricted distribution program, Lenalidomide REMS.

Selected Safety Information: Boxed WARNINGS

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.

INDICATION:

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 only available through a restricted distribution program, Lenalidomide REMS.

Important Safety Information

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 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 while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID.
• 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.

Lenalidomide REMS Program: See Boxed WARNINGS. Prescribers and pharmacies must be certified with the Lenalidomide 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 (CBC) 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, including fatal reactions, have 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 angioedema and anaphylaxis.

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 (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%).

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 REMS Call Center 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 women 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 full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

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

REVLIMID^® and its associated logo are registered trademarks of Celgene Corporation, a Bristol-Myers Squibb Company.

© 2022 Bristol-Myers Squibb Company. 07/22 2003-US-2200186

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 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 non-transplant candidates.

NARRATOR:

INDICATION:

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, Lenalidomide REMS.

Selected Safety Information: Boxed WARNINGS

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 takeaway 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 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.

(The following full Safety and corresponding VO will be scrolling at the end of the presentation)

INDICATION:

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, Lenalidomide REMS.

Important Safety Information

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 while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID.
• 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.

Lenalidomide REMS Program: See Boxed WARNINGS. Prescribers and pharmacies must be certified with the Lenalidomide 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 (CBC) 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, including fatal reactions, have 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 angioedema and anaphylaxis.

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%).
• 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%).

DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to increased C_max 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 REMS Call Center 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 women 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 full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

NARRATOR: To learn more about REVLIMID and the FIRST trial, please visit REVLIMIDHCP.com.

REVLIMID^® and its associated logo are registered trademarks of Celgene Corporation, a Bristol-Myers Squibb Company.

© 2022 Bristol-Myers Squibb Company. 07/22 2003-US-2200187