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This is a nonaccredited promotional activity. This program was developed and approved by Janssen Biotech Incorporated.
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Faculty are compensated to present this information on behalf of the company and must do so in compliance with the US Food and Drug Administration regulations.
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INDICATIONS
DARZALEX® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:
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In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
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Select Important Safety Information.
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CONTRAINDICATIONS
DARZALEX® is contraindicated in patients with a history of severe hypersensitivity, for example, anaphylactic reactions, to daratumumab or any of the components of the formulation.
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Warnings and Precautions: Infusion-Related Reactions
DARZALEX® can cause severe and or serious infusion-related reactions including anaphylactic reactions. These
reactions can be life-threatening, and fatal outcomes have been reported.
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Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening Grade 4 reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.
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Additional Important Safety Information will be reviewed later in this video.
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Please see full Prescribing Information available on this website.
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Do you know how important the duration of frontline DRd treatment is for managing patients with newly diagnosed, transplant-ineligible multiple myeloma?
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Hello, I’m Dr. Fanning.
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Join me as we discover why continuous treatment with frontline DARZALEX® plus lenalidomide and dexamethasone, also known as DRd, is a proven path for newly diagnosed patients with transplant-ineligible multiple myeloma.
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Our first topic will cover the importance of frontline treatment in multiple myeloma and why it is an ideal opportunity for achieving deep response. Next, we’ll shift to topics on DARZALEX® treatment, starting with the results of the MAIA trial that studied continuous treatment with frontline DRd versus Rd, or lenalidomide and dexamethasone alone. Once we’ve covered that, we’ll take a closer look at a post hoc subset analysis of DRd and Rd treatment duration and patient outcomes.
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This subset analysis covers patients treated for at least 18 months and we’ll get a better understanding about maintaining treatment benefits with frontline DRd, looking specifically at time to deepest response and safety over time.
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Research demonstrates that the depth of response patients achieve worsens with later lines of therapy. For example, in this retrospective study conducted in 7 European countries, 435 physicians reviewed 4,997 patient charts to map the course of patients with multiple myeloma and to investigate the factors that influence treatment decisions at different stages of the treatment journey. Depth of response, as assessed by the treating physician, was evaluated at each subsequent line of therapy. Profiles of patients with multiple myeloma during the last 12 months were similar across study sites.
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The likelihood of achieving deep response was found to decrease with subsequent lines of treatment for patients with multiple myeloma. The proportion of patients achieving a complete response decreased from 32% at frontline to 4% at fourth line and 2% at fifth line. Similarly, 74% of patients achieved at least a very good partial response with the frontline treatment, compared with only 11% with the fifth line or later. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice. As you can see, frontline treatment is the most appropriate time to aim for deep response compared with later lines of treatment.
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Before we look at the data, let’s get a good understanding of the trial design.
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MAIA was a large, randomized, open-label, multicenter, active-controlled, phase 3 trial that compared DRd vs Rd in a wide range of adult patients with newly diagnosed, transplant-ineligible multiple myeloma. Three hundred sixty-eight patients were randomized to the DRd arm, and three hundred sixty-nine patients were randomized to the Rd arm. Treatment was continued until disease progression or unacceptable toxicity.
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The primary endpoint was progression-free survival.
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Key secondary endpoints included rates of complete response or better, rates of very good partial response or better, rates of minimal residual disease-negativity, overall response rate, overall survival, duration of response, and safety.
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Baseline demographics and disease characteristics were similar between the 2 treatment groups. In the DRd arm, the median age of patients was 73 years. Thirty-four percent had an Eastern Cooperative Oncology Group Performance Status, or ECOG PS, of 0, 50% had an ECOG PS of 1, and 17% had an ECOG PS of 2 or more. Twenty-seven percent had International Staging System, or ISS, Stage I, 43% percent had ISS Stage II, and 29% percent had ISS Stage III disease.
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Now that we have looked at how the MAIA trial was designed, let’s review the primary results of the trial, which showed that frontline DRd significantly reduced the risk of disease progression or death in patients after 28 months of follow-up.
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Median PFS was not reached with DRd vs 31.9 months with Rd alone. The hazard ratio was 0.56, with a 95% confidence interval that ranged from 0.43 to 0.73. These results were significant, with a P-value of less than 0.0001.
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This translates to a 44% risk reduction for disease progression or death with DRd vs Rd alone.
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The median duration of study treatment was 25.3 months (range 0.1 to 40.44 months) in the DRd group and 21.3 months (range 0.03 to 40.64 months) in the Rd group.
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Now let’s look at long-term progression-free survival.
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After a median follow-up of 64 months, patients were progression-free longer with DRd vs Rd alone.
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The median PFS was 61.9 months with a 95% confidence interval that ranged from 54.8 to not estimable with DRd, versus 34.4 months with a 95% confidence interval that ranged from 29.6 to 39.2 with Rd alone.
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The hazard ratio was 0.55 with a 95% confidence interval that ranged from 0.45 to 0.67.
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This translates to a 45% risk reduction for disease progression or death with DRd vs Rd alone.
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Now, let’s look at the additional efficacy results of overall response rate from the MAIA trial.
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As you can see, a 93% overall response rate was achieved with DRd after a median follow-up of 28 months.
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The median time to response was 1.05 months with DRd with a range from 0.2 to 12.1 months. With Rd the range was from 0.3 to 15.3 months.
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And the median duration of response was not reached with DRd vs 34.7 months with Rd alone, with a 95% confidence interval that ranged from 30.8 to not estimable.
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It is important to note that approximately 50% of patients in the MAIA trial achieved complete response or better with frontline DRd.
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That’s nearly 2 times greater than Rd alone.
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In addition to efficacy, the safety of adding DARZALEX® to lenalidomide and dexamethasone was also evaluated. Adverse reactions you are seeing reflect exposure to DARZALEX® plus Rd for a median treatment duration of 25.3 months and Rd for 21.3 months, as reported in the primary analysis.
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The most frequently reported adverse reactions were diarrhea, upper respiratory tract infection, infusion-related reactions, constipation, peripheral edema, and fatigue.
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Infusion-related reactions with DRd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4. Infusion-related reactions of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion. Most infusion-related reactions occurred during the first infusion.
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Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared with the Rd arm were pneumonia, bronchitis, and dehydration.
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The most frequently reported hematologic laboratory abnormalities were neutropenia, leukopenia, lymphopenia, thrombocytopenia, and anemia.
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Hematologic abnormalities were more prevalent in the DARZALEX® plus Rd arm compared to the Rd arm, except for anemia, which showed a lower incidence in the DARZALEX® plus Rd arm.
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DARZALEX® can cause severe and/or serious infusion-related reactions, including anaphylactic reactions. In clinical trials (monotherapy and combination: N=2,066), infusion-related reactions, occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3 or 4 infusion-related reaction at Week 2 or subsequent infusions.
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Before we move to our next topic on treatment duration and patient outcomes, let’s consider the case of this hypothetical patient. This is Mindy. Imagine she’s a patient in your practice being treated with frontline therapy. She could be a good candidate for the benefits of maintaining treatment on DRd. Let’s consider her case.
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Mindy’s multiple myeloma was diagnosed 12 months ago following lower back and neck pain and was put on frontline DRd. She was ISS disease stage II and her ECOG PS score was 1. She was also on treatment for early-stage Parkinson’s.
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Given her condition and disease presentation, Mindy was considered ineligible for transplant.
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She is currently continuing her treatment with DRd.
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When you start a patient like Mindy on frontline DRd, are you keeping them on treatment until disease progression or unacceptable toxicity, as was done for patients in the MAIA trial?
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Now, let’s shift our attention to a post hoc subset analysis of treatment duration and patient outcomes.
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It’s important to note that this information is not included in the current Prescribing Information and has not been evaluated by the FDA.
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Additionally, no conclusions should be drawn. These data should be understood in the context of the methodology.
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Let’s first look at the methodology of this post hoc subset analysis. To explore the impact of treatment duration on long-term clinical outcomes, a post hoc analysis was conducted based on DRd treatment duration (<18 vs 18 months), excluding patients who discontinued therapy due to disease progression during the first 18 months.
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The DRd arm included 283 patients who were treated for at least 18 months, out of 368 patients of the primary intent-to-treat (ITT) analysis of the MAIA trial. The Rd arm included 204 patients, who were treated for at least 18 months, out of 369 patients of the primary ITT analysis of the MAIA trial.
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Response data presented are cumulative deepest response rates achieved by 6, 9, and 18 months for patients who continued all trial treatment for at least 18 months.
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As you can see, more patients achieved complete response or better by 18 months vs 6 months of DARZALEX® + Rd treatment.
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Rates of complete response or better increased over 6, 9, and 18 months of continuous frontline DRd.
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Approximately 50% of patients achieved complete response or better by 18 months of DRd treatment compared with approximately 9% by 6 months of treatment.
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Post hoc subset analysis of the Rd treatment group also showed that more patients achieved complete response or better by 18 months vs 6 months.
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Rates of complete response or better increased over 6, 9, and 18 months of continuous frontline Rd.
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Approximately 30% of patients achieved complete response or better by 18 months of Rd treatment compared with approximately 4% by 6 months of treatment.
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You can see from the results presented that more patients achieved a complete response or better with DRd by 18 months vs Rd alone. Forty-nine point eight percent of the patients receiving DRd achieved complete response or better by 18 months vs 30.4% receiving Rd.
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This post hoc subset analysis shows the increase in complete response rates over 6, 9, and 18 months with continuous frontline DRd.
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Getting back to the hypothetical patient, Mindy, the duration of treatment may be an important consideration for her multiple myeloma treatment.
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If patients like Mindy do not stay on their treatment beyond 6 months, or even 9 months of therapy, they may not experience the benefits achieved by 18 months of therapy.
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Let’s take a closer look at another post hoc subset analysis that evaluated frequently reported adverse events over time for patients who continued their treatment.
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It’s important to note that this information is not included in the current Prescribing Information and has not been evaluated by the FDA.
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Additionally, no conclusions should be drawn. In the following analysis, treatment-emergent adverse events are presented as observed and should be understood in context with the specific methodology.
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First, let’s review some of the methodology for this analysis. Most frequently reported treatment-emergent adverse events, or TEAEs, that met the threshold of cumulative any-grade greater than or equal to 30%, or Grade 3 or 4 greater than or equal to 10%, are presented here.
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Combined TEAE rates are the sum of the percentages of the most frequently reported events at each cycle period.
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Percentages represent the number of patients with one or more TEAEs by treatment cycle divided by the total number of patients treated within the treatment window.
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Only TEAEs with an onset date falling within the cycle intervals were calculated. Each patient was calculated once per preferred term for each cycle interval. The same patient could be calculated in multiple cycle intervals and for multiple preferred terms. TEAEs may not have resolved by the next cycle.
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Decrease in adverse event rates, or AE rates, over time from treatment initiation was observed for most AEs in both treatment arms. Cataract tended to increase over time in both treatment arms.
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Thirteen percent of intent-to-treat patients discontinued treatment due to a TEAE with DRd vs 22% of the patients with Rd alone.
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In patients who continued treatment, most AE rates decreased over time from treatment initiation to ~30 months for DRd.
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In the Rd arm, patients who continued treatment also experienced decreased AE rates over time from treatment initiation to approximately 30 months.
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You can now see the observed overall AE rates for DRd, which are combined rates of most frequent AEs per treatment cycle.
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When you examine the chart, you can see that in patients who continued treatment, combined rates of frequently reported TEAEs decreased over time from treatment initiation to approximately 30 months for DRd.
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In patients who continued treatment, combined rates of frequently reported TEAEs decreased over time from treatment initiation to approximately 30 months for Rd.
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As an oncologist, you have the opportunity at the time of treatment initiation to set duration of therapy expectations with your patient. This important conversation can help ensure that both you and your patients like Mindy are on the same page in terms of what to expect throughout the course of therapy.
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Before I conclude this video on Advancing Frontline Knowledge and present the summary, I would like to share the Important Safety Information about DARZALEX®.
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IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
DARZALEX® is contraindicated in patients with a history of severe hypersensitivity. For example, anaphylactic reactions to daratumumab or any of the components of the formulation.
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WARNINGS AND PRECAUTIONS
Infusion-Related Reactions
DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3 or 4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision.
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When DARZALEX® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.
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Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.
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To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.
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Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX® infusion. If ocular symptoms occur, interrupt DARZALEX® infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX®.
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Interference With Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test).
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Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX®. Type and screen patients prior to starting DARZALEX®.
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Neutropenia and Thrombocytopenia
DARZALEX® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX® until recovery of neutrophils or for recovery of platelets.
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Interference With Determination of Complete Response
Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.
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Embryo-Fetal Toxicity
Based on the mechanism of action, DARZALEX® can cause fetal harm when administered to a pregnant woman. DARZALEX® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX® and for 3 months after the last dose.
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The combination of DARZALEX® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.
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ADVERSE REACTIONS
The most frequently reported adverse reactions (incidence ≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.
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INDICATIONS
DARZALEX® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:
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In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
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In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.
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In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant.
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In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.
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In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.
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In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
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As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
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Please see full Prescribing Information available on this website.
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In summary, in the treatment of newly diagnosed, transplant-ineligible multiple myeloma, we have seen the benefit of progression-free survival with frontline DRd vs Rd therapy after 28 months and 64 months of follow up.
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We also looked at a post hoc subset analysis of patients who stayed on their treatment for 18 months. We saw that more patients achieved complete response or better at 18 months with DRd and Rd vs 6 months of DRd and Rd.
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For the best chance of achieving progression-free survival seen in the MAIA trial, patients should be treated with DRd until disease progression or unacceptable toxicity.
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Based on this body of evidence from the MAIA trial supporting use of continuous DRd treatment, are you ready to keep your newly diagnosed transplant-ineligible patients on a proven path with DARZALEX® + Rd?
