You’re listening to ReachMD. This medical industry feature titled, "DARZALEX® (daratumumab) in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma: 5-Year Update of the MAIA Study", is brought to you by Janssen Pharmaceuticals, Inc.
Here’s your host, Dr Charles Turck.
This is ReachMD. I’m Dr Charles Turck, and today, we’re joined by Dr Noa Biran, who is an Associate Professor of Medicine at the Department of Medicine at the Hackensack Meridian School of Medicine. Dr Biran is here to talk us through the results from the phase 3 MAIA study, which show the addition of DARZALEX® (or, daratumumab) to lenalidomide and dexamethasone resulted in a statistically significant progression-free survival benefit over lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant and were treated until disease progression, only after the primary 3-year analysis. Furthermore, additional follow-up data was recently published for the 5-year analysis.
Dr Biran let’s dive right in and talk about patients that are ineligible for transplant. What do we need to know about selecting the right treatment upfront?
So as we know, for most patients, the course of disease with multiple myeloma is characterized by multiple relapses. With each successive line of therapy, attrition rates increase.
A retrospective analysis published by Fonseca et al of 3 US databases, the OPTUM™ Commercial Claims database, the OPTUM™ Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Medicare Linked database, looked at patients with newly diagnosed multiple myeloma who did not receive stem cell transplant at any time during follow-up.
For each line of therapy, the proportion of patients receiving a subsequent line of therapy decreased by approximately 50 percent.
So based on this, we know that it can be particularly important to select an effective treatment option in the frontline setting for patients who are not eligible for a transplant as there are fewer opportunities to treat with proven regimens with each successive line of therapy.
Dr Biran, as we know, when it comes to newly diagnosed patients with multiple myeloma who are ineligible for transplant, the MAIA trial supports the use of DARZALEX® (or, daratumumab) in combination with lenalidomide and dexamethasone, or DRd. So, let’s get a better understanding of this treatment option.
But before we dive into our discussion, let’s first review the contraindications, warnings, and precautions for DARZALEX®.
DARZALEX® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:
- 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
- In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
- In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
- In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
- In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
- In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
- 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
Now Dr Biran, could you please tell us a little bit about DARZALEX® and DRd?
Certainly. DARZALEX® is an anti-CD38 antibody that is now approved across multiple lines of therapy in multiple myeloma, including three frontline regimens. As you mentioned, DRd is approved in newly diagnosed patients with multiple myeloma who are ineligible for transplant.
Now, let’s dig a little deeper into the MAIA trial, which supports the use of frontline therapy with DRd in transplant ineligible patients. The 5-year follow-up data, as presented at the European Hematology Association (or, EHA) 26th Annual Congress in 2021, showed the impact of adding DARZALEX® to Rd on overall survival. Could you briefly describe the MAIA study and what makes it important?
Of course. So, the MAIA study established the efficacy and safety of DARZALEX® plus Rd in newly diagnosed, transplant ineligible multiple myeloma. It is a phase 3, open-label, randomized, active-controlled trial in 737 patients with newly diagnosed, transplant-ineligible multiple myeloma.
In this study, key inclusion criteria included an Eastern Cooperative Oncology Group performance status of zero to two and a creatinine clearance of 30 mL/min or higher.
Patients were randomized, 1:1, to receive either DRd or Rd. In the interventional arm, patients received DARZALEX® 16 mg per kg by intravenous infusion, weekly for Cycles 1 through 2, every two weeks for Cycles 3 through 6, and every four weeks for Cycles 7 and beyond, in combination with oral lenalidomide 25 mg daily on Days 1 through 21 and oral dexamethasone 40 mg weekly (or a reduced dose of 20 mg/week for patients >75 years of age or with a body mass index <18.5). The active control arm consisted of oral lenalidomide 25 mg daily on Days 1 through 21 and oral dexamethasone 40 mg weekly (or a reduced dose of 20 mg/week for patients >75 years of age or with a body mass index <18.5). Patients in both arms continued treatment until either their disease progressed, or unacceptable toxicity occurred.
The primary endpoint was progression-free survival. And key secondary endpoints included complete response or better, very good partial response or better, rate of minimal residual disease, or MRD, negativity, overall response rate, overall survival, and safety.
The demographic and clinical characteristics of the two groups were similar at baseline: the median age for both arms was 73 years (range, 45-90); the majority of patients were white, about 92 percent; and 52 percent were male.
Now, given all of this information, we know that the MAIA trial is important because it examined the combination of DARZALEX® with a current standard of care. It also enrolled an older patient population, of which 44 percent were over the age of 75.
As you previously mentioned, the primary endpoint of the MAIA study was progression-free survival, or PFS. With that in mind, what can you tell us about the efficacy of DARZALEX® plus Rd?
Yes, so based on International Myeloma Working Group (IMWG) criteria, the primary endpoint was PFS, defined as time from randomization to either disease progression or death, whichever occurred first.
Keep in mind that in the primary analysis at a median follow-up of approximately 30 months, the median duration of treatment was 25.3 months in the DRd arm and 21.3 months in the Rd arm.
Patients in the DARZALEX® plus Rd arm demonstrated a significant improvement in PFS compared with patients in the Rd arm. This translated to a 44 percent reduction in the risk of disease progression or death with the DRd combination versus Rd alone (hazard ratio [HR]=0.56; 95% confidence interval [CI], ranging 0.43-0.73, P<0.0001).
And at 30 months, about 70.6 percent (95% CI, 65-75.4) of patients showed no disease progression in the DRd arm compared with 55.6 percent (with a 95% CI, ranging 49.5-61.3) of patients in the Rd arm.
As we mentioned earlier, we now have the five-year follow-up of efficacy and safety data from the MAIA trial that was presented at the 2021 EHA Annual Congress. Data on overall survival in the MAIA trial was presented for the first time at this meeting. I want to point out that these results are not included in the current Prescribing Information and have not been evaluated by the US Food and Drug Administration (FDA). Patients in both treatment arms were treated until disease progression.
Overall survival was a secondary endpoint of the MAIA study. After almost five-years of follow-up, 66 percent of patients were still alive with DRd (95% CI, ranging 61-71) versus just 53 percent with Rd (95% CI, ranging 47-59) alone. This translated into a 32 percent reduction in the risk of death with DRd versus Rd alone (HR=0.68; with a 95% CI, ranging 0.53-0.86, and, P=0.0013).
Now let’s look at progression-free survival. The 60-month progression-free survival rate was 52.5% in the DRd arm versus 28.7% in the Rd arm. This represented a 47 percent reduction in the risk of disease progression or death with DRd versus Rd alone. The median progression-free survival was not reached in the DRd arm versus 34.4 months in the Rd arm (HR=0.53; with a 95% CI, ranging 0.43-0.66). Please keep in mind that the 60-month analyses are not included in the FDA-approved Prescribing Information. The 60-month progression-free survival results were not adjusted for multiple comparisons, and no conclusions should be drawn.
In addition, overall survival was a prespecified analysis that has not been yet reviewed by the FDA.
What about the response rates evaluated in the MAIA trial? Could you tell us a little bit about those findings?
Yes, absolutely. In the primary analysis of the MAIA trial, with a follow-up time of approximately 30 months, the DRd arm showed a significant improvement in response rates at 93 percent compared with 81 percent in the Rd arm, with a P-value of less than 0.0001.
Now when we look at the depth of response, nearly twice as many patients achieved a complete response or stringent complete response, 48 percent with DRd versus 25 percent with Rd alone, after a median follow-up of 30 months.
Another secondary endpoint we should keep in mind was the assessment of MRD, which was evaluated at a threshold of 1 tumor cell per 10 to the negative 5 cells in the bone marrow.
Consistent with the higher rates of complete or stringent complete response, the MRD negativity rate was greater with DRd at 24 percent versus 7 percent in the Rd arm.
It’s very encouraging to see the efficacy results in the MAIA trial. Dr Biran, let’s take a look at the safety profile of DARZALEX® plus Rd. What are some of the most common and serious adverse reactions observed in this study? And were there any new safety signals detected after the five-year follow-up?
In the first analysis at a median treatment duration of 25.3 months, the most frequent adverse reactions occurring in 20 percent or greater were infusion-related reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infections, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea, and cough. Adverse reactions that occurred with a frequency between 10 and 20 percent, and with at least a 5 percent greater frequency in the DRd arm, were headache, urinary tract infection, hyperglycemia, hypocalcemia, vomiting, chills, paresthesia, and hypertension.
Serious adverse reactions with a 2 percent greater incidence in the DRd arm compared with the Rd arm were pneumonia, bronchitis, and dehydration.
Patients also experienced treatment-emergent hematologic laboratory abnormalities from baseline in both arms. Except for anemia, which showed a lower incidence in the DRd arm, about 47 percent, when compared with the Rd arm, with an incidence rate of 57 percent, all other hematologic abnormalities were more prevalent in the DRd arm compared with the Rd arm: neutropenia (91% vs 77%), leukopenia (90% vs 82%), lymphopenia (84% vs 75%), and thrombocytopenia (67% vs 58%).
We’ve certainly covered a lot of information, so I’d like to thank Dr Noa Biran for taking us through the MAIA trial and providing her insights on the impact of DARZALEX® plus Rd in patients with newly diagnosed multiple myeloma who are ineligible for transplant.
Thank you, Dr Biran for this insightful discussion.
My pleasure. It was nice to be here. Thank you.
Now before we close, let’s review some important safety information for DARZALEX®.
IMPORTANT SAFETY INFORMATION
DARZALEX® 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
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 3/4 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.
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.
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.
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.
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®.
Interference With Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). 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®.
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.
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.
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.
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.
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.
Thank you, Dr Biran and listeners.
Please see the full Prescribing Information for DARZALEX® available via the podcast host page or at www.darzalexhcp.com.
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