Since the U.S. Food and Drug Administration (FDA) approval of DARZALEX

 (daratumumab) in 2015, the first CD38-directed antibody to treat multiple myeloma has been used in the treatment of more than 68,000 patients in the U.S. alone.

Nearly five years later, the U.S. FDA approved DARZALEX 

 (daratumumab and hyaluronidase-fihj) in May 2020, a subcutaneous formulation of daratumumab for the treatment of multiple myeloma. DARZALEX 

 follows as the only subcutaneous CD38-directed antibody approved across six indications in the front line and relapsed or refractory settings.

The fixed-dose formulation of daratumumab is administered in approximately three to five minutes, significantly less time than the original intravenous formulation, which is administered over several hours.

 was supported by findings from the Phase 3 COLUMBA (

) non-inferiority study, which showed a comparable overall response rate between patients with relapsed or refractory multiple myeloma who have received three or more prior lines of therapy taking DARZALEX

 monotherapy compared with those taking intravenous DARZALEX

 monotherapy (41 percent vs 37 percent, respectively) in patients in the third line of treatment or later. The co-primary endpoint of remaining therapeutic drug concentration (maximum C

 was also non-inferior to intravenous DARZALEX

. Findings from the study additionally demonstrated a nearly two-thirds reduction in systemic administration-related reactions (13 percent vs. 34 percent, respectively). Safety was found to be generally consistent with intravenous DARZALEX

The approval was also based on cross-study comparisons from the Phase 2 PLEIADES study (

 showed comparable clinical activity to several intravenous DARZALEX

 regimens, when used in combination with standard-of-care treatment regimens, such as bortezomib, melphalan and prednisone in newly diagnosed transplant-ineligible multiple myeloma and lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma, who had failed at least one prior therapy.

“The approval of subcutaneous daratumumab marks an important next step, providing comparable efficacy to intravenous daratumumab for approved indications spanning a wide range of newly diagnosed or relapsed and refractory multiple myeloma,” said Saad Z. Usmani, M.D., Division Chief of Plasma Cell Disorders at Levine Cancer Institute. “In clinics like mine, patients may benefit from the three to five-minute injection and the nearly three times fewer systemic administration-related reactions compared to the intravenous formulation.”

 is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation. Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX 

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

 can cause severe and/or serious infusion-related reactions including anaphylactic reactions. See Important Safety Information below.

, researchers worked to provide patients and providers with a different treatment experience for multiple myeloma patients across approved indications. Many patients will be able to receive subcutaneous administration starting with their first dose.

 is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) [Halozyme's 

 drug delivery technology]. The intravenous DARZALEX

 formulation remains available as an option for patients and their physicians.

 marks the first approval for this innovative subcutaneous formulation globally, and Janssen continues to work with health authorities around the world in an effort to bring this new treatment option to patients living with multiple myeloma.

 (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant

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, 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

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

 is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.

Hypersensitivity and Other Administration Reactions

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX 

In a pooled safety population of 683 patients with multiple myeloma (N=490) or light chain (AL) amyloidosis (N=193) who received DARZALEX 

 as monotherapy or in combination, 10% of patients experienced a systemic administration-related reaction (Grade 2: 3.5%, Grade 3: 1%). Systemic administration-related reactions occurred in 9% of patients with the first injection, 0.4% with the second injection, and cumulatively 0.8% with subsequent injections. The median time to onset was 3.2 hours (range: 9 minutes to 3.5 days). Of the 117 systemic administration-related reactions that occurred in 66 patients, 100 (85%) occurred on the day of DARZALEX 

 administration. Delayed systemic administration-related reactions have occurred in less than 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension, and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, and hypotension.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX 

. Consider administering corticosteroids and other medications after the administration of DARZALEX 

 depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

In this pooled safety population, injection-site reactions occurred in 9% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 4.7 days) after starting administration of DARZALEX 

. Monitor for local reactions and consider symptomatic management.

Daratumumab may increase neutropenia 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. In lower body weight patients receiving DARZALEX 

, higher rates of Grade 3-4 neutropenia were observed.

Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX 

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 

 with lenalidomide or thalidomide is contraindicated in pregnant women because lenalidomide and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide or thalidomide prescribing information on use during pregnancy.

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 administration. 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 are 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 

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 DARZALEX 

-treated patients with IgG kappa myeloma protein.

In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX 

 monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, pyrexia, cough, muscle spasms, back pain, vomiting, upper respiratory tract infection, peripheral sensory neuropathy, constipation, and pneumonia.

The most common hematology laboratory abnormalities (≥40%) with DARZALEX 

 are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

 to see the full Prescribing Information.

Mateos M-V et al. Efficacy and Safety of the Randomized, Open-Label, Non-inferiority, Phase 3 Study of Subcutaneous (SC) Versus Intravenous (IV) Daratumumab (DARA) Administration in Patients (pts) With Relapsed or Refractory Multiple Myeloma (RRMM): COLUMBA. 2019 American Society of Clinical Oncology Annual Meeting. June 2019.

Chari A et al. Subcutaneous Daratumumab Plus Standard Treatment Regimens in Patients with Multiple Myeloma across Lines of Therapy: Pleiades Study Update. 2019 American Society of Hematology Annual Meeting. November 2019.

Articles

Since the U.S. Food and Drug Administration (FDA) approval of DARZALEX® (daratumumab) in 2015, the first CD38-directed antibody to treat multiple myeloma has been used in the treatment of more than 68,000 patients in the U.S. alone.

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) Offers Subcutaneous CD38-Directed Antibody to Health Care Providers and Their Multiple Myeloma Patients

In 2019, more than 30,000 Americans are expected to be diagnosed with multiple myeloma, the second most common blood cancer.

 The introduction of new medicines, including proteasome inhibitors and immunomodulatory agents over the last decade, has led to significant progress for patients.

 However, despite the advancements in treatment, multiple myeloma remains an incurable disease.

 Patients are likely to relapse and become refractory to treatment over time, and physicians seek new treatment options.

 (daratumumab), a monoclonal antibody that targets CD38.

 CD38 is expressed on hematopoietic cells, other cell types and tissues, and is overexpressed on multiple myeloma cells.

 DARZALEX inhibits tumor cell growth through direct on-tumor and immunomodulatory mechanisms of actions.

 DARZALEX may also have an effect on normal cells.

 DARZALEX is approved by the U.S. Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.

 The approval of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) was based on the randomized, Phase 3 POLLUX clinical trial of 569 patients with multiple myeloma who had at least one prior line of therapy.

 The D-Rd arm (286 patients) received 25 mg of lenalidomide on days 1-21 of each 28-day Cycle, 40 mg of dexamethasone per week and 16 mg of daratumumab weekly for Cycles 1-2, every 2 weeks for Cycles 3-6 and then every 4 weeks until disease progression.

At a median follow-up of 13.5 months, D-Rd reduced the risk of disease progression or death by 63% compared to patients in the control arm (Rd) who did not receive DARZALEX.

 The median progression-free survival (PFS) for D-Rd had not yet been reached, compared to 18.4 months with Rd alone.

A significantly higher overall response rate (ORR) (91% vs 75%, respectively) was observed with the DARZALEX combination compared to Rd alone. D-Rd resulted in deeper responses, as 42.3% of patients achieved complete response (CR) or better compared to 18.8% of those in the Rd arm.

The most frequent adverse reactions (ARs) (>20%) with D-Rd were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough and dyspnea.

 Serious ARs with at least a 2% greater incidence in the D-Rd arm compared to the Rd arm were pneumonia (12% vs 10%), upper respiratory tract infection (7% vs 4%), influenza and pyrexia (3% vs 1% for each), respectively.

 Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 28% of patients in the D-Rd arm vs 23% in the Rd arm.

 Discontinuation rates due to ARs with D-Rd were similar to Rd alone (7% vs 8%, respectively).

More recently, important longer-term follow-up data have become available from the POLLUX study. In fact, data presented at the American Society of Hematology (ASH) Annual Meeting in December 2018 continued to show positive results for DARZALEX when added to a standard of care of lenalidomide and dexamethasone.

 showed that after a median follow-up of 44.3 months in the intent-to-treat (ITT) patient population treated with D-Rd, these patients had a median PFS of 3.7 years (44.5 months) compared with 1.5 years (17.5 months) among patients who received Rd alone (HR 0.44; 95% confidence interval [CI]: 0.35-0.55).

 The post-hoc analysis was not adjusted for multiplicity.

“We’ve come a long way in the treatment of multiple myeloma in the past decade. But, for those individuals battling this disease, there’s still much more to be done,” said Nizar Bahlis, M.D., Associate Professor, Arnie Charbonneau Cancer Institute, University of Calgary, and Principal Investigator of the POLLUX study sponsored by Janssen Research & Development, LLC. “The addition of DARZALEX to this current standard of care may offer an important option and a way to attack this disease.”

The follow-up data also showed that D-Rd was associated with higher cumulative response rates (based on best response):

Very good partial response or better of 80% vs 49%, respectively

In the updated analysis the median follow-up time was 44.3 months

Data are for the response-evaluable population

The post-hoc analysis was not adjusted for multiplicity

Bone marrow aspirates from subjects who maintained a CR or stringent CR were sent to the central lab for minimal residual disease (MRD) assessment at 3-, 6-, and 12-month intervals using the clonoSEQ assay v2.0 at a sensitivity threshold of 10—

 Results showed 30% of patients achieved MRD-negativity in the D-Rd arm vs 5% of patients in the Rd arm.

The most common (≥5%) Grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd were neutropenia (56%), anemia (18%), thrombocytopenia (15%), lymphopenia (6%), febrile neutropenia (6%), pneumonia (15%), diarrhea (10%), fatigue (7%), cataract (6%), hypokalemia (6%) and hypophosphatemia (6%).

 Fifteen percent of patients discontinued treatment due to TEAEs in both the D-Rd and Rd arms.

Researchers found that DARZALEX continued to show higher rates of PFS over time and higher cumulative response rates with longer-term follow-up.

 We continue to explore the addition of DARZALEX to standard of care treatment regimens across stages of the disease.

*Patients with an MRD-positive test or patients who had not undergone MRD testing were considered to be MRD positive. Sustained MRD-negativity were defined as maintenance of MRD negativity at the 10-5 threshold for >= 6 months or >= 12 months.

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

 can cause severe and/or serious infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were grade 1-2. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue 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 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.

 — 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 are 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

 may increase neutropenia 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. DARZALEX

 dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX

 is recommended. Consider supportive care with growth factors.

 may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX

 dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX

 is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response

 — Daratumumab is a human 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.

 — The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.

 in combination with bortezomib, melphalan, and prednisone (DVMP), the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (48%), infusion reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (58%), neutropenia (44%), and thrombocytopenia (38%).

 in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were neutropenia (53%) and lymphopenia (52%).

 in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (48%) and thrombocytopenia (47%).

 in combination with pomalidomide and dexamethasone, the most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Treatment-emergent hematology Grade 3-4 laboratory abnormalities ≥20% were anemia (30%), neutropenia (82%), and lymphopenia (71%).

 as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The overall incidence of serious adverse reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (40%) and neutropenia (20%).

Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX

 did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX

 with bortezomib or pomalidomide did not affect the pharmacokinetics of bortezomib or pomalidomide.

For the full U.S. Prescribing Information, please click 

American Cancer Society. What are the key statistics about multiple myeloma? 

http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-key-statistics

Multiple Myeloma Research Foundation. About Multiple Myeloma. 

Larocca, Alexxandra et al. Emerging drugs and combinations to treat multiple myeloma. 

Bahlis, NJ et al. Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial. 

DARZALEX® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.

Bahlis, Nizar et al. Three-year follow up of the Phase 3 POLLUX study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in relapsed or refractory multiple myeloma (RRMM). Paper presented at: Annual Meeting of the American Society of Hematology. December 2018; San Diego, CA.

New data presented at this year’s American Society of Hematology Annual Meeting showed that adding DARZALEX® (daratumumab) to standard of care multiple myeloma therapies may extend survival and achieve levels of minimal residual disease not previously seen.

Sponsored Content by Janssen Pharmaceutical Companies of Johnson & Johnson

Articles

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) Offers Subcutaneous CD38-Directed Antibody to Health Care Providers and Their Multiple Myeloma Patients

Seeking Ways to Extend Progression-Free Survival for Patients with Multiple Myeloma