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Combination therapy has become a common way to treat many cancers, as the complexity presented by certain types requires a variety of therapies to attack it. This is particularly true in the treatment of multiple myeloma, an incurable blood cancer that develops when plasma cells grow uncontrollably in the bone marrow.1

Approximately 32,000 people will be diagnosed with multiple myeloma in the U.S. this year alone.2 And although there has been an emergence of new treatment options over the last decade to treat this rare disease, there continues to be a need for new treatment options, particularly for those who are ineligible for stem cell transplant.3,4

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The U.S. Food and Drug Administration (FDA) recently approved DARZALEX® (daratumumab) in combination with lenalidomide and dexamethasone (Rd) for the treatment of patients with newly diagnosed multiple myeloma who are transplant ineligible. DARZALEX is a monoclonal antibody that targets CD38.5 CD38 is expressed on hematopoietic cells, other cell types and tissues, and is overexpressed on multiple myeloma cells.5 DARZALEX inhibits tumor cell growth through direct on-tumor and immunomodulatory mechanisms of actions.5 DARZALEX may also have an effect on normal cells.5

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. See additional Important Safety Information below.

“This new triplet therapy received approval less than 4 months after a supplemental Biologics License Application was submitted to the FDA,” said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. “This approval of DARZALEX underscores the significant clinical benefit of this CD38 monoclonal antibody and our efforts to advance more effective frontline treatment paradigms to change the disease course of multiple myeloma.”

The FDA based its approval on results from the randomized, open-label, multicenter Phase 3 MAIA study (MMY3008), which showed DARZALEX+Rd reduced the risk of disease progression or death by 44% in newly diagnosed patients with multiple myeloma who are transplant ineligible compared with treatment with Rd alone (Hazard Ratio [HR] = 0.56; 95 percent confidence interval [CI]: 0.43-0.73; p<0.0001).5 The median progression-free survival for DARZALEX+Rd has not yet been reached, compared with 31.9 months for patients who received Rd alone.5 The MAIA trial included 737 patients with newly diagnosed multiple myeloma ineligible for high-dose chemotherapy and transplant aged 45-90 years old.5 Investigators randomly assigned patients to receive either DARZALEX+Rd or Rd alone in 28-day cycles.5

In the study, DARZALEX+Rd demonstrated deep and durable responses in newly diagnosed multiple myeloma patients who are ineligible for transplant.5 The data showed the addition of DARZALEX resulted in an increase in the complete response rate or better compared with the Rd treatment arm (48% vs. 25%), and a 93% overall response rate was achieved with DARZALEX+Rd compared with 81% with Rd alone.5 Additionally, DARZALEX+Rd induced a minimal residual disease negativity rate that was greater than threefold higher at 24% compared with 7% with Rd alone.5

The patients who participated in this study had a median age of 73, reinforcing the importance of the data for those who are older at the time of diagnosis, as the median age of people diagnosed is approximately 69 years old.6

“This approval supports the addition of daratumumab in combination with lenalidomide and dexamethasone for newly diagnosed patients with multiple myeloma who are transplant ineligible,” added Dr. Saad Usmani, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, and MAIA study investigator. “This regimen offers an important frontline treatment option for this patient population, and it has been submitted to the NCCN Multiple Myeloma Panel for review and consideration for potential inclusion in the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®).”

The most frequent (≥20%) adverse reactions were infusion reactions, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, pyrexia, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea and cough.5 Serious adverse reactions with a 2% greater incidence in the DARZALEX+Rd arm compared with the Rd arm were pneumonia (15% vs. 8%), bronchitis (4% vs. 2%) and dehydration (2% vs. <1%), respectively.5 Treatment-emergent Grade 3/4 hematology laboratory abnormalities (≥20%) were neutropenia (56%), lymphopenia (52%) and leukopenia (35%).5 The safety profile of DARZALEX was consistent with that of previous studies.5 See Important Safety Information below.

The MAIA study and resulting FDA approval add to the existing evidence that DARZALEX provides added clinical benefit in the frontline setting for newly diagnosed patients with multiple myeloma who are transplant ineligible.5 DARZALEX was first approved for patients with newly diagnosed multiple myeloma who are transplant ineligible in May 2018 based on findings from the Phase 3 ALCYONE study in combination with bortezomib, melphalan and prednisone.5

DARZALEX is the first and only CD38 monoclonal antibody approved for multiple myeloma, including for newly diagnosed transplant ineligible patients.5 This marks the sixth FDA-approved indication for DARZALEX.5

DARZALEX is available as 100 mg/5 mL and 400 mg/20 mL strength for IV infusion.5

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Important Safety Information5

CONTRAINDICATIONS

DARZALEX® (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

Infusion Reactions – DARZALEX® 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 DARZALEX®. 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.

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 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®.

Neutropenia and Thrombocytopenia – DARZALEX® may increase neutropenia and/or thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to the 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 and/or platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors for neutropenia or transfusions for thrombocytopenia.

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.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions, neutropenia, thrombocytopenia, fatigue, asthenia, nausea, diarrhea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, bronchitis, pneumonia and upper respiratory tract infection.

DARZALEX® in combination with lenalidomide and dexamethasone (DRd): The most frequent (≥20%) adverse reactions for newly diagnosed or relapsed refractory patients were, respectively, infusion reactions (41%, 48%), diarrhea (57%, 43%), nausea (32%, 24%), fatigue (40%, 35%), pyrexia (23%, 20%), upper respiratory tract infection (52%, 65%), muscle spasms (29%, 26%), dyspnea (32%, 21%), and cough (30%, 30%). In newly diagnosed patients, constipation (41%), peripheral edema (41%), back pain (34%), asthenia (32%), bronchitis (29%), pneumonia (26%), decreased appetite (22%), and peripheral sensory neuropathy (24%) were also reported. In newly diagnosed patients, serious adverse reactions (≥2% compared to Rd) were dehydration (2%), bronchitis (4%), and pneumonia (15%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were leukopenia (35%), neutropenia (56%), and lymphopenia (52%). In relapsed/refractory patients, serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were neutropenia (53%) and lymphopenia (52%).

DARZALEX® in combination with bortezomib, melphalan, and prednisone (DVMP): The most frequently reported adverse reactions (≥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%).

DARZALEX® in combination with bortezomib and dexamethasone (DVd): The most frequently reported adverse reactions (≥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%).

DARZALEX® in combination with pomalidomide and dexamethasone (DPd): 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% of patients included pneumonia (7%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were anemia (30%), neutropenia (82%), and lymphopenia (71%).

DARZALEX® as monotherapy: The most frequently reported adverse reactions (≥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%).

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

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References

  1. American Cancer Society. “About Multiple Myeloma.” Available at: https://www.cancer.org/cancer/multiple-myeloma/about/what-is-multiple-myeloma.html. Accessed June 2019. 
  2. American Cancer Society. “Key Statistics About Multiple Myeloma.” Available at: https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed June 2019. 
  3. Diamond, E., Lahoud, OB., Landau H. Managing multiple myeloma in elderly patients. Leukemia & Lymphoma. 2017. https://doi.org/10.1080/10428194.2017.1365859. Accessed June 2019. 
  4. Rajkumar, V. Treatment of multiple myeloma. Nat Rev Clin Oncol. 2011.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773461/. Accessed June 2019.
  5. DARZALEX (Prescribing Information). Horsham, PA: Janssen Biotech, Inc.
  6. National Cancer Institute, surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Myeloma. https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed June 2019. 

Topics:

Hematologic Cancers Multiple Myeloma