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About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects plasma cells and accounts for approximately 10 percent of hematologic cancers. Progress in treating the disease has focused on extending survival through stem cell transplants; however, transplants are not a cure for multiple myeloma.1 The good news for patients is there have been scientific advancements over the last two decades that have led to a shift in how multiple myeloma is treated in conjunction with transplants. 

Autologous Stem Cell Transplantation in Myeloma
Autologous stem cell transplantation (ASCT) remains the standard of care (SOC) for treating newly diagnosed multiple myeloma in young and in select, fit, elderly patients.2 Physicians continue to explore additional approaches to achieve deep and durable responses from upfront therapy for this patient population. 2 

DARZALEX® Indication for Transplant-Eligible Patients
Providing effective treatments has been a determined effort across the research community. The U.S. Food and Drug Administration (FDA) approved DARZALEX® (daratumumab) in combination with bortezomib, thalidomide, and dexamethasone (VTd) in newly diagnosed patients who are eligible for autologous stem cell transplant (ASCT). DARZALEX® is the only CD38-directed antibody approved to treat newly diagnosed, transplant-eligible multiple myeloma patients.3  


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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 indication for daratumumab in the frontline setting is based on results from the Phase 3 CASSIOPEIA trial, which demonstrated that 29 percent of newly diagnosed multiple myeloma patients achieved a stringent complete response post consolidation when treated with the combination of DVTd versus VTd alone,” added Dr. Saad Usmani, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System. “With a robust set of data in various settings, daratumumab regimens represent important treatment options for multiple myeloma patients. ”

A Closer Look at the Data
This expanded indication was based on results of the randomized, open-label, multicenter, Phase 3 CASSIOPEIA (MMY3006) study sponsored by the French Intergroupe Francophone du Myelome (IFM) in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and Janssen Research & Development, LLC.3 Primary endpoint of the trial was stringent complete response (sCR) assessed 100 days after transplant, or immediately following consolidation if greater than 100 days.3,4 Results from the study demonstrated that sCR rate was significantly higher in the DARZALEX®+VTd (29 percent) arm compared with VTd alone (20 percent) (Odds Ratio [OR] = 1.60; 95 percent confidence interval [CI], 1.21–2.12; P=0.0010).3,5 

After consolidation, DARZALEX®+VTd showed increased rate of complete response or better (39 percent vs. 26 percent) (OR = 1.82; 95 percent CI, 1.40-2.36) and very good partial response or better (83 percent vs. 78 percent) (OR = 1.41; 95 percent CI, 1.04-1.92) compared to VTd alone, respectively.3 The results demonstrated an overall response rate (ORR) of 93 percent for patients treated with DARZALEX®+VTd compared with 90 percent in the VTd arm.3

Additionally, at a median follow-up of 18.8 months patients in the DARZALEX®+VTd arm experienced a 53 percent reduction in the risk of disease progression or death vs. VTd alone [HR=0.47; 95% CI, 0.33–0.67; P<0.0001).4,5  

“The approval based on the CASSIOPEIA study marks the first CD38-directed therapy for the treatment of adult patients with newly diagnosed, transplant-eligible multiple myeloma,” said Andree Amelsberg, M.D., MBA, Vice President, U.S. Medical Affairs, Janssen Oncology. “We’re proud to build on the success of DARZALEX in the multiple myeloma frontline setting in combination with additional treatment regimens to offer healthcare providers important options in the treatment of this complex disease.”

Safety 

The most frequently reported adverse reactions in the CASSIOPEIA study (incidence ≥20 percent) were infusion-related 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.3 In the DARZALEX®+VTd combination arm, infusion-related reactions occurred in 35 percent of patients.3 See Important Safety Information below. 

Conclusion 

New developments in the understanding and treatment of multiple myeloma continue to impact patient outcomes. The CASSIOPEIA study and resulting FDA approval add to the body of evidence that DARZALEX® provides added clinical benefit to VTd in the frontline setting for all newly diagnosed transplant-eligible patients with multiple myeloma. This approval marks the seventh for DARZALEX® since it was first approved in November 2015 as a monotherapy for patients with multiple myeloma 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.3

Since its approval in 2018, more than 100,000 patients have been treated worldwide with DARZALEX®.3 

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Important Safety Information for DARZALEX® (daratumumab)

INDICATIONS

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

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

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

Infusion-Related Reactions

DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. 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, 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.

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.

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 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.

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.

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.

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. 

Please click here to see the full Prescribing Information.

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References

  1. Harousseau, J. and Moreau, P. Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med 2009; 360:2645-2654. Accessed July 2020.
  2. Hamed, R.A., Bazarbachi, A.H., Malard, F., et al. Current Status of Autologous Stem Cell Transplantation for Multiple Myeloma. Blood Cancer Journal. 2019:9:44. Accessed July 2020.
  3. DARZALEX (Prescribing Information). Horsham, PA: Janssen Biotech, Inc.
  4. Moreau, P., Attal, M., Hulim, C., et al. Phase 3 Randomized Study of Daratumumab + Bortezomib/Thalidomide/Dexamethasone (D-VTd) vs VTd​ in Transplant-eligible Newly Diagnosed Multiple Myeloma: CASSIOPEIA Part 1 Results.  Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31–June 4, 2019; Chicago, IL.
  5. Moreau P., Attal M., Hulin C., et al. Bortezomib, Thalidomide, and Dexamethasone With or Without Daratumumab Before and After Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma (CASSIOPEIA): a Randomised, Open-Label, Phase 3 Study. Lancet. 2019;394(10192):29-38.