DARZALEX® (Daratumumab) Shows Overall Survival Benefit and Continued Improvement in Progression-Free Survival in Patients with Newly Diagnosed Multiple Myeloma Who Are Ineligible for Transplant

ORLANDO, Fla., Dec. 9, 2019 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today overall survival (OS) results from the Phase 3 ALCYONE study (Abstract #859), which showed the addition of DARZALEX^® (daratumumab) to bortezomib, melphalan and prednisone (D-VMP) improved OS in patients with newly diagnosed, transplant-ineligible multiple myeloma, with a 40 percent reduction in the risk of death compared to VMP alone.¹ These updated data from the ALCYONE study also demonstrated that the addition of DARZALEX^® to VMP resulted in higher rates of minimal residual disease (MRD) negativity.¹ These data are the first OS results from the ALCYONE study and are being featured during an oral session at the 2019 American Society of Hematology (ASH) Annual Meeting in Orlando. The data were simultaneously published in The Lancet.

"As a physician treating patients with multiple myeloma, I want to achieve the deepest response in the frontline setting to hopefully provide long-term benefit," said Maria-Victoria Mateos, M.D., Ph.D., Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain, and a study investigator. "This longer follow-up from the ALCYONE study is encouraging because we see that adding daratumumab to VMP in the frontline setting can provide an important overall survival advantage compared with a current standard of care."

Results of a prespecified interim analysis, after a median duration of follow-up of more than three years, showed an estimated 42-month OS rate of 75 percent for DARZALEX^®-VMP versus 62 percent for VMP, with a statistically significant improvement in OS observed for DARZALEX^®-VMP versus VMP alone (hazard ratio [HR]=0.60; 95 percent confidence interval [CI], 0.46-0.80; P=0.0003).¹ Of note, median OS was not assessed in either group and follow-up is ongoing. In addition, DARZALEX^®-VMP resulted in a median progression-free survival (PFS) of 36.4 months versus 19.3 months with VMP alone after a median follow-up of 40.1 months (HR=0.42; 95 percent CI, 0.34-0.51; P<0.0001).¹ The results also demonstrated that DARZALEX^®-VMP achieved significantly higher rates of MRD-negativity compared to VMP alone (28 percent vs. 7 percent, respectively) at a threshold of one tumor cell per 10^-5 white cells.¹

The most common Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥3 percent for DARZALEX^®-VMP arm compared to the VMP arm included neutropenia (40.2 percent vs. 39 percent), thrombocytopenia (34.7 percent vs. 37.9 percent), anemia (17.3 percent vs. 19.8 percent) and pneumonia (13 percent vs. 4.2 percent).¹ Grade 5 TEAEs were 6.9 percent in the DARZALEX^®-VMP treatment arm compared with 5.6 percent in the VMP arm and discontinuation due to TEAEs was 6.9 percent in the DARZALEX^®-VMP arm vs. 9.3 percent in the VMP arm, and the rate of invasive second primary malignancy in the DARZALEX^®-VMP vs. VMP treatment arms were 4.9 percent vs. 4.5 percent, respectively.¹ No new safety concerns were identified.¹

Additional data from longer follow-up (median of 36.4 months) from the Phase 3 MAIA study (Abstract #1875) presented at ASH 2019 demonstrated DARZALEX^® in combination with lenalidomide and dexamethasone continued to significantly reduce the risk of disease progression or death by ≥44 percent in patients with newly diagnosed multiple myeloma who are transplant ineligible, compared to treatment with Rd alone (HR = 0.56; 95 percent CI: 0.44-0.71; P<0.0001), with no new safety concerns after three years of follow-up with DARZALEX^®-Rd.² Additionally, time from randomization to progression on next-line treatment or death (PFS2) favored the DARZALEX^® arm (HR = 0.69; 95 percent CI, 0.53-0.91; P=0.0079).² 

Common Grade 3/4 TEAEs occurring in ≥10 percent of patients in the DARZALEX^®-Rd arm compared to the Rd arm were neutropenia (51 percent vs. 35 percent), lymphopenia (15 percent vs. 11 percent), pneumonia (15 percent vs. 9 percent), anemia (14 percent vs. 21 percent), leukopenia (11 percent vs. 6 percent) and hypokalemia (10 percent vs. 10 percent), respectively.² The most common serious TEAE in the DARZALEX^®-Rd arm compared to the Rd arm was pneumonia (14 percent vs. 9 percent, respectively).² The most common Grade 3/4 infection rates were 36 percent in the DARZALEX^®-Rd treatment arm compared with 27 percent in the Rd arm.² In the DARZALEX^®-Rd arm, 9 percent of patients discontinued treatment due to TEAEs, compared with 18 percent of patients in the Rd arm.²  

"The data we are presenting at ASH demonstrate the benefit of DARZALEX-based regimens in the frontline setting as supported by deep, durable responses and significantly prolonged survival," said Yusri Elsayed, M.D., MHSc., Ph.D., Vice President, Hematologic Malignancies Disease Area Leader, Janssen Research & Development, LLC. "We remain committed to the study of DARZALEX with the goal of making a difference in the lives of patients diagnosed with multiple myeloma."

About the ALCYONE Study¹
The randomized, open-label, multicenter Phase 3 ALCYONE (MMY3007) study enrolled 706 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem cell transplant (ASCT). The median age was 71 years (range: 40-93). Patients were randomized to receive up to nine cycles of either DARZALEX^®-VMP or VMP alone. In the DARZALEX^®-VMP arm, patients received 16 mg/kg of DARZALEX^® once weekly for the first six weeks (Cycle 1), followed by once every three weeks for the next 48 weeks (Cycles 2–9). Following the nine cycles, patients in the DARZALEX^®-VMP arm continued to receive 16 mg/kg of DARZALEX^® once every four weeks until disease progression.

About the MAIA Trial²
The randomized, open-label, multicenter Phase 3 study included 737 newly diagnosed patients aged 45-90 years old (median age of 73) with multiple myeloma ineligible for high-dose chemotherapy and ASCT. Patients were randomized to receive either DARZALEX^®-Rd or Rd alone in 28-day cycles. In the DARZALEX^®-Rd treatment arm, patients received DARZALEX^® 16 mg/kg IV weekly for cycles 1–2, every two weeks for cycles 3–6 and every 4 weeks for cycle 7 and thereafter.

About DARZALEX^® 
DARZALEX^® (daratumumab), the first CD38-directed antibody approved anywhere in the world, is the only CD38-directed antibody approved to treat multiple myeloma.³ CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.⁴ DARZALEX^® binds to CD38 and inhibits tumor cell growth causing myeloma cell death.³ DARZALEX^® may also have an effect on normal cells.³ DARZALEX^® is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.^{5,6,7,8,9,10,11,12} Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such as smoldering myeloma.^13,14

In the U.S., DARZALEX^® received initial FDA approval 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.¹⁵ DARZALEX^® received additional approvals in November 2016 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.¹⁶ In June 2017, DARZALEX^® received approval in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI.¹⁷ In May 2018, DARZALEX^® received approval in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT, making it the first monoclonal antibody approved for newly diagnosed patients with this disease.¹⁸ In June 2019, DARZALEX^® received approval in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are transplant ineligible.¹⁹ In September 2019, DARZALEX^® received approval in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT.²⁰

In August 2012, Janssen Biotech, Inc. entered into a global license and development agreement with Genmab A/S, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX^®.²¹ For the full U.S. Prescribing Information, please visit www.DARZALEX.com.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.^22,23 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow. In 2019, it is estimated that 32,110 people will be diagnosed and 12,960 will die from the disease in the U.S.²³ While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.²⁴

DARZALEX^® IMPORTANT SAFETY INFORMATION

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%), peripheral sensory neuropathy (24%), and decreased appetite (22%) were also reported. In newly diagnosed patients, serious adverse reactions (≥2% compared to Rd) were pneumonia (15%), bronchitis (4%), and dehydration (2%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were neutropenia (56%), lymphopenia (52%), and leukopenia (35%). 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 bortezomib, thalidomide, and dexamethasone (DVTd): The most frequent adverse reactions (≥20%) were infusion reactions (35%), nausea (30%), upper respiratory tract infection (27%), pyrexia (26%), and bronchitis (20%). Serious adverse reactions (≥2% compared to the VTd arm) were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (59%), neutropenia (33%), and leukopenia (24%).

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 neutropenia (82%), lymphopenia (71%), and anemia (30%).

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%).

Please click here to see the full Prescribing Information.

About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenGlobal. Janssen Research & Development, LLC and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding the benefits of DARZALEX^® (daratumumab) for the treatment of patients with multiple myeloma. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2018, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in the company's most recently filed Quarterly Report on Form 10-Q and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither the Janssen Pharmaceutical Companies of Johnson & Johnson nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 

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