Application sup­ported by the Phase 3 MAIA study being reviewed under the FDA Real-Time Oncology Review pilot pro­gram

{{image}}Raritan, NJ (Press Release) – The Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson announced today the sub­mission of a supple­mental Biologics License Application (sBLA) to the U.S. Food and Drug Admin­istra­tion (FDA) seeking approval of DARZALEX® (dara­tu­mu­mab) in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone (Rd) for the treat­ment of patients with newly diag­nosed multiple myeloma who are in­eli­gible for au­tol­o­gous stem cell trans­plant (ASCT).

The sBLA, based upon data from the Phase 3 MAIA (MMY3008) clin­i­cal study, is being reviewed by the FDA under the Real-Time Oncology Review (RTOR) pilot pro­gram, which for certain appli­ca­tions allows the FDA to review data before the applicant formally submits the com­plete appli­ca­tion. It aims to explore a more efficient review process to help ensure treat­ments are avail­able as soon as possible for patients. Selection into the RTOR pilot pro­gram does not guar­an­tee or influence approvability of the supple­mental appli­ca­tion.

"We are pleased to com­plete the latest DARZALEX sub­mission based upon the Phase 3 MAIA study, which eval­u­ated the efficacy and safety of this anti-CD38 mono­clonal anti­body as a com­bi­na­tion regi­men for newly diag­nosed patients with multiple myeloma who are trans­plant in­eli­gible," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Vice Pres­i­dent, Hematologic Malignancies Disease Area Leader, Janssen Research & Development, LLC. "We look for­ward to closely col­lab­o­rating with the Agency through­out the expedited Real-Time Oncology Review process in sup­port of this newly diag­nosed, trans­plant in­eli­gible multiple myeloma patient pop­u­la­tion for whom a com­bi­na­tion treat­ment regi­men with DARZALEX may be useful."

Data from the Phase 3 MAIA study were presented at the 2018 American Society of Hematology (ASH) Annual Meeting and featured in the Late-Breaking Abstract session. The study found that at a median follow-up of 28 months, DARZALEX-Rd reduced 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 (Hazard Ratio [HR] = 0.56; 95 per­cent con­fi­dence in­ter­val [CI]: 0.43-0.73; p<0.0001).¹ The median pro­gres­sion-free survival for DARZALEX-Rd has not yet been reached, com­pared to 31.9 months for patients who received Rd alone.¹ The addi­tion of DARZALEX resulted in deeper responses com­pared to Rd alone, in­­clud­ing in­­creased rates of com­plete response or better (48 per­cent vs. 25 per­cent).1 An im­proved over­all response rate was also dem­onstrated (93 per­cent vs. 81 per­cent).¹

The most common Grade 3/4 treat­ment-emergent adverse events for DARZALEX-Rd (≥10 per­cent) in­cluded neu­tro­penia (50 per­cent), lymphopenia (15 per­cent), pneu­monia (14 per­cent) and anemia (12 per­cent).¹ Infusion-related reac­tions occurred in 41 per­cent of patients, three per­cent of which were Grade 3/4.¹ The safety profile of DARZALEX was con­sis­tent with that of pre­vi­ous studies.¹

About the Real-Time Oncology Review Program

The RTOR pilot pro­gram aims to explore a more efficient review process to ensure safe and effective treat­ments be­come avail­able to patients earlier while main­taining the quality of review. Applications are subject to the usual benefit-risk evaluation by FDA scientists. The RTOR pilot pro­gram is specific to the U.S. regu­la­tory path­way.

About the MAIA Trial¹

The ran­dom­ized, open-label, multi­center, Phase 3 study in­cluded 737 newly diag­nosed patients with multiple myeloma in­eli­gible for high-dose chemo­ther­apy and ASCT aged 45 – 90 years old (median age of 73). 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 milligrams per kilo­gram (mg/kg) IV weekly for Cycles 1 – 2, every two weeks for Cycles 3 – 6 and every 4 weeks for Cycle 7 and there­after. Patients in the DARZALEX-Rd and Rd treat­ment arm received 25 mg of lena­lido­mide on Days 1 – 21 of each 28-day Cycle, and dexa­meth­a­sone at 40 mg once a week for each Cycle. Patients in both treat­ment arms con­tinued until disease pro­gres­sion or unacceptable toxicity.

About DARZALEX® (dara­tu­mu­mab)

DARZALEX® (dara­tu­mu­mab), the first CD38-directed anti­body approved any­where in the world, is the only CD38-directed anti­body approved to treat multiple myeloma.² CD38 is a surface protein that is present in high numbers on multiple myeloma cells, re­gard­less of the stage of disease.³ DARZALEX binds to CD38 and inhibits tumor cell growth causing myeloma cell death.2 DARZALEX may also have an effect on nor­mal cells.² 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.^{4,5,6,7,8,9,10,11} 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.^12,13

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.¹⁴ 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.¹⁵ 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.¹⁶ Most recently, 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.¹⁷

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.¹⁸ 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.^19,20 When damaged, these plasma cells rapidly spread and replace nor­mal cells with tumors in the bone marrow.^19,20 In 2019, it is esti­mated that 32,110 people will be diag­nosed, and 12,960 will die from the disease, in the U.S.²¹ 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 counts, tiredness, high cal­cium levels, kidney problems or in­fec­tions.²²

IMPORTANT SAFETY INFORMATION²

CONTRAINDICATIONS

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.

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 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.

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 – 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.

Thrombocytopenia – DARZALEX® 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.

Adverse Reactions – 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 patients who received DARZALEX® 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 patients who received DARZALEX® 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 patients who received DARZALEX® 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 patients who received DARZALEX® 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%).

In patients who received DARZALEX® 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%).

DRUG INTERACTIONS

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.

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 members 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 devel­op­ment of DARZALEX. 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. None of the Janssen Pharma­ceu­tical Com­panies nor Johnson & Johnson under­takes to update any for­ward-looking state­ment as a result of new in­for­ma­tion or future events or devel­op­ments.

References

1. Clinicaltrials.gov. Study Comparing Dara­tu­mu­mab, Lenalidomide, and Dexamethasone with Lenalidomide and Dexamethasone in Participants with Previously Untreated Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT02252172. Accessed March 2019.
2. DARZALEX Prescribing Information, June 2018.
3. Fedele G et al. CD38 Ligation in Peripheral Blood Mononuclear Cells of Myeloma Patients Induces Release of Protumorigenic IL-6 and Impaired Secretion of IFNγ Cytokines and Proliferation. Mediators Inflamm. 2013;564687.
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9. Janssen Research & Development, LLC. A Study of VELCADE (Bortezomib) Melphalan-Prednisone (VMP) Compared to Dara­tu­mu­mab in Combination With VMP (D-VMP), in Participants With Previously Untreated Multiple Myeloma Who Are Ineligible for High-Dose Therapy (Asia Pacific Region). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT03217812?term=MMY3011&rank=1 Identifier: NCT03217812.
10. European Myeloma Network. Compare Progression Free Survival Btw Dara­tu­mu­mab/Pomalidomide/Dexamethasone vs Pomalidomide/Dexamethasone (EMN14). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24] Available at: https://clinicaltrials.gov/ct2/show/NCT03180736?term=MMY3013&rank=2 Identifier: NCT03180736
11. Amgen. Study of Carfilzomib, Dara­tu­mu­mab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma. (CANDOR). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24] Available at: https://clinicaltrials.gov/ct2/show/NCT03158688?term=NCT03158688&rank=1 Identifier: NCT03158688.
12. Janssen Research & Development, LLC. A Study to Evaluate 3 Dose Schedules of Dara­tu­mu­mab in Participants With Smoldering Multiple Myeloma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 March 19]. Available at: https://clinicaltrials.gov/ct2/show/NCT02316106?term=smm2001&rank=1 Identifier: NCT02316106.
13. Janssen Research & Development, LLC. An Efficacy and Safety Proof of Concept Study of Dara­tu­mu­mab in Relapsed/Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 March 19]. Available at: https://clinicaltrials.gov/ct2/show/NCT02413489?term=lym2001&rank=1 Identifier: NCT02413489
14. Janssen Biotech, Inc. "DARZALEX® (dara­tu­mu­mab) Approved by U.S. FDA: First Human Anti-CD38 Monoclonal Antibody Available for the Treatment of Multiple Myeloma. ^[1]" Issued November 16, 2015.
15. Janssen Biotech, Inc. "DARZALEX® (dara­tu­mu­mab) Approved by U.S. FDA in Combination with Two Standard of Care Regimens for the Treatment of Patients with Multiple Myeloma Who Have Received At Least One Prior Therapy. ^[2]" Issued November 21, 2016.
16. Janssen Biotech, Inc. "DARZALEX® (dara­tu­mu­mab) Approved by the U.S. FDA in Combination with Pomalidomide and Dexamethasone for Patients with Multiple Myeloma Who Have Received At Least Two Prior Therapies. ^[3]" Issued June 16, 2017.
17. Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson. "Janssen Announces DARZALEX® (dara­tu­mu­mab) U.S. FDA Approval for Newly Diagnosed Patients with Multiple Myeloma who are Transplant Ineligible. ^[4]" Issued May 7, 2018.
18. Janssen Biotech, Inc. "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Dara­tu­mu­mab. ^[5]" Issued August 30, 2012.
19. Kumar, SK et al. Leukemia. 2012 Jan; 26(1):149-57.
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Source: Janssen.