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      1. EMEA/
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      4. DARZALEX® (daratumumab) subcutaneous formulation shows 51 percent reduction in risk of progression to active multiple myeloma for patients with high-risk smouldering multiple myeloma
      Oncology

      DARZALEX® (daratumumab) subcutaneous formulation shows 51 percent reduction in risk of progression to active multiple myeloma for patients with high-risk smouldering multiple myeloma

      First subcutaneous anti-CD38 therapy to demonstrate potential to prevent end-organ damage, and extend progression-free survival and overall survival based on findings from Phase 3 AQUILA study1

      December 8, 2024
      9 min read

      BEERSE, BELGIUM (8 December 2024) – Janssen-Cilag International NV, a Johnson & Johnson company, today announced data from the Phase 3 AQUILA study showing that DARZALEX® (daratumumab) subcutaneous (SC) formulation significantly delayed progression from high-risk smouldering multiple myeloma (SMM) to active multiple myeloma (MM) and extended overall survival compared to the current standard of care of active monitoring.1 The data were presented for the first time as an oral presentation at the 2024 American Society of Hematology (ASH) Annual Meeting (Abstract #773), taking place in San Diego, California, United States from 7-10 December, as part of the Press Programme and were selected for the Best of ASH session.1 The data were also simultaneously published in The New England Journal of Medicine.2

      “Patients with high-risk smouldering multiple myeloma, which has no approved treatment, have a high probability of progressing to active multiple myeloma – a life-threatening stage of the disease,” said Meletios A. Dimopoulos, M.D., Professor and Chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine and presenting author.* “Findings from AQUILA highlight the potential of early intervention with daratumumab SC to delay disease progression, extend overall survival and prevent end-organ damage associated with active multiple myeloma.”

      In the AQUILA study, 194 patients received daratumumab SC and 196 patients were actively monitored per current standard of care treatment for high-risk SMM.1 At a median follow-up of 65.2 months (range, 0-76.6), patients who received daratumumab SC showed statistically significant improved progression-free survival (PFS; defined as progression to active MM, as assessed according to the International Myeloma Working Group diagnostic criteria for MM [SLiM-CRAB], or death) vs patients who underwent active monitoring; 63.1 percent in the daratumumab arm vs 40.8 percent in the active monitoring arm remained alive and progression-free at 60 months (Hazard Ratio [HR], 0.49; 95.0 percent Confidence Interval [CI], 0.360.67; p<0.001).1 Among patients who were retrospectively categorised as having high-risk SMM, per the current Mayo 2018 criteria (20/2/20), median PFS was not reached in the daratumumab arm and was 22.1 months in the active monitoring arm (HR, 0.36; 95.0 percent CI, 0.23-0.58).1 Overall survival was also extended with daratumumab SC, with 5-year survival rates of 93.0 percent vs 86.9 percent for active monitoring (HR, 0.52; 95.0 percent CI, 0.27-0.98).1

      “Smouldering multiple myeloma represents a critical gap in care, with patients currently limited to treatment-free active monitoring upon diagnosis,” said Edmond Chan, MBChB, M.D. (Res), EMEA Therapeutic Area Lead Hematology, Johnson & Johnson Innovative Medicine. “The AQUILA study offers a compelling case for shifting the treatment paradigm towards early disease interception for high-risk patients, showing treatment with fixed-duration daratumumab SC reduces end-organ damage and disease progression. These results underscore our commitment to addressing unmet needs and changing the way we manage multiple myeloma in its earliest stages.”

      Additionally, patients who received daratumumab SC saw a higher overall response rate of 63.4 percent compared to 2.0 percent with active monitoring (p<0.001).1 Median time to first-line MM treatment was not reached for patients receiving daratumumab SC compared to 50.2 months with active monitoring (HR, 0.46; 95 percent CI, 0.33-0.62; nominal p<0.0001).1,3

      “We are encouraged by the findings from the AQUILA study, which may help to underscore the critical role of early disease intervention and potential to improve outcomes for patients with high-risk smouldering multiple myeloma,” said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine. “This proactive approach further highlights our goal of evolving the standard of care for patients at every stage of the disease.” -490393

      Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 40.4 percent of patients treated with daratumumab SC and 30.1 percent of patients actively monitored.1 The most common (≥5 percent in either group) Grade 3/4 TEAE was hypertension (5.7 percent vs 4.6 percent, respectively).1 The frequency of TEAEs leading to discontinuation of daratumumab SC was low (5.7 percent), as was the incidence of fatal TEAEs in both groups (0.5 percent vs 2.0 percent, respectively).1

      Last month, Johnson & Johnson submitted an Extension of Indication application to the European Medicines Agency and a supplemental Biologics License Application to the U.S. Food and Drug Administration for daratumumab SC and DARZALEX FASPRO®, respectively, for the treatment of adult patients with high-risk SMM based on the Phase 3 AQUILA data.4

      About the AQUILA Study
      AQUILA (NCT03301220) is a randomised, multicentre Phase 3 study investigating daratumumab SC vs active monitoring in patients (n=390) with high-risk smouldering multiple myeloma (SMM).5 The primary endpoint is progression-free survival and secondary endpoints include time to progression, overall response rate and overall survival.5 Patients in the study were diagnosed with SMM in the last five years and were excluded if they had prior exposure to approved or investigational treatments for SMM or multiple myeloma.5

      About Smouldering Multiple Myeloma
      SMM is an early precursor of active multiple myeloma where abnormal cells can be detected in the bone marrow, but patients are typically asymptomatic.6,7 People living with SMM tend not to show signs or symptoms typically associated with active myeloma, such as bone pain, bone fractures, kidney problems, or anaemia, however as abnormal plasma cells are present, organ damage may begin and progress asymptomatically.7,8 Approximately fifteen percent of all cases of newly diagnosed multiple myeloma are classified as SMM, and half of those diagnosed with high-risk SMM will progress to active multiple myeloma within two years.9

      About Multiple Myeloma
      Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.10,11 In multiple myeloma, these malignant plasma cells continue to proliferate, accumulating in the body and crowding out normal blood cells, as well as often causing bone destruction and other complications.11 In the European Union, it is estimated that more than 35,000 people were diagnosed with multiple myeloma in 2022, and more than 22,700 patients died.12 Whilst some patients with multiple myeloma initially have no symptoms, others can have common signs and symptoms of the disease, which can include bone fracture or pain, low red blood cell counts, fatigue, high calcium levels, infections, or kidney damage.13

      About Daratumumab and Daratumumab SC
      Johnson & Johnson is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease.

      In August 2012, Janssen Biotech, Inc., a Johnson & Johnson company and Genmab A/S entered a worldwide agreement, which granted Johnson & Johnson an exclusive licence to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 585,000 patients worldwide.14 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma.15 Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE® drug delivery technology.15

      CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.15 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death.15 Daratumumab may also have an effect on normal cells.15 Data across ten Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival.15,16,17,18,19,20,21,22,23,24

      For further information on daratumumab, please see the Summary of Product Characteristics at: https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf.

      About Johnson & Johnson
      At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity.

      Learn more at www.innovativemedicine.jnj.com/emea. Follow us at www.linkedin.com/company/jnj-innovative-medicine-emea. Janssen-Cilag International NV, Janssen Pharmaceutica NV, Janssen-Cilag Limited, Janssen Biotech, Inc., and Janssen Research & Development, LLC are Johnson & Johnson companies.

      Cautions Concerning Forward-Looking Statements
      This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of daratumumab. 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 materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, Janssen Pharmaceutica NV, Janssen-Cilag Limited, Janssen Biotech, Inc., Janssen Research & Development, LLC 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; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behaviour 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 31, 2023, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form -490393

      10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at http://www.sec.gov/, http://www.jnj.com/ or on request from Johnson & Johnson. None of Janssen-Cilag International NV, Janssen Pharmaceutica NV, Janssen-Cilag Limited, Janssen Biotech, Inc., Janssen Research & Development, LLC nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

      *Meletios A. Dimopoulos, M.D., Professor and Chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, and presenting author, has provided consulting, advisory, and speaking services to Janssen; he has not been paid for any media work.

      Media contact:
      Jenni Mildon
      [email protected]
      +44 7920 418 552

      Investor contact:
      Lauren Johnson
      [email protected]

      CP-490393
      December 2024

      1 Dimopoulos MA et al. Phase 3 Randomized Study of Daratumumab Monotherapy Versus Active Monitoring in Patients With High-risk Smoldering Multiple Myeloma: Primary Results of the AQUILA Study. Oral presentation. American Society of Hematology (ASH) Annual Meeting; December 7-10, 2024.
      2 Dimopoulos MA et al. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. The New England Journal of Medicine 2024. DOI: 10.1056/NEJMoa2409029 Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2409029. Last Accessed: December 2024.
      3 Dimopoulos MA et al. Phase 3 Randomized Study of Daratumumab Monotherapy Versus Active Monitoring in Patients With High-risk Smoldering Multiple Myeloma: Primary Results of the AQUILA Study. Abstract #773. American Society of Hematology (ASH) Annual Meeting; December 7-10, 2024.
      4 Johnson & Johnson (2024, 08 November). Johnson & Johnson submits applications in the U.S. and EU seeking approval of DARZALEX FASPRO®/DARZALEX® (daratumumab) as subcutaneous monotherapy for high-risk smouldering multiple myeloma [Press Release]. Available here: https://innovativemedicine.jnj.com/emea/johnson-johnson-submits-applications-in-the-u-s-and-eu-seeking-approval-of-darzalex-faspro-darzalex-daratumumab-as-subcutaneous-monotherapy-for-high-risk-smouldering-multiple-myeloma.
      5 ClinicalTrials.Gov. A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma. Available at: https://clinicaltrials.gov/study/NCT03301220. Last accessed: December 2024.
      6 Myeloma UK. Smouldering myeloma. Available at: https://www.myeloma.org.uk/wp-content/ uploads/2023/04/Myeloma-UK-Smouldering-Myeloma-Infosheet.pdf. Last accessed: December 2024.
      7 WebMD. Smoldering Multiple Myeloma. Available at: https://www.webmd.com/cancer/multiple-myeloma/smoldering-multiple-myeloma. Last accessed: December 2024
      8 American Cancer Society. About multiple myeloma. Available at: https://www.cancer.org/cancer/types/multiple-myeloma/about/what-is-multiple-myeloma.html. Last accessed: December 2024.
      9 Rajkumar SV, Kumar S, Lonial S, Mateos MV. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022 Sep 5;12(9):129.
      10 Abdi J, et al. Drug resistance in multiple myeloma: latest findings on molecular mechanisms. Oncotarget 2013;4(12):2186-2207.
      11 American Society of Clinical Oncology. Multiple myeloma: introduction. Available at: https://www.cancer.net/cancer-types/multiple-myeloma/introduction. Last accessed: December 2024.
      12 ECIS - European Cancer Information System. Estimates of cancer incidence and mortality in 2022, by country. Multiple myeloma. Available at:
      https://ecis.jrc.ec.europa.eu/explorer.php?$0-0$1-All$2-All$4-1,2$3-51$6-0,85$5-2022,2022$7-7$CEstByCountry$X0_8-3$X0_19-AE27$X0_20-No$CEstBySexByCountry$X1_8-3$X1_19-AE27$X1_-1-1$CEstByIndiByCountry$X2_8-3$X2_19-AE27$X2_20-No$CEstRelative$X3_8-3$X3_9-AE27$X3_19-AE27$CEstByCountryTable$X4_19-AE27. Last accessed: December 2024.
      13 American Cancer Society. Multiple myeloma: early detection, diagnosis and staging. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/8740.00.pdf. Last accessed: December 2024.
      14 Johnson & Johnson [data on file]. RF-439245. Number of patients treated with DARZALEX® worldwide as of 30 October 2024.
      15 Janssen EMEA. European Commission Grants Marketing Authorisation for DARZALEX® (Daratumumab) Subcutaneous Formulation for All Currently Approved Daratumumab Intravenous Formulation Indications. Available at: www.businesswire.com/news/home/20200604005487/en/European-Commission-GrantsMarketingAuthorisation-forDARZALEX%C2%AE%E2%96%BC-daratumumab-SubcutaneousFormulation-for-all-CurrentlyApproved-Daratumumab-Intravenous-Formulation-Indications. Last accessed: December 2024.
      16 Moreau P, 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, openlabel, phase 3 study. Lancet 2019;394(10192):29-38.
      17 Facon T, et al. MAIA Trial Investigators. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med 2019;380(22):2104-2115.
      18 Mateos MV, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. The Lancet 2020;395:P132-141.
      19 Dimopoulos MA, et al. APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22(6):801-812.
      20 Palladini G, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood 2020;2;136(1):71-80.
      21 Chari A, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 2017;130(8):974-981.
      22 Bahlis NJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia 2020;34(7):1875-1884.
      23 Mateos MV, et al. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR. Clin Lymphoma Myeloma Leuk 2020;20(8):509-518.
      24 Usmani, S Z. et al. Daratumumab + Bortezomib/Lenalidomide/Dexamethasone in Patients With Transplant-ineligible or Transplant-deferred Newly Diagnosed Multiple Myeloma: Results of the Phase 3 CEPHEUS Study. Oral presentation. 21st International Myeloma Society (IMS) Annual Meeting. September 25 – 28, 2024.