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

The Janssen Pharmaceutical Companies of Johnson & Johnson announced today overall survival (OS) results from the Phase 3 ALCYONE study, 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 daratumumab 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 (Abstract #859) 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 pre-specified 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 daratumumab-VMP versus 62 percent for VMP, with a statistically significant improvement in OS observed for daratumumab-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 reached in either group and follow-up is ongoing. In addition, daratumumab-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 daratumumab-VMP achieved significantly higher rates of MRD-negativity compared to VMP alone (28 percent vs. 7 percent respectively), at a threshold of one tumour cell per 10^-5 white cells.¹

The most common Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥3 percent for daratumumab-VMP compared to the VMP arm were neutropenia (40.2 percent vs. 39 percent), thrombocytopenia (34.7 percent vs. 37.9 percent), anaemia (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 daratumumab-VMP treatment arm compared with 5.6 percent in the VMP arm and discontinuation due to TEAEs was 6.9 percent vs. 9.3 percent.¹ The rate of invasive second primary malignancy was 4.9 percent in the daratumumab-VMP treatment arm compared with 4.5 percent in the VMP arm.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 daratumumab in combination with lenalidomide and dexamethasone (D-Rd) 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 daratumumab-Rd.² Additionally, time from randomisation to progression on next-line treatment or death (PFS2) favoured the daratumumab arm (HR=0.69; 95 percent CI, 0.53-0.91; p=0.0079).²

“Transplant ineligible represents the largest group of newly diagnosed patients with multiple myeloma, and they have the highest unmet need. Accordingly, the advances presented at ASH on the ALCYONE and MAIA studies for this population are very significant,” said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. “The results show the benefit of adding daratumumab on OS and PFS in the frontline setting – an improvement which could open the door to helping even more patients with multiple myeloma live longer.”

The most common Grade 3/4 TEAEs (≥10 percent) for patients in the daratumumab-Rd compared to the Rd arm were neutropenia (51 percent vs. 35 percent), lymphopenia (15 percent vs. 11 percent), pneumonia (15 percent vs. 9 percent), anaemia (14 percent vs. 21 percent), leukopenia (11 percent vs. 6 percent) and hypokalaemia (10 percent vs. 10 percent).² The most common serious TEAE was pneumonia (14 percent vs. 9 percent) in the daratumumab-Rd arm compared to the Rd arm.² The most common Grade 3/4 infection rates were 36 percent in the daratumumab-Rd treatment arm compared with 27 percent in the Rd arm.²

#ENDS#

In Europe, daratumumab is indicated: ³

• in combination with lenalidomide and dexamethasone or bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant
• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy
• as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy

About the ALCYONE study (NCT02195479)⁴

The randomised, open-label, multicentre 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. The median age was 71 years (range: 40-93).¹ Patients were randomised to receive up to nine cycles of either daratumumab-VMP or VMP alone. In the daratumumab-VMP arm, patients received 16 mg/kg of daratumumab 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 daratumumab-VMP arm continued to receive 16 mg/kg of daratumumab once every four weeks until disease progression.

About the MAIA study (NCT02252172)⁵

In this open-label, multicentre Phase 3 study 737 patients were randomised to receive either daratumumab-Rd or Rd alone in 28-day Cycles. The median age was 73 years (range: 45-90).² In the daratumumab-Rd treatment arm, patients received daratumumab 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. The primary endpoint was progression-free survival, defined as the time from date of randomisation to either progressive disease, or death, whichever occurred first. Patients in the daratumumab-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 daratumumab

Daratumumab is a first-in-class⁶ biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.⁷ Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.³ A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.³

Since launch, daratumumab has been used to treat more than 100,000 patients worldwide.⁸ Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.^{9,10,11,12,13,14,15,16} Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.^17,18 For more information, please see www.clinicaltrials.gov.

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

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.¹⁹

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.²⁰ In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.²¹ Almost 60 percent of patients with MM do not survive more than five years after diagnosis.²²

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.²³ Refractory multiple myeloma is when a patient’s disease progresses within 60 days of their last therapy.^24,25 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.²⁶ While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.²⁷ Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have poor prognoses and few treatment options available.²⁸

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/emea. Follow us at www.twitter.com/janssenEMEA for our latest news.

Cilag GmbH International; Janssen Biotech, Inc. and Janssen-Cilag International NV are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

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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 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 materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, Janssen-Cilag Limited, Janssen Biotech, Inc., any of the Janssen Pharmaceutical Companies of Johnson & Johnson 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 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 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.

References

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¹ Maria-Victoria Mateos et al.Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Patients With Transplant-ineligible Newly Diagnosed Multiple Myeloma: Overall Survival in ALCYONE. 2019 American Society of Hematology Annual Meeting. December 2019.
² Nizar Bahlis et al. Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant: Updated Analysis of MAIA. 2019 American Society of Hematology Annual Meeting. December 2019.
³ European Medicines Agency. DARZALEX summary of product characteristics, August 2019. Available at: https://www.ema.europa.eu/documents/product-information/darzalex-epar-product-information_en.pdf Last accessed December 2019.
⁴ Dimopoulos MA, Mateos MV, Cavo M, et al.One-year update of a phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in patients (Pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): ALCYONE. Presented at 60th Annual Meeting and Exposition of the American Society of Hematology (ASH), San Diego, CA, USA, 1-4 December 2018: abstract 156.
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