Johnson & Johnson Seeks FDA Approval of Daratumumab for Smoldering Multiple Myeloma

Johnson & Johnson submitted an application to the FDA for the approval of daratumumab (Darzalex) as a subcutaneous monotherapy for high-risk smoldering multiple myeloma (SMM), potentially making it the first treatment option for patients at high risk of developing multiple myeloma (MM). The applications, submitted in the United States and Europe, are supported by data from the phase 3 AQUILA study (NCT03301220).¹

Multiple myeloma cells | Image Credit: © Сергей Косилко - stock.adobe.com

MM is the second most common hematologic malignancy characterized by the proliferation of mature, but dysfunctional B lymphocytes. This overproduction of cells leads to renal failure, brittle bones, and immune suppression. Patients with SMM have an annual risk of progressing to MM of 10% every year, which is highest in the first 5 years following diagnosis. Approximately 15% of all cases of newly diagnosed MM are classified as SMM, and half of those diagnosed as high-risk will progress to active MM.^2-4

SMM is a precancerous disease in which low levels of myeloma cells are detected; however, they are not high enough to result in significant symptoms or to be classified as overt MM. Some patients with high-risk SMM may begin to experience fatigue, weight loss, headaches, weakness, and, in some cases, tingling or numbing of the extremities. As of 2024, there is no approved treatment for SMM and clinical practice focuses on observation, relying on identifying signs of biochemical progression or end organ damage. In multiple studies, it has been shown that patients with high risk of progression may benefit from earlier therapeutic intervention with agents such as daratumumab.²

Daratumumab is a monoclonal antibody that targets CD38, a glycoprotein highly expressed on malignant cells that compromises treatment response, as well as enhance the proliferation of diseased cells. Initially approved in November 2015, daratumumab has 9 indications including treatment of MM in the frontline, as well as for newly diagnosed patients who are transplant eligible and ineligible. In the phase 3, randomized, open-label, multicenter AQUILA study, researchers aim to determine whether or not subcutaneously administered daratumumab prolongs progression-free survival (PFS) in 390 patients with high-risk SMM.⁵

The patients were randomized to receive daratumumab (1,800 mg DARA + rHuPH20 [2,000 U/mL] administered by manual injection (15 mL) over approximately 5 minutes at alternating abdominal locations every week for Cycles 1 and 2, every 2 weeks for Cycles 3 to 6, and every 4 weeks thereafter for up to 39 cycles or 36 months; 28-day cycles) compared with active monitoring. The primary end point of the study is progression free survival, which secondary end points of time to progression, overall response rate, and overall survival.⁶

“There remains an unmet need for early interventions and treatments that are both effective and well tolerated in people living with [SMM] at high-risk of progressing to active [MM],” Yusri Elsayed, MD, MHSc, PhD, global therapeutic area head in oncology for innovative medicine at Johnson & Johnson, said in a news release. “[Daratumumab] has changed the standard of care in [MM], and with these submissions to the FDA and EMA, this therapy could become the first approved treatment for patients with high-risk [SMM], potentially shifting the treatment paradigm.”⁴

REFERENCES

1. A study of subcutaneous daratumumab versus active monitoring in participants with high-risk smoldering multiple myeloma. ClinicalTrials.gov Identifier: NCT03301220. Updated October 26, 2024. Accessed November 11, 2024. https://clinicaltrials.gov/study/NCT03301220

2. Gerlach A. Carfilzomib, lenalidomide, and dexamethasone: a curative approach for smoldering multiple myeloma. Pharmacy Times. November 1, 2024. Accessed November 11, 2024. https://www.pharmacytimes.com/view/carfilzomib-lenalidomide-and-dexamethasone-a-curative-approach-for-smoldering-multiple-myeloma

3. Gerlach A. Targeting resistance: navigating the complexity of the tumor microenvironment and car t-cell efficacy. Pharmacy Times. August 16, 2024. Accessed November 11, 2024. https://www.pharmacytimes.com/view/targeting-resistance-navigating-the-complexity-of-the-tumor-microenvironment-and-car-t-cell-efficacy

4. Johnson & johnson submits applications in the u.s. and eu seeking approval of darzalex faspro® / darzalex® as subcutaneous monotherapy for high-risk smoldering multiple myeloma. News release. Johnson & Johnson. November 8, 2024. Accessed November 11, 2024. https://www.jnj.com/media-center/press-releases/johnson-johnson-submits-applications-in-the-u-s-and-eu-seeking-approval-of-darzalex-faspro-darzalex-as-subcutaneous-monotherapy-for-high-risk-smoldering-multiple-myeloma

5. Gerlach A. Daratumumab treatment advancements in newly diagnosed multiple myeloma. Pharmacy Times. June 3, 2024. Accessed November 11, 2024. https://www.pharmacytimes.com/view/daratumumab-treatment-advancements-in-newly-diagnosed-multiple-myeloma

6. Rajkumar SV, Voorhees PM, Goldschmidt H, Baker RI, et al. Randomized, open-label, phase 3 study of subcutaneous daratumumab (dara sc) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (smm): aquila. J Clin Oncol. June 1, 2018. doi:10.1200/JCO.2018.36.1_suppl.TPS8062