Sanofi’s Sarclisa subcutaneous formulation approved in Japan for patients with multiple myeloma

Japan Approves Sanofi's Subcutaneous Sarclisa for Multiple Myeloma

Sanofi's subcutaneous (SC) formulation of Sarclisa (isatuximab) has received approval in Japan from the Ministry of Health, Labour and Welfare for treating multiple myeloma (MM). This approval covers relapsed or refractory MM (R/R MM) in combination with pomalidomide and dexamethasone (Pd) or carfilzomib, and newly diagnosed MM (NDMM) with bortezomib, lenalidomide, and dexamethasone (VRd). The decision is based on the pivotal IRAKLIA phase 3 study, which demonstrated non-inferior efficacy and pharmacokinetics compared to the intravenous (IV) formulation. The SC formulation significantly reduces treatment burden and enhances convenience, with the potential to be administered via an on-body injector (OBI). In the IRAKLIA study, Sarclisa SC-Pd achieved a 71.1% objective response rate (ORR) versus 70.5% for Sarclisa IV-Pd, and notably, infusion reactions were 1.5% for SC-Pd compared to 25% for IV-Pd. This marks the second global approval for Sarclisa SC, following the EU.

• The Ministry of Health, Labour and Welfare in Japan has approved Sanofi's Sarclisa subcutaneous formulation for multiple myeloma. This approval expands treatment options for both relapsed or refractory MM, in combination with pomalidomide and dexamethasone (Pd) or carfilzomib, and newly diagnosed MM, in combination with bortezomib, lenalidomide, and dexamethasone (VRd). This is particularly significant given the steady increase in new MM diagnoses in Japan, addressing a critical unmet need for new front-line and R/R treatment approaches.
• The approval is primarily supported by results from the IRAKLIA phase 3 study (NCT05405166), which established non-inferiority of Sarclisa SC compared to its IV formulation. In adult patients with R/R MM, Sarclisa SC-Pd achieved an objective response rate (ORR) of 71.1%, closely matching the 70.5% ORR seen with Sarclisa IV-Pd (risk ratio: 1.008; p=0.0006). Crucially, the SC formulation dramatically reduced infusion reactions to 1.5%, compared to 25% with the IV formulation, while maintaining a consistent overall safety profile with only low-grade local injection site reactions.
• The subcutaneous formulation of Sarclisa represents a significant advancement in patient convenience, easing the treatment burden associated with intravenous administration. A regulatory submission for the CirCLIQ on-body injector (OBI), based on the enFuse platform by Enable Injections, is currently under review in Japan. If approved, Sarclisa SC could become the first anticancer treatment administered via an OBI and the first MM medicine in Japan to offer both manual SC injection and OBI administration, providing unprecedented flexibility and improving the patient experience.

Addressing Multiple Myeloma Treatment Burden with Sarclisa SC

Multiple myeloma remains an incurable malignancy despite significant therapeutic advances, including the introduction of immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, and autologous stem cell transplantation. The evolving treatment landscape has paradoxically introduced new complexities, as broader frontline use of novel agents has narrowed the pool of effective options at relapse.

• Persistent incurability and relapse: Drug resistance remains the primary obstacle in multiple myeloma management; the majority of patients develop resistance over successive treatment lines, and relapse continues to be an inevitable challenge regardless of initial response depth.

• Growing double-refractory population: Increasing frontline exposure to lenalidomide and anti-CD38 agents has produced a growing cohort of double-refractory patients, for whom evidence-based treatment guidance is limited and effective therapeutic options are scarce.

• Limited efficacy in later lines: Available second- and third-line therapies for relapsed/refractory multiple myeloma demonstrate restricted efficacy and tolerability, representing a substantial unmet clinical need across patient subgroups.

• Poorly understood resistance mechanisms: The mechanisms underlying resistance to novel immunotherapies — including monoclonal antibodies, immunoconjugates, T-cell–engaging antibodies, and CAR-T cells — remain incompletely characterised; impaired death receptor signalling has been identified as one emerging resistance pathway specific to T-cell–mediated immunotherapies.

• Toxicity and treatment complexity: The increasing complexity and duration of recommended regimens require heightened vigilance for cumulative adverse effects, particularly in frail patients or those with comorbidities; premature dose reduction or discontinuation driven by toxicity can compromise both quality of life and clinical outcomes.

• Healthcare access and affordability: Novel therapies, despite their clinical promise, are not universally affordable across all healthcare systems, limiting equitable patient access to advances in care.

Pivotal IRAKLIA Study: Sarclisa SC's Efficacy and Safety

The DREAMM-7 trial, a global phase 3 randomized study (NCT04246047), evaluated belantamab mafodotin plus bortezomib and dexamethasone (BVd) versus daratumumab, bortezomib, and dexamethasone (DVd) in 494 patients with relapsed or refractory multiple myeloma. At a median follow-up of 39.4 months, BVd demonstrated a compelling overall survival advantage, with median OS not reached in either arm but a significantly lower hazard of death with BVd (HR 0.58; 95% CI 0.43–0.79; p=0.0002). MRD-negativity rates among patients achieving complete response or better were 25% with BVd versus 10% with DVd, and median duration of response was 40.8 months versus 17.8 months, respectively. Median PFS2 was not reached with BVd compared to 33.4 months with DVd (HR 0.59; 95% CI 0.45–0.77). From a safety standpoint, grade 3–4 thrombocytopenia was the most frequent serious adverse event with BVd (56% vs. 35%), and serious adverse events overall occurred in 53% of BVd-treated patients versus 38% in the DVd arm. Treatment-related deaths occurred in seven patients on BVd, most commonly due to pneumonia.

The MagnetisMM-3 trial (NCT04649359), a phase 2 study of elranatamab monotherapy in triple-class refractory multiple myeloma, enrolled 184 ELRA-treated patients and demonstrated clinically meaningful improvements in patient-reported outcomes (PROs) relative to physician's choice of therapy. After false discovery rate adjustment, greater mean improvements from baseline were observed with elranatamab across multiple PRO domains, including general quality of life (EQ-5D-5L index at visit 6), the Visual Analog Scale (visit 5), Patient Global Impressions of Change (visits 2–6), disease symptoms (visit 4), and Patient Global Impressions of Severity (visits 4–5). The DART4MM trial, an open-label single-arm multicentric phase 2 study, assessed daratumumab monotherapy in 50 MRD-positive newly diagnosed myeloma patients who had achieved at least a very good partial response following first-line therapy. At the primary endpoint of 6 months, 30% of patients achieved MRD negativity; at 24 months, 22% remained MRD negative. At a median follow-up of 50 months, median PFS reached 45 months, and OS was not reached. Notably, achieving at least one MRD-negative timepoint conferred a significant PFS benefit (61 vs. 26 months; p=0.0009).

A systematic review and meta-analysis of elotuzumab, incorporating 6 randomized controlled trials (N=1,736), provided a comprehensive safety characterization of this SLAMF7-targeting monoclonal antibody. Elotuzumab was associated with a reduced incidence of neutropenia (RR=0.86; 95% CI: 0.76–0.98), but increased risks of pneumonia (RR=1.30; 95% CI: 1.07–1.59), diarrhea (RR=1.16; 95% CI: 1.05–1.30), pyrexia (RR=1.47; 95% CI: 1.10–1.96), and infections (RR=1.09; 95% CI: 1.03–1.15). At grade 3–4 severity, elotuzumab was associated with significantly elevated risks of lymphopenia (RR=1.86; 95% CI: 1.31–2.64; p=0.0005), pneumonia (RR=1.57; 95% CI: 1.11–2.23), cataracts (RR=2.87; 95% CI: 1.15–7.21), and infections (RR=1.30; 95% CI: 1.04–1.62), underscoring the importance of vigilant monitoring for immune-mediated and infectious complications in elotuzumab-containing regimens.

Sarclisa SC's Competitive Edge in the Anti-CD38 Landscape

Several anti-CD38 monoclonal antibodies are in active clinical development for relapsed/refractory multiple myeloma (RRMM), sharing isatuximab's core mechanism of targeting the CD38 transmembrane glycoprotein. Daratumumab is the most clinically advanced comparator, with a robust trial portfolio spanning Phase 1/II through Phase 3, while emerging agents such as mezagitamab, MOR202, and TAK-079 represent the next wave of CD38-directed therapeutics. The table below summarises key trials, agents, and their intervention models where data are available.

Sarclisa SC: Elevating Convenience in Multiple Myeloma Treatment

The recent Japanese approval of Sanofi's subcutaneous (SC) Sarclisa (isatuximab) marks a significant step forward in the management of multiple myeloma (MM), reflecting a broader industry movement towards patient-centric innovation. This new formulation, validated by the IRAKLIA study, offers non-inferior efficacy and pharmacokinetics compared to the intravenous (IV) version, while dramatically reducing infusion reactions from 25% to a mere 1.5%. For patients, this translates into substantially reduced treatment burden and enhanced convenience, which are critical factors in a chronic disease requiring long-term therapy.

This strategic move positions Sarclisa more competitively within the crowded CD38 monoclonal antibody market. While the convenience of SC administration is a clear advantage, it's important to acknowledge that other CD38 inhibitors already offer similar formulations. Therefore, Sanofi's success will hinge on effectively communicating the specific benefits and overall value proposition of Sarclisa SC, particularly its potential for on-body injector (OBI) administration, which could offer unparalleled flexibility.

However, the shift to SC does not alter the underlying safety profile of isatuximab. Clinical data consistently highlight risks such as neutropenia, infections (including pneumonia), and thrombocytopenia, which necessitate continued vigilant monitoring and proactive management regardless of the administration route. Real-world adoption will also be a key determinant of success. While studies like IZALCO indicate strong patient preference for OBI, ensuring widespread uptake and sustained adherence will require robust patient education and support systems. This approval not only extends Sarclisa's lifecycle but also reinforces the importance of continuous innovation in drug delivery to improve patient experience and optimize clinical outcomes in MM.