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Findings from a prospective phase 2 clinical trial show that isatuximab (Sarclisa), an anti-CD38 monoclonal antibody, is an effective and well-tolerated treatment for patients with relapsed and/or refractory systemic light chain (AL) amyloidosis.¹

The SWOG S1702 trial (NCT03499808) was a multicenter, cooperative group phase 2 study designed to address this gap by evaluating the efficacy and safety of isatuximab monotherapy for patients with relapsed/refractory AL amyloidosis.

Isatuximab demonstrated high rates of deep and rapid hematologic responses, which were associated with organ function improvement and favorable survival outcomes. The median follow-up was 21.7 months.

The overall response rate was 77 patients (n = 27/35). This was significantly greater than the null hypothesis rate of 10% (P < .0001). The complete response (CR) rate was 6% (n = 2), partial response (PR) was 20% (n = 7), and very good partial response (VGPR) was 51% (n = 18). The hematologic CR rate increased from 6% to 17% (n = 6). The median time to PR or better was 1.1 months, and the median time to VGPR or better was 3 months. At 24 months, the estimated rate of patients remaining in hematologic response was 81%.

The cardiac response was 57% (n = 8/14 evaluable patients with baseline NT-proBNP ≥ 650 pg/mL). The renal response was 50% (n = 7/14 patients with renal involvement). The median time to renal response was 18.5 months. Responses were observed in 100% of patients with gastrointestinal (2/2) and liver (1/1) involvement.

The 24-month estimated overall survival rate was 85% (95% CI, 73%–97%). The 24-month estimated progression-free survival rate was 74% (95% CI, 59%–88%).

The 2 patients who had prior daratumumab (hyaluronidase-fihj; Darzalex Faspro) exposure did not respond to isatuximab. High response rates (PR or better) were observed across cytogenetic subgroups, including translocation t(11;14) (90%) and gain 1q (n = 3/3).

Safety Findings

Isatuximab was well-tolerated, with 49% of patients completing the full 24 planned treatment cycles. Grade 3 or 4 treatment-related adverse events (TRAE) occurred in 23% of patients.

Infusion-related reactions (IRR) occurred in 49% of patients (n = 17/35), and reactions were predominantly grade 1 or 2. Of the total patients, 1 experienced a grade 4 IRR and permanently discontinued treatment. Beyond the first cycle of therapy, no IRRs occurred.

The most common TRAEs of any grade were lymphocyte count decrease (26%), anemia (23%), diarrhea (20%), fatigue (20%), headache (17%), upper respiratory infection (17%), and lung infection (17%). Of the patients, 2 experienced grade 3 lung infections (pneumonia); both had severe hypogammaglobulinemia (IgG <400 mg/dL) prior to the event.

Study Design and Methodology

The study was a single-arm, 2-stage, multicenter phase 2 trial. From March 2018 to September 2019, 43 patients were registered across 20 institutions. Of these, 36 were eligible and 35 received at least 1 dose of isatuximab, forming the evaluable patient cohort.

Isatuximab was administered at 20 mg/kg intravenously. Patients were treated weekly on days 1, 8, 15, and 22 of treatment for the first 28-day cycle, then on days 1 and 15 for cycles 2 through 24. Patients received premedication with diphenhydramine, methylprednisolone, ranitidine, and acetaminophen to mitigate IRRs. All patients received antiviral prophylaxis (eg, acyclovir) and were recommended to receive a proton pump inhibitor.

Patient Characteristics

The median age of the 35evaluable patients was 70 years. The cohort had received a median of 1 prior treatment line. Cardiac (71%) and renal (40%) involvement were the most common.

Of the total patients, 54% were female and 46% were male. Patients had an ECOG performance score of 0 to 2.

The demonstrated safety and efficacy support the investigation of isatuximab in combination regimens.

“The current clinical trial was designed and conducted prior to the approval of daratumumab in combination with cyclophosphamide, bortezomib [Velcade], and dexamethasone [VCd] in the front-line setting,” said Parker T et al, authors of the study. “With this approval, most patients are now exposed to an anti-CD38 monoclonal antibody, which was not the case in the current trial as only 2 patients here had received prior treatment with daratumumab. Importantly, these 2 patients did not achieve a hematologic response.”

In the ANDROMEDA trial (NCT03201965),² which the above approval was founded upon, patients received up to 24 cycles of treatment prior to discontinuation.As continuous maintenance therapy is not typically given in AL amyloidosis, there may be a role for retreatment with an anti-CD38 monoclonal antibody at the time of progression. Additional studies are needed to determine the efficacy of isatuximab in AL amyloidosis following daratumumab exposure.

REFERENCES

1.Parker T, Rosenthal A, Sanchorawala V et al. Isatuximab for relapsed and/or refractory AL amyloidosis: results of a prospective phase 2 trial (SWOG S1702). Blood (2025) 146 (21): 2507–2516. doi: 10.1182/blood.2024027962

2.A study to evaluate the efficacy and safety of daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to CyBorD alone in newly diagnosed systemic amyloid light-chain (AL) amyloidosis. ClincalTrials.gov. Updated May 25, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT03201965