Isatuximab: surface strike, deep response in AL amyloidosis Free

In this issue of Blood, Parker et al¹ report the results of a cooperative group phase 2 study (SWOG S1702) evaluating single-agent isatuximab, a CD38 monoclonal antibody (MoAb), in patients with relapsed/refractory amyloid light-chain (AL) amyloidosis, marking the first prospective isatuximab evaluation in this disease. Among the 35 evaluable patients, the overall hematologic response rate was 77%, with 57% achieving a complete response or very good partial response. Cardiac and renal responses were observed in 57% and 50% of eligible patients, respectively, including several deep organ responses. Notably, the 2 patients with prior daratumumab exposure, although not refractory to it, did not respond to isatuximab, suggesting potential epitope-specific differences may influence therapeutic activity. Treatment was generally well-tolerated, with only 1 grade 4 infusion-related reaction leading to discontinuation, and responses were durable (2-year PFS, 74%), even though 18 of the 35 evaluable patients did not complete the 24 cycles of therapy. The authors’ findings underscore the therapeutic impact of CD38-targeted agents in AL amyloidosis and highlight isatuximab as a promising option in this disease.

The primary therapeutic goal in AL amyloidosis is to eliminate the underlying plasma cell clone responsible for producing the amyloidogenic light chains. To date, all treatments have been adapted from regimens originally developed for multiple myeloma (MM), a more prevalent plasma cell malignancy, but may be tailored to the unique clinical features of AL amyloidosis. Isatuximab follows this trajectory. It was first approved for MM^2,3 and is now being explored in AL amyloidosis. The current study was built on the transformative success of daratumumab, which demonstrated significant efficacy, first in the relapsed/refractory AL amyloidosis setting, and later as part of frontline therapy. In combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD), daratumumab has enabled over half of newly-diagnosed patients with AL amyloidosis to achieve complete hematologic responses and has conferred a survival advantage over CyBorD alone.⁴ Isatuximab now enters this evolving therapeutic landscape with encouraging early results and the potential to expand treatment options for patients with AL amyloidosis.

When comparing the results of this study to other prospectively tested therapies in AL amyloidosis, anti-CD38 MoAbs consistently stand out for their ability to induce deep hematologic responses, yielding some of the most impactful advances in AL treatment to date. This raises an important question: what underlies their remarkable efficacy? Is it solely due to targeting CD38 on plasma cells, or are broader mechanisms at play? CD38 is expressed on clonal plasma cells in AL amyloidosis, though its density may vary.⁵ Although a definitive explanation has yet to be determined, exploring the unique biological and immunologic features of AL amyloidosis may offer valuable clues.

Clonal plasma cells (PCs) in AL amyloidosis exhibit lower genetic complexity and reduced proliferative capacity compared to those in MM, rendering the clone itself biologically less aggressive. However, the production of amyloidogenic, misfolded light chains impose proteotoxic stress on these cells, prompting the upregulation of antiapoptotic mechanisms to sustain survival. This biological behavior may underline the clinical efficacy of bortezomib, a proteasome inhibitor, in a subset of patients with AL amyloidosis, wherein disruption of proteostasis induces profound endoplasmic reticulum stress and triggers apoptosis in clonal PCs. Conversely, in patients with augmented antiapoptotic signaling, bortezomib response may be limited. Notably, the presence of t(11;14), the most prevalent cytogenetic abnormality in AL amyloidosis (observed in ∼50% of cases), correlates with elevated BCL-2–mediated survival signaling. The dominance of this translocation in AL amyloidosis likely reflects an intrinsic reliance on antiapoptotic pathways as an adaptive mechanism to counterbalance intracellular stress induced by light-chain toxicity.

In contrast to treatments that work on intracellular machinery, MoAbs work by binding to domains on the cell surface of their targets, which leads to several elimination pathways, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and direct apoptosis, that rely more on binding efficiency and immune system engagement than on disrupting internal cellular processes. A key factor for the success of anti-CD38 MoAbs may be a dual mechanism of action of these antibodies. Beyond directly killing the clonal PCs, anti-CD38 MoAbs are known to deplete CD38-positive immunosuppressive cells, such as T regulatory cells and myeloid-derived suppressor cells.⁶ These suppressive cells may create a protective microenvironment that sustains the amyloid-producing plasma cell clone. By targeting these cells, the therapy may effectively “release the brakes” on the patient’s immune system, allowing for a more robust and effective attack on the underlying plasma cell clone. In a single-cell transcriptomic study, Gort-Freitas et al⁷ identified expansion of monocytes and CD4⁺ T-cell subsets in the bone marrow of patients with AL amyloidosis, along with elevated inflammatory signaling and preserved effector function, suggesting that T-cell activity may be relatively intact in AL amyloidosis, which may enhance ADCC and phagocytosis. Wang et al⁸ profiled immune checkpoint expression in peripheral blood and bone marrow from patients with AL amyloidosis. They found higher levels of PD-1⁺ regulatory T cells in AL amyloidosis compared to MM, whereas patients with MM exhibited greater TIGIT⁺ T-cell expression, a marker more strongly associated with terminal exhaustion. These findings suggest that although patients with AL amyloidosis show signs of immune suppression, they may have less deeply exhausted effector T-cell populations than those with MM. Together, these studies support the notion that AL amyloidosis is characterized by a distinct and potentially more responsive immune landscape, which may enhance the efficacy of immunotherapies such as anti-CD38 MoAbs.

In summary, the efficacy of CD38-directed therapies like isatuximab may be enhanced in AL amyloidosis by a more favorable immune microenvironment. AL amyloidosis is characterized by less immune exhaustion and preserved effector cell function, allowing for stronger antibody-dependent and immunomodulatory responses. These features may contribute to the robust therapeutic outcomes observed with anti-CD38 MoAbs. Moreover, MoAbs exert their effects primarily through extrinsic pathways, such as ADCC and complement activation, and are therefore, largely indifferent to the intrinsic antiapoptotic mechanisms that characterize AL amyloidosis PCs. This functional independence from intracellular survival signaling enables MoAbs to bypass a key resistance feature of AL amyloidosis biology. The current study lays important clinical groundwork for further exploration of isatuximab in AL amyloidosis across treatment settings and combination strategies.

Conflict-of-interest disclosure: A.D. serves on the advisory board and independent review committee of Janssen; receives research funding from Alnylam, Pfizer, Takeda, Bristol Myers Squibb, and AbbVie; and serves on the scientific advisory board of HaemaLogiX. E.M. declares no competing financial interests.