International Myeloma Working Group Immunotherapy Committee Recommendation on Sequencing Immunotherapy for Treatment of Multiple Myeloma

Research Summary

Advances in T-cell redirecting therapy (TCRT), which includes chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (TCEs), have favorably altered the treatment landscape of multiple myeloma (MM). Previous recommendations on TCRT use in relapsed/refractory MM (RRMM) were published by the International Myeloma Working Group (IMWG), but the increasing utilization of TCRTs among patients with MM necessitated updated recommendations. As such, the IMWG Immunotherapy Committee convened a panel of 30 experts to provide recommendations on immunotherapy sequencing in MM.¹ A summary of their findings is presented below.

Triple-class drug exposure has been shown to be safe before TCRT, based on data from CAR-T clinical trials. Therefore, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), (naked) monoclonal antibodies, and/or corticosteroids can be safely used immediately prior to TCRT. A two-week washout period between the last dose of the conventional agent and apheresis (if the patient is receiving CAR-T therapy) or TCE initiation is recommended. Bendamustine and high-dose alkylators should be avoided before TCRT, as they can negatively impact outcomes.

Bridging therapy (BT) is an important consideration when pursuing CAR-T therapy. BT is administered after apheresis with the goal of providing disease control while the CAR-T product is being manufactured. It is recommended that patients with heavily pretreated RRMM receive BT if disease burden is high or if high morbidity prior to CAR-T infusion is likely. To avoid toxicity immediately before lymphodepleting chemotherapy, front-loaded regimens are preferred. Choice of BT should be individualized based on various factors, including exposure/refractoriness status and toxicity. Agents with a low risk of infections and cytopenia are preferred. PIs, IMiDs, anti-CD38 monoclonal antibodies, and dexamethasone represent several potential BT options.

The impact of prior treatments on the immune system can impact TCRT response, as in the case of bendamustine- or alkylator-related lymphopenia, which can result in poorer CAR-T therapy outcomes or inability to manufacture a viable CAR-T product. Additionally, factors such as T-cell dysfunction, effector-to-target ratio, and disease burden can contribute to worse responses in patients treated with sequential TCRT. Outcomes might also be poorer in patients who receive sequential treatment with TCRTs that target the same antigen (eg, B-cell maturation antigen [BCMA], G protein–coupled receptor class C group 5 member D [GPRCD5]).

Before autologous CAR-T therapy, holding therapy with TCE should be avoided, as TCE exposure can lead to lymphopenia and T-cell dysfunction, and research has shown that risk of manufacturing failure is increased and responses are less durable in patients who proceed immediately to CAR-T therapy from TCE, compared to those who did not. Collection of T cells prior to CAR-T manufacturing is not recommended in TCE-treated patients; in cases wherein CAR-T therapy follows TCE treatment, patients should undergo a four-week washout period before apheresis, or, if possible, cells should be collected before the start of TCE treatment. TCE can be considered as BT, particularly if it targets a different antigen than the CAR-T therapy.

Clinical trial data have shown that patients treated with BCMA-targeted TCRT after treatment with a BCMA-targeted antibody drug conjugate (ADC) experienced poor progression-free survival (PFS) and disease control. Non-BCMA-targeted TCRT might be a potential treatment option following BMCA-targeted ADC use, but currently, data on this sequencing option are limited. It is recommended that in patients who are eligible for both BCMA-targeted ADC and BCMA-targeted TCRT, treatment with BCMA-targeted TCRT is pursued first, due to its increased activity and impaired efficacy associated with use after a BCMA-targeted ADC.

Existing data suggest that treatment with a BCMA-targeted TCE followed by another TCRT, regardless of target antigen, negatively impacts durability of response. Experts recommend that patients who are candidates for both BCMA-targeted CAR-T and TCE therapies receive initial treatment with CAR-T therapy; this recommendation was made due to the response to TCE treatment following CAR-T therapy, as well as the notable, extended treatment-free period patients typically experience following BCMA-targeted CAR-T therapy, which allows for a wider variety of salvage options for those who experience disease progression.

For patients treated with BCMA-targeted CAR-T therapy who experience relapse, both BCMA- and GPRC5D-targeted TCRT can be considered as subsequent treatment options, though the former might result in weaker treatment response.

Data on GPRC5D-targeted TCRT following TCRT are limited, though current research indicates that GPRC5D-targeted TCRT use does not compromise response to TCRTs with alternative targets. Response rates and PFS have been observed to be low in patients treated with PIs, IMiDs, and anti-CD38 monoclonal antibodies following TCRT use. Further research on the use of non-TCRTs following TCRT use is warranted.

Reference

1. Costa LJ, Banerjee R, Mian H, et al. International Myeloma Working Group Immunotherapy Committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia. 2025;39:543–554.