The outcomes of patients with multiple myeloma relapsing after 4 prior lines of therapy have improved in recent years with the US Food and Drug Administration (FDA) approval of several CAR T-cell therapies and bispecific T-cell engagers. Choosing between these and other regimens that are being evaluated in clinical trials is based on patient- and tumor-related factors.

There are multiple considerations when choosing therapies for patients with multiple myeloma after 4 lines of therapy. These include the patient’s performance status and fitness level, and whether they have comorbidities such as renal failure, neuropathy, and cardiac dysfunction. We also consider the drugs that the patient’s multiple myeloma has been exposed to and to which it is resistant. The goal of therapy is also important (ie, are we trying to achieve a very deep response or maintain disease control?). Finally, the genetic characteristics of the tumor should be considered.

FDA-approved options for patients who have had 4 or more treatments include CAR T-cell therapies targeting BCMA (ciltacabtagene autoleucel and idecabtagene vicleucel) and bispecific T-cell engagers directed against BCMA (teclistamab-cqyv and elranatamab-bcmm) and GPRC5D (talquetamab-tgvs). These therapies have high response rates, and the depth of response is high in complete responders, as evidenced by measurable residual disease (MRD) negativity. We are fortunate to have such active agents for patients who had few options not long ago. Multiple ongoing studies are evaluating novel CAR T-cell and bispecific T-cell engager agents, with each agent alone or in combination with another agent of the same class, to avoid the development of resistance and thereby enhance the durability of responses.

Alternative therapies for patients with advanced relapsed/refractory multiple myeloma include selinexor, a nuclear export inhibitor that appears active alone and in combination with dexamethasone, bortezomib plus dexamethasone, and anti-CD38 monoclonal antibodies. However, this agent does have adverse events, especially nausea, anorexia, and weight loss. Combination conventional chemotherapy is another option, and it can achieve responses even in advanced multiple myeloma. However, the responses are transient, and considerable myelosuppression that lasts several weeks or longer can occur.

These immunotherapies have been evaluated to treat earlier relapsed multiple myeloma as well. The KarMMa-3 randomized clinical trial compared 5 FDA-approved doublet and triplet therapies with idecabtagene vicleucel to treat patients with triple-class–exposed (IMiD, proteasome inhibitor, and anti-CD38 monoclonal antibody) relapsed/refractory multiple myeloma after 2 or more lines of therapy. Median progression-free survival was 13.3 months for idecabtagene vicleucel vs 4.4 months for standard regimens, and it was FDA approved in this setting.

The CARTITUDE-4 randomized clinical trial compared 2 FDA-approved regimens (daratumumab, pomalidomide, and dexamethasone [DPd] or pomalidomide, bortezomib, and dexamethasone [PVd]) with ciltacabtagene autoleucel in patients with relapsed multiple myeloma who had received at least 1 line of prior therapy, including an IMiD and a proteasome inhibitor, and whose disease was lenalidomide refractory. Median progression-free survival was not reached with ciltacabtagene autoleucel vs 11.8 months for standard regimens, and it was FDA approved in this setting. Of note, anti-CD38 monoclonal antibodies are commonly used as part of combination induction therapies, limiting the implications of this study for real-world practice.

There is an urgent need for new end points in drug development for multiple myeloma that read out earlier and result in faster access to new drugs. A recent FDA Oncologic Drugs Advisory Committee (ODAC) meeting evaluated MRD-negative complete response (CR) as an end point to support the accelerated approval of multiple myeloma drugs. The analysis included data from robust randomized controlled studies from the United States, Europe, the Middle East, Africa, and Asia that enrolled newly diagnosed patients who were transplant eligible and ineligible and patients with relapsed/refractory multiple myeloma. These studies varied in design, lines of therapy, treatment strategies, MRD testing methods, timing and/or number of assessments, and sensitivity levels, and they are largely representative of a wide spectrum of treatment options and clinical practice. The combined results of individual patient-level and trial-level surrogacy supported the use of MRD-negative CR as an early end point that is reasonably likely to predict clinical benefit. Importantly, MRD-negative CR was unanimously endorsed as an early end point for accelerated drug approval in multiple myeloma by the ODAC on April 12, 2024, allowing for the earlier identification of effective and safe novel agents in multiple myeloma.