Sequencing New Immunotherapies for Multiple Myeloma: Practical Guidance for Patients

Table of Contents

• Key Points
• Background: Why This Guidance Matters
• The New Immunotherapy Drugs Explained
• How Doctors Choose a Treatment
• Why Resistance Develops and Why Sequence Matters
• BCMA CAR T-Cell Therapy After Prior BCMA Treatment
• Sequencing BCMA- and GPRC5D-Directed Therapies
• Key Recommendations from the European Myeloma Network
• Limitations of the Evidence
• What This Means for Patients
• Frequently Asked Questions
• Source Information

Key Points

• For eligible patients, BCMA-targeting CAR T-cell therapy should be selected before BCMA-targeting bispecific antibodies or antibody-drug conjugates, when CAR T-cell therapy is available within a short time frame.
• Prior BCMA-directed therapy reduces the efficacy of subsequent BCMA-directed CAR T-cell therapy, with lower response rates and shorter progression-free survival in several studies.
• Switching to a different target antigen, such as GPRC5D, is more effective than reusing the same antigen with a different mode of action.
• Bridging therapy with a GPRC5D-directed bispecific antibody after apheresis may reduce tumor burden and improve subsequent CAR T-cell therapy results.
• Creating a bispecific antibody-free interval may improve the efficacy of sequential bispecific antibody use.

Background: Why This Guidance Matters

Multiple myeloma (MM) is a cancer of plasma cells, a type of white blood cell found in bone marrow. Patients who are newly diagnosed with multiple myeloma are increasingly treated with combinations of three or four drugs. These combinations include CD38-targeting antibodies, immunomodulatory drugs (IMiDs, which modify the immune system), and proteasome inhibitors (PIs, which block a structure inside cells that breaks down proteins).

Many patients eventually develop disease that no longer responds to these treatments. This is called relapsed/refractory multiple myeloma. New drugs with entirely new ways of attacking the cancer are needed for these patients at the time of first relapse or later.

Several studies have shown that immunotherapies targeting two specific proteins on myeloma cells — BCMA and GPRC5D — are highly active in these patients. Immunotherapy is a treatment that uses the body's immune system to fight cancer. Because so many new options now exist, choosing which drug to use and in what order has become increasingly complex.

This review from the European Myeloma Network (EMN) provides recommendations on how to best incorporate these new therapies into the current treatment landscape. The recommendations are based on the evidence available at the time of writing.

The New Immunotherapy Drugs Explained

Three main types of BCMA- and GPRC5D-directed immunotherapies are now available: CAR T-cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). Each works differently.

CAR T-cell therapy involves collecting a patient's own T cells (immune cells), genetically engineering them to recognize a target on cancer cells, and then returning them to the patient. This process takes time because the cells must be manufactured. There are currently two BCMA-directed CAR T-cell therapies approved for relapsed/refractory multiple myeloma:

• Cilta-cel (brand name Carvykti) — approved for patients with lenalidomide-refractory multiple myeloma after at least 1 prior treatment line.
• Ide-cel (brand name Abecma) — approved for patients with triple-class-exposed multiple myeloma after at least 2 prior treatments. "Triple-class-exposed" means the patient has been exposed to three major classes of drugs: CD38 antibodies, IMiDs, and PIs.

Cilta-cel binds simultaneously to two distinct BCMA epitopes (target sites), which gives it high-avidity binding. Avidity means the strength with which the therapy attaches to its target. This may explain why cilta-cel has higher activity than ide-cel. However, cilta-cel therapy is also associated with a higher rate of severe CRS, severe ICANS, and delayed neurotoxicity compared to ide-cel.

CRS stands for cytokine release syndrome, an immune reaction that can cause fever and other symptoms. ICANS stands for immune effector cell-associated neurotoxicity syndrome, which involves neurological symptoms. Neurotoxicity means damage or dysfunction of the nervous system.

In contrast to CAR T-cell products, which must be manufactured for each patient, bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) are immediately available "off-the-shelf" drugs. This allows doctors to treat patients with aggressive relapse right away, without waiting for manufacturing.

The BCMA-targeting bispecific antibodies are:

• Teclistamab (brand name Tecvayli)
• Elranatamab (brand name Elrexfio)
• Linvoseltamab

These three drugs are approved for the treatment of triple-class-exposed multiple myeloma. Talquetamab (brand name Talvey) is currently the only approved GPRC5D-targeting bispecific antibody, with the same label indication.

The FcRH5-targeting bispecific antibody cevostamab is effective in heavily pretreated multiple myeloma, but it is currently not approved.

The approved BCMA- and GPRC5D-targeting bispecific antibodies have comparable efficacy (how well they work). Both types are associated with a similar risk of CRS and ICANS. However, the risk of infection is higher with BCMA-targeting bispecific antibodies. Talquetamab is associated with skin and nail disorders, oral adverse events such as dysgeusia (altered or distorted taste), dysphagia (difficulty swallowing), and dry mouth. Talquetamab also causes weight decrease and, less frequently, cerebellar toxicity (problems with coordination and balance caused by effects on the cerebellum, a part of the brain).

The antibody-drug conjugate belantamab mafodotin (belamaf) consists of an anti-BCMA antibody covalently linked to a microtubule-disrupting agent called monomethyl auristatin F (MMAF). Microtubules are structures inside cells that help them divide; disrupting them helps kill cancer cells.

As a single agent (monotherapy), belamaf has modest activity, with an overall response rate (ORR) of 32% in patients with triple-class refractory multiple myeloma. ORR is the percentage of patients whose cancer shrinks or disappears after treatment. Triple-class refractory means the disease no longer responds to CD38 antibodies, IMiDs, and PIs.

Corneal epithelial changes are common with belamaf. The cornea is the clear front surface of the eye, and these changes can result in blurred vision and dry eyes. However, corneal toxicity can be effectively managed with extended dose intervals without impacting efficacy. Patients receiving belamaf should undergo ophthalmic examinations (eye exams) before and during the first treatment cycles, and upon worsening of symptoms.

Belamaf received conditional approval by the FDA (U.S. Food and Drug Administration) and EMA (European Medicines Agency) in 2020. It was withdrawn from the market in November 2022 by the FDA and in February 2024 by the EMA. This withdrawal followed the results of the DREAMM-3 trial, which showed similar progression-free survival (PFS) with belamaf versus pomalidomide-dexamethasone. PFS is the length of time during and after treatment that a patient lives with the disease but it does not get worse.

More recently, however, results from two phase 3 trials showed superiority of belamaf-bortezomib-dexamethasone (BVd) and belamaf-pomalidomide-dexamethasone (BPd) over standard-of-care treatments. In July 2025, the EMA approved both belamaf-based combinations for the treatment of patients who received at least one prior therapy. In October 2025, the FDA approved BVd for patients who received at least 2 prior lines of therapy, including a PI and an IMiD.

How Doctors Choose a Treatment

Treatment choice for relapsed/refractory multiple myeloma is increasingly complex. This complexity comes from the availability of multiple regimens and the absence of randomized studies that evaluate the best sequence of anti-myeloma regimens. Randomized studies are trials in which patients are assigned to different treatments by chance, which is the most reliable way to compare them.

Clinical decision-making regarding treatment choice and drug sequencing is guided by several factors:

• Patient-related factors (such as age, general health, and other medical conditions)
• Disease characteristics (such as how aggressive the myeloma is and its genetic features)
• Patient preferences
• Prior therapy exposure (which drugs the patient has already received)
• Refractory status (which drugs the disease no longer responds to)
• Availability of drugs
• The impact of prior treatment regimens on subsequent therapy

The optimal sequencing of T-cell redirecting bispecific antibodies, CAR T-cell therapies, antibody-drug conjugates, and other therapies remains an area of active research. The goals of this research are to improve efficacy, minimize toxicity, and enhance cost-effectiveness.

In this review, the European Myeloma Network provides a comprehensive overview of available evidence on sequential use of BCMA- and GPRC5D-targeting immunotherapies, including the recently approved belamaf-based regimens. The authors also provide recommendations on how to best incorporate these new therapies into the present treatment landscape. The authors also provide guidance on the optimal sequence of these different immunotherapies to improve clinical outcomes for patients with multiple myeloma.

Why Resistance Develops and Why Sequence Matters

Because BCMA- and GPRC5D-directed immunotherapies are now available in similar therapeutic settings, a key challenge is how to sequence these agents to optimize clinical outcomes. Understanding resistance mechanisms is important to guide clinical practice.

Resistance means the cancer stops responding to a treatment. Several mechanisms can cause resistance when these immunotherapies are used one after another:

• Antigen loss or reduced antigen expression: Exposure to these new immunotherapies may reduce the amount of target protein on the surface of myeloma cells, or cause the target to disappear entirely. This is called (functional) antigen loss. It can have a negative impact on the efficacy of subsequent therapies that target the same tumor antigen.
• Selection of T-cell-resistant clones: Prior T-cell immunotherapy may allow myeloma cell populations that resist T cells to survive and grow. A clone is a group of identical cancer cells.
• Impact on T-cell quantity or quality: Prior T-cell immunotherapy can affect the number and fitness of a patient's T cells, which are needed for subsequent T-cell therapies to work.
• Steric hindrance: If the epitopes (binding sites) of two bispecific antibodies or CARs targeting the same antigen are closely spaced, the binding of one antibody or CAR may physically block the binding of another antibody or CAR to its target.

Altogether, these effects may have implications for the proper use and efficacy of subsequent relapse regimens.

To what extent a prior BCMA-directed therapy results in steric hindrance is currently unknown. Steric hindrance thereby impairs the recognition of tumor cells by a subsequent BCMA-targeting bispecific antibody, BCMA-targeting ADC, or BCMA-directed CAR T-cell. This probably depends on the extent of overlapping epitopes, binding affinity, half-life of the BCMA-directed therapy, and presence of a BCMA-free interval. The impact of steric hindrance with GPRC5D-directed therapies used in sequence is also unknown.

BCMA CAR T-Cell Therapy After Prior BCMA Treatment

The registrational studies of approved BCMA-directed immunotherapies excluded patients who previously received BCMA-directed therapy. Registrational studies are the trials used to gain drug approval. Although larger studies are needed, there is increasing evidence that patients who have been exposed to BCMA-targeted therapy can still respond to subsequent therapy with a different anti-BCMA modality.

However, the efficacy of a second BCMA-directing modality is generally reduced by prior BCMA-directed treatment. This effect seems to be less pronounced when BCMA-directed CAR T-cell therapy is given first.

Patients who previously received non-cellular BCMA-targeted therapy (an ADC or a bispecific antibody) experienced substantially impaired duration of response and PFS following BCMA-directed CAR T-cell therapy. Response rates were only modestly reduced. This is clearly illustrated in cohort C of the CARTITUDE-2 study.

In CARTITUDE-2 cohort C, clinical outcomes with cilta-cel were inferior in patients previously exposed to non-cellular BCMA-targeting agents. This was compared to results in BCMA-naïve patients (patients who had never received BCMA-targeted therapy):

• ADC-exposed group (n=13): ORR 61.5%; median PFS 9.5 months
• Bispecific antibody-exposed group (n=7): ORR 57.1%; median PFS 5.3 months

The safety profile of cilta-cel in patients with prior BCMA exposure was consistent with that observed in BCMA-naïve patients.

Similarly, in a real-world study with 236 patients treated with cilta-cel, prior BCMA-directed therapy (n=33) was associated with an inferior response rate compared to patients who were not previously BCMA exposed:

• ORR: 70% vs. 92%
• At least complete response (≥CR): 42% vs. 75%

Median PFS was only 13.6 months for patients with prior BCMA-directed therapy, while median PFS was not reached in all 236 patients (12-month PFS: 68%). Although patient numbers are limited, there was no difference in PFS across different types of prior BCMA-targeted therapy (ADC versus bispecific antibody versus CAR T-cell therapy).

Furthermore, in a large cohort of 203 patients who received commercial ide-cel, prior BCMA-directed therapy (n=50; 25%) was an independent predictor for inferior outcomes:

• ORR: 74% vs. 88%
• ≥CR: 29% vs. 48%
• Median PFS: 3.2 vs. 9.0 months for patients with prior BCMA-directed therapy versus those without

Although the number of patients was relatively small, the impact of prior BCMA-targeting bispecific antibodies (n=7) and ADCs (n=38) was more pronounced compared to prior BCMA-directed CAR T-cell therapy (n=5):

• ORR with prior bispecific antibody: 86%
• ORR with prior ADC: 68%
• ORR with prior CAR T-cell therapy: 100%
• Median PFS with prior bispecific antibody: 2.8 months
• Median PFS with prior ADC: 3.2 months
• Median PFS with prior CAR T-cell therapy: not reached

A larger retrospective CIBMTR analysis included 821 patients treated with standard-of-care ide-cel. That analysis also showed that prior non-cellular BCMA-directed therapy was associated with inferior PFS and overall survival (OS). Prior non-cellular BCMA-directed therapy was 14.1% of patients, including ADC (n=113) or bispecific antibody (n=3). This was compared to patients who did not receive prior BCMA-directed therapy:

• Median PFS: 5.3 months vs. 9.7 months
• 1-year OS: 52% vs. 70%

OS means overall survival, the length of time from treatment that patients are still alive. Other real-world studies also support these findings.

Sequencing BCMA- and GPRC5D-Directed Therapies

The available evidence that guides the sequencing of BCMA- and GPRC5D-targeting modalities is currently based on nonrandomized prospective studies with limited numbers of patients and retrospective analyses. Nonrandomized means patients were not assigned to treatments by chance. Retrospective means the data were collected by looking back at past patient records.

The authors focus on approved treatment options, but they also briefly discuss sequencing of therapies in advanced stages of clinical development, including immunotherapies directed at other targets.

Several key principles emerge from the evidence:

1. BCMA-targeting bispecific antibodies and ADCs should preferably be avoided before CAR T-cell therapy. Some studies have shown that these agents negatively influence clinical outcomes after CAR T-cell therapy.
2. CAR T-cell therapy should be selected first, and bispecific antibodies and/or belamaf later in the disease course. This recommendation applies if patients are eligible for CAR T-cell therapy and if CAR T-cell therapy is available within a short time frame.
3. Bridging therapy with GPRC5D-directed bispecific antibodies can be considered. Bridging therapy is treatment given between the time cells are collected and the time CAR T-cells are infused. Initiation of a GPRC5D-directed bispecific antibody after apheresis (the process of collecting the patient's cells) can significantly reduce tumor burden. This was shown to improve the efficacy of consecutive BCMA-directed CAR T-cell therapy.
4. Target switch is a more effective strategy than using agents that target the same antigen. Sequential treatment with agents targeting the same antigen, but with different modes of action, is feasible. However, several studies have demonstrated that switching to a different target antigen is more effective.
5. Creating a bispecific antibody-free interval may improve efficacy. There is increasing evidence indicating that the efficacy of sequential use of bispecific antibodies can be improved by creating a bispecific antibody-free interval.

Key Recommendations from the European Myeloma Network

The European Myeloma Network makes the following practical recommendations for sequencing BCMA- and GPRC5D-targeting immunotherapies in multiple myeloma:

1. For patients who are eligible for CAR T-cell therapy and when CAR T-cell therapy is available within a short time frame, select CAR T-cell therapy first.
2. Use bispecific antibodies and/or belamaf later in the disease course, after CAR T-cell therapy.
3. Avoid BCMA-targeting bispecific antibodies and ADCs before CAR T-cell therapy whenever possible, because these agents may negatively influence outcomes after CAR T-cell therapy.
4. Consider bridging therapy with GPRC5D-directed bispecific antibodies, initiated after apheresis, to significantly reduce tumor burden before CAR T-cell infusion; talquetamab bridging should be reserved for patients with no other bridging options.
5. When sequential treatment is needed, prefer switching to a different target antigen rather than reusing the same antigen with a different mode of action.
6. Consider creating a bispecific antibody-free interval to improve the efficacy of sequential bispecific antibody use.

The optimal treatment sequence depends on various patient- and tumor-related features. It also depends on reimbursement and availability issues, which vary between countries and healthcare systems.

Limitations of the Evidence

The recommendations in this guideline are based on nonrandomized prospective studies with limited numbers of patients and retrospective analyses. This means the evidence is not as strong as it would be from large randomized controlled trials.

Many of the studies described included small numbers of patients who had prior BCMA-directed therapy before receiving CAR T-cell therapy. For example, some analyses included only 5 to 50 patients with prior BCMA exposure. Larger studies are needed to confirm these findings.

The registrational studies of approved BCMA-directed immunotherapies excluded patients who previously received BCMA-directed therapy. This means the approved drugs were not formally tested in patients who had already received another BCMA-targeting treatment.

The extent to which prior BCMA-directed therapy causes steric hindrance, and how this impairs recognition of tumor cells by subsequent therapies, is currently unknown. The impact of steric hindrance with GPRC5D-directed therapies used in sequence is also unknown.

Treatment selection and sequencing also depend on reimbursement and availability issues, which are not medical factors but can significantly affect what treatments patients can actually receive.

What This Means for Patients

If you have relapsed/refractory multiple myeloma and your doctor is considering BCMA- or GPRC5D-targeting immunotherapy, the order in which these treatments are given matters. The evidence shows that giving BCMA-targeting bispecific antibodies or antibody-drug conjugates before BCMA-targeting CAR T-cell therapy can reduce how well the CAR T-cell therapy works afterward.

This means that if you are eligible for CAR T-cell therapy and it can be arranged within a short time, your medical team may recommend CAR T-cell therapy first. Bispecific antibodies and belamaf-based regimens would then be reserved for later in your treatment course.

If you need treatment to control your myeloma while waiting for CAR T-cells to be manufactured, your doctor may consider a GPRC5D-directed bispecific antibody as bridging therapy. This approach has been shown to reduce tumor burden and improve the results of subsequent CAR T-cell therapy.

If you have already received one BCMA-targeting therapy and need another treatment, switching to a therapy that targets a different antigen (such as GPRC5D) may be more effective. This may be more effective than using another BCMA-targeting drug. Your doctor may also consider a treatment-free interval between bispecific antibodies to improve their effectiveness.

It is important to discuss with your healthcare team which treatments you have already received, how your myeloma responded to them, and what options are available to you. The optimal sequence depends on your individual situation, including your general health, the characteristics of your myeloma, and what drugs are available and reimbursed in your healthcare system.

Frequently Asked Questions

What is the main recommendation for sequencing BCMA-targeting immunotherapies?

The European Myeloma Network recommends giving BCMA-targeting CAR T-cell therapy before BCMA-targeting bispecific antibodies or antibody-drug conjugates. This is because several studies show that using those other BCMA drugs first reduces how well CAR T-cell therapy works afterward. The guidance applies when patients are eligible for CAR T-cell therapy and it is available within a short time frame.

If I've already had a BCMA-targeting treatment, can I still benefit from CAR T-cell therapy?

Yes, but the benefit may be reduced. In a real-world study of 236 patients, those with prior BCMA-directed therapy had an overall response rate of 70% versus 92% in those without, and median progression-free survival of 13.6 months versus not reached. In another study of 203 patients, prior BCMA therapy predicted worse outcomes. Response rates were only modestly reduced, but duration of response was substantially impaired.

What is bridging therapy and when might it be used?

Bridging therapy is treatment given between the time your cells are collected for CAR T-cell therapy and the time the CAR T-cells are infused. A GPRC5D-directed bispecific antibody, such as talquetamab, can be considered as bridging. Starting it after apheresis may significantly reduce tumor burden and improve the efficacy of the subsequent BCMA-directed CAR T-cell therapy.

Why does the order of these immunotherapies matter?

Using one BCMA-targeting therapy can cause resistance to later ones. Mechanisms include antigen loss (the target protein disappearing from myeloma cells), selection of T-cell-resistant clones, and effects on T-cell quantity or quality. Also, if binding sites overlap, one drug may physically block another from attaching. Switching to a different target antigen, such as GPRC5D, appears more effective than reusing the same antigen.

What are the side effects of BCMA- and GPRC5D-targeting bispecific antibodies?

Both types have comparable efficacy and similar risk of cytokine release syndrome (CRS) and ICANS (neurological symptoms). However, BCMA-targeting bispecific antibodies carry a higher risk of infection. Talquetamab, which targets GPRC5D, is associated with skin and nail disorders, altered taste, difficulty swallowing, dry mouth, weight decrease, and less frequently, cerebellar toxicity affecting coordination and balance.

What is belantamab mafodotin and is it available?

Belantamab mafodotin (belamaf) is an antibody-drug conjugate targeting BCMA. It was withdrawn from the market in 2022–2024, but in 2025 the EMA approved two belamaf-based combinations, and the FDA approved one, for patients who received prior therapies. It can cause corneal changes leading to blurred vision and dry eyes, which are managed with extended dose intervals and eye exams.

How strong is the evidence behind these sequencing recommendations?

The recommendations are based on nonrandomized prospective studies with limited numbers of patients and retrospective analyses, not large randomized trials. Many studies included only 5 to 50 patients with prior BCMA exposure. The registrational trials of approved BCMA-directed immunotherapies excluded patients who had previously received BCMA-directed therapy. Larger studies are needed to confirm these findings.

I have relapsed/refractory multiple myeloma and my doctor wants to start a BCMA bispecific antibody before CAR T-cell therapy — should I get a second opinion on the sequencing?

Yes, this is a reasonable point to seek a second opinion. Giving BCMA-targeting bispecific antibodies or antibody-drug conjugates before BCMA-targeting CAR T-cell therapy can reduce how well the CAR T-cell therapy works afterward, so guidance recommends selecting CAR T-cell therapy first when a patient is eligible and it is available within a short time frame, reserving bispecific antibodies and belamaf for later. A second opinion can review your prior treatments and whether a different target, such as GPRC5D, or a bispecific-free interval fits your situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Sequencing BCMA‐ and GPRC5D‐targeting immunotherapies in multiple myeloma- Practical guidance from the European Myeloma Network

Authors: Niels W. C. J. van de Donk, Philippe Moreau, Jesus F. San-Miguel, Maria-Victoria Mateos, Meletios A. Dimopoulos, Sonja Zweegman, Francesca Gay, Monika Engelhardt, Roberto Mina, Elena Zamagni, Michel Delforge, Meral Beksac, Andrew Spencer, Fredrik Schjesvold, Christoph Driessen, Martin Kaiser, Aurore Perrot, Ralph Wäsch, Charlotte L. B. M. Korst, Annemiek Broijl, Cyrille Touzeau, Salomon Manier, Roman Hajek, Jelena Bila, Guldane C. Seval, Michael O'Dwyer, Heinz Ludwig, Carlos Fernandez de Larrea, Rakesh Popat, Pellegrino Musto, Paula Rodriguez-Otero, Kwee Yong, Marin Kortüm, Leo Rasche, Evangelos Terpos, Marc S. Raab, Mario Boccadoro, Pieter Sonneveld, and Hermann Einsele, on behalf of the EMN Guidelines Committee

Publication: HemaSphere, 2025;9:e70260

DOI: 10.1002/hem3.70260

Article type: Guidelines — Evidence-Based

Received: 1 September 2025 | Accepted: 25 October 2025

This patient-friendly article is based on peer-reviewed research.