Key Clinical Summary: Advancing Care in Relapsed/Refractory Multiple Myeloma | Roundtable

This is a summary of a presentation by Joshua Richer, MD and Ajay Nooka, MD which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This activity is supported by an independent medical educational grant from Johnson & Johnson. This online education program has been designed for for US Healthcare Professionals only.

Implementing Outpatient and Hybrid Delivery of BCMA BsAbs

Patient Selection Criteria: For safe outpatient or hybrid model administration, candidate selection should be individualized based on specific risk stratification factors. Fitter patients with a lower disease burden, reliable caregiver support, and no underlying cognitive issues are ideal candidates.

Contraindications for Outpatient Pathways: High-risk patients - such as those who are older or frailer, have an aggressive disease status, possess a high marrow involvement (>60%), or exhibit cytopenias that necessitate ongoing transfusions or growth factor support - should be admitted for inpatient management to safely monitor for acute toxicities.

Impact of Route of Administration on CRS Timing:

Subcutaneous (SubQ) Formulations: Agents like teclistamab and elranatamab carry a median time to cytokine release syndrome (CRS) onset of 1 to 2 days post-administration.
Intravenous (IV) Formulations: Agents such as linvoseltamab feature a significantly accelerated median time to CRS onset of approximately 10 to 12 hours due to higher peak serum concentrations. In practice, this compressed window allows centers to safely monitor patients in an inpatient setting overnight after the first dose and discharge them the following morning if stable.

Prophylactic Management and Prevention Frameworks: Incorporating prophylactic tocilizumab (e.g., administered at 8 mg/kg within 10 hours before the first step-up dose) is a highly effective, NCCN-guideline-supported strategy that reduces overall CRS incidence to under 10%, rendering the majority of remaining events low-grade (Grade 1).

Symptom Management Coordination and Escalation Workflows:

Clinical Infrastructure: Establishing outpatient pathways requires intensive nurse expertise, robust coordination among care teams, and clear communication mechanisms.
At-Home Protocols: Discharged patients must be provided with dedicated 24/7 contact cards and an on-hand prescription for dexamethasone (referred to as a "pocket dex") to immediately address low-grade CRS under remote clinical guidance.
Emergency Benchmarks: Immediate presentation to an emergency department or specialized oncologic/overnight observation unit is mandatory if a patient develops severe toxicities, immune effector cell-associated neurotoxicity syndrome (ICANS), a drop in blood pressure, or a fever exceeding 38°C.

Proactive Longitudinal Infection-Mitigation Strategies

Mechanisms Driving Infection Vulnerability: BCMA-directed BsAbs broadly target BCMA molecules, which are expressed on both malignant and normal plasma and B cells. This continuous, multi-pronged T-cell redirection leads to profound B-cell aplasia and deep hypogammaglobulinemia, exposing patients to a prolonged risk of high-grade infections.
Pre-Treatment and Baseline Screening Interventions: Prior to initiating continuous therapy, clinical teams must ensure patients are up-to-date on all vaccinations (including COVID-19) and undergo comprehensive infectious disease screening for Hepatitis B (HBV), Hepatitis C (HCV), and HIV.

Prophylactic Medication Protocols:

Antiviral and Antimicrobial Coverage: Continuous, long-term prophylaxis is mandatory using acyclovir to prevent HSV/VZV reactivation, alongside standard regimens (e.g., trimethoprim-sulfamethoxazole or atovaquone) to protect against Pneumocystis jirovecii pneumonia (PJP).
Growth Factor Support: Granulocyte colony-stimulating factor (G-CSF) should be utilized supportively to manage emergent high-grade neutropenia during treatment.

Immunoglobulin (IgG) Replacement Approaches:

Primary vs. Secondary Prophylaxis: In contrast to the secondary prophylaxis strategies used with anti-CD38 monoclonal antibodies, BCMA-directed therapies warrant universal primary prophylaxis. Monthly intravenous immunoglobulin (IVIG) replacement should be initiated upfront for all patients to significantly reduce serious, high-grade infections—regardless of baseline IgG levels.
Post-Therapy Continuation: Because B-cell aplasia persists long after treatment cessation, monthly IgG replacements must be maintained for 4 to 5 months following the discontinuation of the BCMA BsAb.

Temporal Patterns of Clinical Infections (MajesTEC-1 Data): Fungal infections and PJP typically manifest early within the first 6 months of starting treatment, whereas viral and gastrointestinal complications peak within the first 12 months. In contrast, respiratory tract infections (predominantly Grade 1/2) and COVID-19 remain persistent, long-term risks throughout the duration of continuous therapy.

Dose Optimization and Spacing Frameworks: The frequency of infections declines noticeably as the therapy moves away from weekly tracking. Once a patient achieves their best clinical response (typically within 1 to 6 months), shifting the dosing interval from weekly to biweekly or monthly mitigates T-cell exhaustion, reduces the incidence of new-onset Grade $\geq$3 infections, and improves long-term safety.

Optimizing Treatment Sequencing and Combination Therapy in RRMM

Evolution of the Relapsed/Refractory Multiple Myeloma (RRMM) Landscape: Five years ago, patients with triple-class refractory disease (refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies) faced poor outcomes, with expected response rates around 30% and a median progression-free survival (PFS) of roughly 3 months. The integration of BCMA-directed BsAbs, CAR T-cell therapies, antibody-drug conjugates (ADCs), and alternative-target BsAbs has shifted treatment paradigms into earlier relapse lines.

Clinical Framework for Treatment Selection and Antigen Sequencing:

Anti-CD38 Triplet Resurgence: Traditional anti-CD38 triplet regimens (e.g., DKD, DPD) remain vital second-line selections, particularly for patients who are not yet anti-CD38 refractory and are being actively bridged toward a definitive CAR T-cell collection.
CAR T-Cell vs. Bispecific Antibody Selection: CAR T-cell therapies offer a "one-and-done" treatment schedule that preserves long-term quality of life and isolates the risk of acute neurotoxicity or CRS to a single event window. Conversely, continuous BsAb regimens bypass manufacturing delays and deliver immediate disease control, making them optimal for aggressively progressing patients.
Sequential Target Sequencing: Retreatment using a secondary BCMA-directed agent is feasible, but success depends heavily on the duration of the treatment-free interval between therapies. Transitioning from a BCMA CAR T-cell therapy to a BCMA BsAb allows ample time for antigen recovery. Continuous pressure from back-to-back BCMA biologics increases the risk of antigen loss or mutation. In such scenarios, clinicians should rotate to alternative antigens like GPRC5D or execute an "Oreo cookie approach" by sandwiching a non-T-cell redirecting asset (such as a belantamab mafodotin ADC combination) between lines of cellular therapy to give the host immune system time to recover.

Content is accurate as of the date of release.