Teclistamab–Daratumumab Approved for Relapsed/Refractory Myeloma

The US Food and Drug Administration (FDA) has approved a new combination treatment for patients with relapsed/refractory multiple myeloma (RRMM). The approved treatment is a BCMA-targeted approach consisting of teclistamab-cqyv (Tecvayli), a B-Cell Maturation Antigen (BCMA)–directed bispecific T-cell engager, given with daratumumab and hyaluronidase-fihj (Darzalex Faspro), an anti-CD38 human monoclonal antibody. The FDA approved the BCMA-targeted immunotherapy for the treatment of patients with relapsed/refractory multiple myeloma, including patients for whom their disease has relapsed or for whom their prior treatments did not work. This new, powerful, targeted immunotherapy approach will soon be available to patients and their physicians. The approval is supported by data from the MajesTEC-3 study (NCT05083169).

Paradigm Shift in Treating Myeloma

This approval gives all of us pause for consideration of clinical sequencing and treatment of complex toxicities, primarily related to the cost of dual-biologic (and sometimes triple) regimens. This is an off-the-shelf immunotherapy approach, which represents a paradigm shift in the treatment of myeloma, given that the majority of our patients are triple-class exposed. While exposure to the three main classes of myeloma drugs (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies) has been sequential, with treatment given with both a PI/IMiD and then an anti-CD38 antibody (after failure of PI/IMiD based therapy), this approval allows for simultaneous exposure to all three classes of drugs. Patients who have failed both PI/IMiD based regimens would typically then be given an anti-CD38 antibody.

Why It Matters

Synergistic Mechanisms and Clinical Depth

Despite advances in the management of multiple myeloma, relapsed or refractory (RR) multiple myeloma remains a difficult-to-treat disease. The lines of therapy continue to become more defined, but the dropout between lines has become increasingly more challenging. Choosing a second-line “rescue” strategy is probably more difficult now than it was a year ago. The last 18 months have seen breakthroughs in the development of BCMA-targeted therapies, none perhaps more impactful than allogeneic CAR-T. The prospect of durable MRD-negative remissions in RR myeloma is within our grasp, even with the current challenges in accessibility and manufacturability of an “off-the-shelf” product. Yes, isn’t there an equivalence in depth of efficacy between cell therapy and simple infusion of stem cells?

In addition to the emerging class of single-agent combination biologics that target two myeloma antigens, several novel therapies are effective when administered in combination. Teclistamab is a BisScFv-IgG1 construct that hand-delivers CD3-expressing T cells to BCMA-expressing myeloma cells. Daratumumab is a CD38-targeting monoclonal antibody that has shown clinical activity in heavily pretreated patients with multiple myeloma and appears to induce myeloma cell death through several distinct mechanisms, most notably antibody-dependent cellular cytotoxicity (ADCC).

the majesTEC-3 Study

Integration of immunotherapy in the treatment of multiple myeloma is rapidly becoming a new standard of care to improve patient outcomes. This research found that an immunotherapy-only combination (teclistamab, BCMA-directed bispecific T-cell engager + daratumumab, anti-CD38 monoclonal antibody) achieved superior overall survival compared to standard of care in patients with early-line relapsed multiple myeloma. Patients treated with teclistamab plus daratumumab were compared with patients treated with the investigator’s choice of a triplet regimen, including daratumumab plus pomalidomide/dexamethasone or daratumumab plus bortezomib/dexamethasone. A total of 587 patients with relapse or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy, including a proteasome inhibitor and lenalidomide, were treated in this study.

Insights from the MajesTEC-3 Study

• Deepened Responses: Data indicate that the combination produces significantly higher rates of Minimal Residual Disease (MRD) negativity compared to monotherapies. This is clinically vital because MRD negativity is increasingly recognized as a surrogate for long-term progression-free survival (PFS).
• Overcoming Resistance: For patients who previously progressed on daratumumab monotherapy, the addition of the bispecific teclistamab appears to “re-sensitize” the immune environment, allowing the anti-CD38 therapy to regain efficacy through synergistic T-cell activation.
• The risk of disease progression or death was reduced by 83% (Hazard Ratio: 0.17).
• At 36 months, the estimated PFS rate was 83.4% for the Tec-Dara group compared to 29.7% for the standard care group.
• The median PFS for the Tec-Dara group had not yet been reached at the time of analysis (vs. 18 months for the control).
• Overall Response Rate (ORR): 89.0% for Tec-Dara vs. 75.3% for standard care.
• Complete Response or Better (≥CR): 81.8% vs. 32.1%.
• MRD Negativity: 58.4% of patients in the Tec-Dara group achieved minimal residual disease (MRD) negativity, significantly higher than the 17.1% in the control group.
• The study demonstrated a significant survival benefit (Hazard Ratio: 0.46), with 3-year OS rates of 83.3% for Tec-Dara vs. 65.0% for standard care.

Healthsystems and Operationalization

This approval will change the approach to subsequent therapy to an “immunotherapy first” strategy. Administering and monitoring for teclistamab will not be straightforward. Infusion centers will need to coordinate the dose escalation with the 1-day overlap with other therapies, in addition to administering Darzalex Faspro subcutaneously. Staff will need specialized training to identify signs of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) induced by T-cell-engaging therapies.

Who It Affects

The Stakeholder Ecosystem

1. Patients: The Search for Durability

Late-line patients with relapsed or refractory multiple myeloma (RRMM) who have received 3 prior lines of therapy could be primary beneficiaries of teclistamab. While patients with RRMM who have exhausted all standard of care options may benefit from CAR-T, this approach comes with the caveat of only leading to deep remission without further chemotherapy, and the time-intensive process of manufacture and administration (‘vein-to-vein’). An off-the-shelf alternative could be particularly beneficial for these patients with very aggressive disease, who need to begin treatment as quickly as possible.

2. Clinicians: The Sequencing Dilemma.

For oncologists and hematologists, this is just another addition to an already overcrowded kitchen. What will be the timing of this BCMA bispecific in relation to their current therapeutic armamentarium?

- - The CD38 Question: If a patient is refractory to daratumumab, is the combination still effective? MajesTEC-3 suggests yes, but clinicians must weigh the patient’s performance status and the risk of cumulative immune suppression. - Infection Surveillance: Because both drugs target plasma cells and their precursors, patients face a heightened risk of hypogammaglobulinemia. Clinicians must now integrate regular Intravenous Immunoglobulin (IVIG) infusions and aggressive antimicrobial prophylaxis into the standard care plan.

3. Health Systems and Payers: The Economic Reality

Payers and policymakers should consider the clinical value against the high short-term cost of such therapies. Manufacturers and health systems must evaluate the evidence for these expensive drugs.

- - Prior Authorization: Payers likely will restrict use strictly to the FDA-labeled indication (typically, patients who have received 4+ prior lines). - Resource Allocation: Specialized monitoring (often requiring hospitalization for the initial step-up doses of teclistamab) places a burden on inpatient bed capacity.

What Changes

Operationalizing Innovation

1. New Standards in Safety and Monitoring

Teclistamab (PXD-109) also has a Risk Evaluation and Mitigation Strategy (REMS), which includes mandatory toxicity reporting. The REMS for teclistamab is combined with the daratumumab REMS.

- - Cytokine Release Syndrome (CRS) Management: CRS occurred in 60.1% of patients, but all cases were Grade 1 or 2 (no high-grade events) and were managed using standard protocols without requiring treatment discontinuation. Clinicians must have Tocilizumab on-site and ready for administration. - Neurotoxicity (ICANS): The incidence was very low (1.1%), and all cases resolved. Continuous neurologic assessments during the first week of therapy are mandatory to catch ICANS early.

2. Shift in Administration Logistics

The subcutaneous formulation of Darzalez (daratumumab) given as Darzalex Faspro (with auction spray) will undoubtedly shorten infusion time for patients versus the original (iv) daratumumab. Nevertheless, patients, caregivers, and practice staff will continue to endure a long overall clinic experience when adding teclistamab to their triplet regimen.

3. Data Collection and Real-World Evidence

After MajesTEC-3 got the green light, the attention has shifted to populating the public registries with the real data. Now we just need to get some real-world numbers on how this thing performs in:

- - Renal Impairment: Many myeloma patients have compromised kidney function, a group often underrepresented in trials. - Older Adults: The average age of myeloma diagnosis is 66-70 years old. The tolerability of dual-immune modulation in the frail elderly is a critical area for post-marketing surveillance.

Clinical Decision-Making and Future Outlook

When considering this approach for your patient, consider the benefits versus risks. This combination of two different mechanisms of action, both targeting BCMA and each resulting in T cell-mediated killing of BCMA-expressing cells, as well as targeting of CD38, will result in augmented anti-tumor activity, but also increased immune modulation.

Managing the “Immune Exhaustion” Risk.

The phenomenon of T-cell exhaustion has gained attention in myeloma, as it is possible that long-term continued stimulation of T cells by teclistamab and/or other CAR-T cell therapies could ablate antitumor immunity. Further study will be needed to clarify this hypothesis. Is a fixed duration of therapy (e.g., stop after MRD negative X months) safer than our current treat until progression until adverse effects approach prohibitive levels strategy?

Practical Preparation for Teams

For clinicians, the steps are immediate:

- - Infection Prophylaxis: Serious (Grade 3/4) infections occurred in 54.1% of the Tec-Dara group. However, the study noted that new-onset high-grade infections decreased over time as patients transitioned to monthly dosing and received prophylactic immunoglobulin (IVIG) supplementation. Update protocols to include PJP (Pneumocystis jirovecii pneumonia) and shingles prophylaxis for all patients on this combination. - Vaccination Timing: Patients should ideally be up to date on vaccinations before starting therapy, as the combination significantly blunts the ability to mount a new immune response. - Laboratory Oversight: Regular monitoring of IgG levels. If levels drop below 400 mg/dL, IVIG replacement should be considered to prevent severe sinopulmonary infections.

The Policy Perspective

Going forward, these data will need to be incorporated into the policy guidelines of professional societies such as the NCCN (National Comprehensive Cancer Network) and ASCO, and determine where this combination fits within their treatment algorithm relative to the other CAR-T options (Abecma, Carvykti, etc). However, given the data demonstrate equivalency to CAR-T in terms of PFS, this combination may have several advantages as it is potentially comparable or even superior to other CAR-T options in terms of immediate availability and non-manufacturing related delays.

Conclusion: Realizing the Promise

In a clinical trial of 171 patients with relapsed or refractory multiple myeloma, the addition of teclistamab to daratumumab and carfilzomib improved overall survival, depth, and duration of response, compared to the current standard of care, carfilzomib, daratumumab, and dexazoxime. The results could establish this “off-the-shelf” combination of two immunotherapies as the new standard of care for patients with multiple myeloma in the second line of treatment. Teclistamab in combination with daratumumab is an important addition to the off-the-shelf immunotherapy armamentarium for patients with relapsed/refractory myeloma. For those who cannot afford the time needed to manufacture a CAR-T cell product or live too far from a cellular therapy center, this powerful new option is a welcome addition. Even if we can get the tumors to shrink, there is another battle to be fought: for the health care system to manage the immune activation, versus the risk of potentially life-threatening infections and serious side effects. But so far, the thoughtful and individualized use of this combination, combined with the safety protocols outlined in MajesTEC-3, along with some good policy work to make it accessible to those who need it most, looks to be the endgame for myeloma.

References

1. https://clinicaltrials.gov/study/NCT05083169