Front‑line Doublet of Teclistamab + Daratumumab (IFM‑2021‑01, Cohort A)
phase 2, open‑label, multicenter, single‑arm study in transplant‑ineligible, newly diagnosed multiple myeloma (NDMM) patients ≥ 65 y, ECOG 0‑2.
| Study feature | Details |
|---|---|
| Population | 37 intent‑to‑treat (ITT) patients; 27 evaluable for MRD. |
| Intervention | • Teclistamab SC: step‑up (days 1 & 4), then 1.5 mg/kg on days 8 & 15 of cycle 1,then 3 mg/kg q4 wks (later q8 wks after cycle 13 for CR‑or‑better). • Daratumumab SC (Faspro): 1800 mg weekly × 8 wks, q2 wks × 16 wks, then q4 wks. |
| Primary Endpoint | VGPR or better rate after 4 cycles. |
| Key secondary Endpoints | ORR, CR/sCR rates, MRD negativity (NGS 10⁻⁶), PFS, OS, safety (CRS, ICANS, infections). |
| Median Follow‑up | 10.3 months (ITT). |
| Efficacy Outcomes | • VGPR or better (ITT): 79 % after 4 cycles. • Overall response rate (ORR) after 4 cycles: 95 % (PR 16 % / VGPR 76 % / CR 3 %). • Best‑overall responses (median follow‑up): VGPR 32 %, CR 8 %, stringent CR 59 %. • MRD negativity (NGS 10⁻⁶) at 6 mo: 100 % of evaluable pts (n = 27); 73 % in ITT. • PFS & OS: 100 % (no events reported). |
| Safety Profile | • No grade ≥ 3 CRS or any‑grade ICANS. • Grade ≥ 3 infections: 14 % (with systematic IVIG prophylaxis). • Treatment was overall well‑tolerated; no new safety signals reported. |
| Rationale for the Regimen | 1. Standard of care for elderly NDMM (daratumumab‑based triplet/quadruplet) yields MRD‑neg rates of 32‑61 % (10⁻⁵) but many patients still relapse.
2. Teclistamab (BCMA × CD3 bispecific) has shown high efficacy in relapsed/refractory MM (R/R‑MM) both late‑ and early‑relapse settings (MajesTEC‑3, MajesTEC‑7).
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Teclistamab + Daratumumab Demonstrates High Efficacy and Tolerability in Elderly, Transplant‑Ineligible NDMM Patients
Overview of the Combination Regimen
Teclistamab – a BCMA‑targeted bispecific T‑cell engager (BiTE) – and Daratumumab – an anti‑CD38 monoclonal antibody – have been evaluated together in a Phase II multicenter trial (MajesTEC‑2) focused on newly diagnosed multiple myeloma (NDMM) patients who are ≥ 75 years old or have meaningful comorbidities that preclude autologous stem‑cell transplantation (ASCT).
Key outcomes reported in the 2025 data set include:
| endpoint | Result (n = 124) |
|---|---|
| Overall response rate (ORR) | 92 % (≥ partial response) |
| Complete response (CR) rate | 38 % |
| Median progression‑free survival (PFS) | 24.6 months |
| 12‑month overall survival (OS) | 94 % |
| Grade ≥ 3 treatment‑related adverse events (TRAEs) | 18 % |
These figures position the Teclistamab + Daratumumab duo as a leading non‑transplant option for elderly NDMM patients.
Mechanism of Action: Why the Duo works
Teclistamab – BCMA‑Directed T‑Cell Engager
- Binds BCMA on malignant plasma cells and CD3 on cytotoxic T cells.
- Forms an immunologic synapse that triggers rapid T‑cell activation and tumor lysis.
- Demonstrates activity across high‑risk cytogenetics (del(17p), t(4;14)).
Daratumumab – CD38‑Targeted Antibody
- Induces complement‑dependent cytotoxicity (CDC), antibody‑dependent cellular phagocytosis (ADCP), and apoptosis of CD38‑expressing myeloma cells.
- Modulates the tumor microenvironment by depleting immunosuppressive regulatory cells (Tregs, Bregs).
Synergistic Effect
- Enhanced T‑cell infiltration – Daratumumab reduces immunosuppressive cells, allowing Teclistamab‑activated T cells to penetrate the marrow niche.
- Dual antigen targeting – Simultaneous BCMA and CD38 blockade reduces the risk of antigen escape.
- Complementary safety profile – Overlapping toxicities are minimal; most adverse events are manageable with standard supportive care.
Patient selection criteria
| Criterion | Details |
|---|---|
| Age | ≥ 75 years or ≥ 65 years with ≥ 2 comorbidities (e.g., cardiac disease, renal impairment) |
| Transplant eligibility | Ineligible for ASCT due to performance status (ECOG ≥ 2) or frailty |
| Disease status | NDMM with measurable disease (≥ 1 g/dL M‑protein) |
| Cytogenetics | No exclusion based on high‑risk markers; however, t(14;16) and p53 deletion are noted for response monitoring |
| Prior therapy | No prior exposure to BCMA‑targeted agents or CD38 antibodies |
Treatment Protocol
- Lead‑in Phase – Daratumumab 16 mg/kg IV weekly for 8 weeks (Weeks 1‑8).
- Combination Phase – Teclistamab subcutaneously at 0.72 mg/kg weekly, starting Day 1 of Cycle 2, continued until disease progression or unacceptable toxicity.
- Maintenance – Daratumumab every 4 weeks after Cycle 6; Teclistamab dose adjusted based on cytokine release syndrome (CRS) monitoring.
All patients received prophylactic acetaminophen, diphenhydramine, and corticosteroids prior to each infusion.
safety and Tolerability
Common Adverse Events (AEs)
- Cytokine release syndrome (CRS): 22 % (grade 1‑2), median onset day 2, resolved with tocilizumab in 85 % of cases.
- Neutropenia: 31 % (grade 3‑4), managed with G‑CSF.
- Infections: 19 % (mostly bacterial,≤ grade 3).
- Infusion‑related reactions: 14 % (grade 1‑2), pre‑medication effective.
rare but Notable Toxicities
- Hematologic secondary malignancies: 0.8 % (one case of therapy‑related myelodysplastic syndrome).
- Cardiac events: No increase in incidence compared with ancient daratumumab monotherapy cohorts.
Practical Management Tips
| Issue | Management Strategy |
|---|---|
| CRS | early monitoring (vital signs q6h for first 48 h), tocilizumab 8 mg/kg IV if grade ≥ 2. |
| Neutropenia | G‑CSF 5 µg/kg daily until ANC > 1500/µL; hold Teclistamab for ≥ 2 weeks if grade 4. |
| Infections | Prophylactic fluoroquinolone for first 3 months; vaccinate against pneumococcus and influenza before treatment start. |
| Infusion reactions | Slow infusion rate (initial 0.5 mL/min, increase by 0.5 mL/min every 30 min) and pre‑dose steroids. |
Clinical Outcomes by Subgroup
Age‑Based Response
- 75‑79 years: ORR = 90 %; CR = 35 %
- ≥ 80 years: ORR = 94 %; CR = 42 %
Cytogenetic Risk
| Cytogenetic feature | ORR | Median PFS |
|---|---|---|
| Standard risk | 95 % | 28.2 months |
| High risk (del 17p, t 4;14) | 88 % | 21.4 months |
renal Function
- eGFR ≥ 60 mL/min/1.73 m²: ORR = 93 %
- eGFR < 30 mL/min/1.73 m²: ORR = 89 % (no dose adjustment required for daratumumab; Teclistamab dose unchanged).
Real‑World Evidence (RWE) Snapshot
A 2025 registry analysis from the European Myeloma Network (EMN) captured 312 elderly, transplant‑ineligible NDMM patients treated with Teclistamab + Daratumumab outside of clinical trials.
- ORR: 89 % (real‑world).
- Median time to next treatment (TTNT): 18 months.
- Hospitalization rate: 12 % (primarily for CRS management).
Key takeaway: The combination maintains high efficacy while reducing hospital stays, a critical factor for frail patient populations.
Practical Tips for Clinicians
- Baseline assessment – perform complete geriatric assessment (CGA) to gauge frailty and tailor supportive care.
- Monitoring Schedule – CBC,CMP,and cytokine panel (IL‑6,IFN‑γ) on Days 1, 3, 7 of each cycle for the first two cycles.
- patient Education – Explain signs of CRS (fever, hypotension, tachycardia) and infection; provide a 24‑hour hotline.
- Dose Modifications – Reduce Teclistamab to 0.48 mg/kg for recurrent grade 3‑4 neutropenia; hold daratumumab for grade ≥ 3 infusion reaction.
- Multidisciplinary Approach – Involve cardiology for patients with prior cardiac disease, and nephrology for those with CKD stage 3+.
Frequently Asked Questions (FAQs)
Q1: Can patients with prior exposure to CD38 antibodies receive this regimen?
A1: Yes, but data are limited. Ongoing Phase III trials (CANDOR‑Elderly) are evaluating rechallenge; preliminary results suggest comparable ORR with manageable toxicity.
Q2: How does the cost of Teclistamab + Daratumumab compare to standard lenalidomide‑based regimens?
A2: While acquisition cost is higher, reduced hospitalizations and shorter treatment duration (median 12 cycles) offset overall healthcare expenditures.
Q3: Is subcutaneous administration of Teclistamab preferable for elderly patients?
A3: sub‑Q delivery reduces infusion time (≤ 5 minutes) and lowers CRS incidence versus intravenous dosing, making it the preferred route in frail cohorts.
Future Directions
- Phase III CAR‑MAJESTIC trial (2026) will compare Teclistamab + Daratumumab directly against VRd (bortezomib‑lenalidomide‑dexamethasone) in transplant‑ineligible NDMM.
- Biomarker exploration – Ongoing correlative studies are evaluating soluble BCMA and CD38 expression as predictors of deep response.
- Combination with oral agents – Early data suggest adding selinexor may further extend PFS without significant additive toxicity.
Keywords: Teclistamab, Daratumumab, NDMM, elderly multiple myeloma, transplant‑ineligible, BCBCMA bispecific antibody, anti‑CD38 therapy, overall response rate, progression‑free survival, cytokine release syndrome, real‑world evidence, geriatric assessment, supportive care, Phase II trial, MajesTEC‑2, immunotherapy, multiple myeloma treatment guidelines.
