MajesTEC-2: High ORR With Teclistamab Combo in Relapsed/Refractory MM 

Initial results from the phase 1b MajesTEC-2 trial suggest that combining teclistamab with daratumumab, lenalidomide, and dexamethasone is safe and can lead to deep and durable responses.2 

The study ( Identifier NCT04722146) included 32 patients with relapsed/refractory MM who had received 1-3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug. 

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Following step-up dosing, patients received weekly doses of teclistamab at 0.72 mg/kg (n=13) or 1.5 mg/kg (n=19), with a transition to 3 mg/kg once every 2 weeks starting at cycle 3. The patients also received daratumumab at 1800 mg every week in cycles 1-2, every other week in cycles 3-6, and once a month for cycle 7 and beyond. Lenalidomide was given at 25 mg daily for 21 days each cycle, starting at cycle 2. Dexamethasone was given at 40 mg once weekly in cycles 2-4. 

CRS occurred in 81.3% of patients, and all cases were grade 1-2. Other common AEs were infections (90.6%) and neutropenia (84.4%). There were no cases of ICANS. Two patients died from AEs, 1 due to COVID-19 and 1 due to multiorgan failure from sepsis.

The median follow-up was 8.4 months. The ORR was 93.5%, and 54.8% of patients achieved a CR or better. The median time to first response was 1.0 month, and the median time to CR or better was 3.0 months. 

Urvi A. Shah, MD

This combination “is promising, with rapid responses that deepen over time,” said study presenter Emma Searle, MD, PhD, of the University of Manchester in the UK.

“We are interested in using teclistamab more upfront, earlier in the treatment setting, to see if we can improve outcomes instead of waiting until all other therapies have failed,” said Dr Shah, who was not involved in this trial.

OPTIMUM/MUKnine: Extended and Intensified Consolidation for Ultra-High-Risk MM

The phase 2 OPTIMUM/MUKnine trial enrolled patients with newly diagnosed, ultra-high-risk MM.3 Many of these patients relapse after autologous stem cell transplant (ASCT), and there is no standard treatment for them, noted study presenter Martin F. Kaiser, MD, of The Royal Marsden Hospital NHS Foundation Trust in London, UK. 

The trial ( Identifier NCT03188172) included 107 patients — 9 with primary plasma cell leukemia and 98 with ultra-high-risk MM, based on the presence of 2 or more high-risk cytogenetic abnormalities and gene expression signatures.

Patients received induction with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone. This was followed by high-dose melphalan and ASCT with bortezomib weekly after hematopoietic recovery. Patients then received 6 cycles of consolidation with daratumumab plus bortezomib, lenalidomide and dexamethasone (consolidation 1) and 12 cycles of daratumumab plus bortezomib and lenalidomide (consolidation 2). They received maintenance with daratumumab plus lenalidomide until progression. 

Dr Kaiser and colleagues compared these patients to 120 patients in the phase 3 Myeloma XI trial ( Identifier NCT01554852) who had similar clinical and molecular features and were recruited in the same health care system. In Myeloma XI, patients received induction with cyclophosphamide, lenalidomide, and dexamethasone, with or without carfilzomib, followed by high-dose melphalan and ASCT, followed by observation or lenalidomide maintenance.5

Dr Kaiser presented data at a median follow-up of 41.2 months. All patients in the OPTIMUM cohort had completed consolidation 2. The 12-month PFS rate was 87.7% in the OPTIMUM cohort and 83.8% in the Myeloma XI cohort. The 24-month PFS rate was 77.9% and 49.6%, respectively. The 30-month PFS rate was 77% and 39.8%, respectively.

Dr Kaiser noted that there was no formal overall survival (OS) comparison, but there was a signal suggesting that long-term OS is superior in the OPTIMUM cohort. The 12-month OS rate was 92.4% in the OPTIMUM cohort and 94.9% in the Myeloma XI cohort. The 24-month OS rate was 86.6% and 81.2%, respectively. The 30-month OS rate was 83.5% and 73.5%, respectively. 

In the OPTIMUM cohort, the most common AEs during consolidation 2 were thrombocytopenia (20.0% grade 2; 22.5% grade 3; and 5.0% grade 4), neutropenia (23.8%, 40.0%, and 3.8%, respectively), and infection (23.8%, 12.5%, and 2.5%, respectively). 

Patients had dose reductions of bortezomib due to hematologic AEs (28.8%), non-hematologic AEs (32.5%), or other reasons (1.3%). Patients also had dose reductions of lenalidomide due to hematologic AEs (21.3%), non-hematologic AEs (25.0%), or other reasons (3.8%). One patient had a dose reduction of daratumumab, but it was not due to AEs.

These results suggest that extended and intensified consolidation with daratumumab plus bortezomib, lenalidomide, and dexamethasone is an effective treatment option for patients with ultra-high-risk MM or plasma cell leukemia, Dr Kaiser said. The researchers are trying to get this treatment regimen approved in the National Health Service in the UK.