Relapsed/Refractory Multiple Myeloma

Teclistamab Demonstrates Continued Promise in Relapsed/Refractory MM

  • March 16, 2021
  • 5 mins read

According to outcomes from an ongoing phase 1 study, a bispecific BCMA (B-cell maturation antigen) x CD3 antibody named Teclistamab demonstrated promising clinical activity, as well as tolerable safety profile, in patients with relapsed/refractory multiple myeloma. 

Outcomes specified that at the recommended phase 2 dose (RP2D), the objective RR with teclistamab was noted as 73% and the very good partial response rate (VGPR) or better was noted as 55%; the CR rate or better was noted as 23%.

The teclistamab was also appeared to be well tolerated at the recommended phase 2 dose, which was 1500 μg/kg and was administered subcutaneously, the highest tolerated dose was unidentified, and all the data of cytokine release syndrome were of either grades 1 or 2 and were generally confined to step-up doses and the initial full doses of the treatment.

According to Alfred L. Garfall, MD, an assistant professor of medicine at the Hospital of the University of Pennsylvania, “Teclistamab is an off-the-shelf therapy targeting B-cell maturation antigen, demonstrated promising efficacy in the heavily pretreated patients with r/r MM.”

There continues to be an unmet requirement for patients with r/r MM, he elaborated; for those who progress on available therapies, the ORR is noted as 30%, the median PFS is an estimated to be around 90 days, and the median OS ranges from 6-11 months. 

As a bispecific BCMA (B-cell maturation antigen) x CD3 antibody, it specificat redirects the CD3+ T cells to B-cell maturation antigen expressing cells. Teclistamab is involved in order to induce the T-cell–mediated destruction of myeloma cells from preclinical models as well as heavily pretreated patients.

Initial outcomes of the phase 1 study, which came out at the 2020 ASCO Virtual Scientific Program, demonstrated that this agent was found to be absolutely safe as well as effective in patients with r/r MM.

In the updated outcomes of the carried out study, Garfall presented additional data of teclistamab administered intravenously or subcutaneously in patients with r/r multiple myeloma.

In order to be eligible for the enrollment, the patients had to have measurable myeloma that was r/r or intolerant to the established treatment, hemoglobin that was minimum 8 g/dL, platelets that were minimum 75 x 109/L, and WBC counts that were minimum 1.0 x 109/L. Patients could not be given prior B-cell maturation antigen-targeted treatment. 

The carried out study comprised a couple of cohorts: intravenously (n = 84) and subcutaneously (n = 65) administration. The recommended dosing schedule in each cohort comprised 1-3 step-up doses before week 1, followed by the full doses in weeks 1-3.

In the intravenous cohort, the doses increased after 0.3 to 19.2 μg/kg with a highest dose of 720 μg/kg, the subcutaneous cohort began at 80 μg/kg and increased up to 3000 μg/kg. The initial every-2-week intravenous dose was switched to weekly intravenous or subcutaneous plus or minus step-up dosing. The investigators considered 1500 μg/kg as the recommended phase 2 dose. 

Premedication together with dexamethasone was limited to the step-up doses and the initial full dose, and there was no steroid needed after the initial complete dose. 

On behalf of the overall study population (n = 149), the median age is noted as 63 years (range, 24 to 84), and 22% of patients were aged 70 years and older, and the number of male patients 54%. About 12% of patients had at least 1 extramedullary plasmacytomas, and the median years since diagnosis was noted as 7 years. A total 32% of patients had high-risk cytogenetics, and 85% of patients had a prior transplantation.

On behalf of prior lines of therapy the median number was noted as 6 (range, 2 to 14); most patients (96%) were exposed to 3 classes of therapy, and 69 percent of patients were the penta-refractory. Patients were refractory to carfilzomib (66%), pomalidomide 77%), and anti-CD38 antibodies (93%), and 91 percent of the patients were refractory to their last line of therapy. 

The baseline characteristics were identical overall and in the cohort of patients on the recommended phase 2 dose (n = 33), except there were some patients with bone marrow plasma cells at 60 percent or more (10 percent). 

The primary end point in part-I of the trial was the recommended phase-2 dose; in part-II, the major concern appeared and that was safety and probability at the recommended phase-2 dose, as well as pharmacodynamics and pharmacokinetics, and antitumor activity. 

The updated outcomes also demonstrated that at the recommended phase-2 dose, the median time to first confirmed response was noted as one month (range, 0.3 to 3), 70% of patients with triple-class refractory responded to the treatment, and 75% of patients with penta-refractory responded. 

The maximum active doses were between 270 to 720 ug/kg administered intravenously and 720-3000 μg/kg administered subcutaneously. At these considered doses, the ORR (objective response rate) was noted as 69%, 59% of patients had a very good partial response rate or more, and a CR or better occurred in 26% of these patients. In the intravenous cohort (n = 27) and subcutaneous cohort (n = 41), the objective RR noted as 67% and 71%, respectively. 

In the subcutaneous cohort, the objective response rate was noted as 46% at the 80 μg/kg plus 240 μg/kg dose (n = 13), 60% at the 720 μg/kg dose (n = 15), and 73% at the 1500 μg/kg (n = 22), in which the good partial response rate or better was noted as 55%. 

Of about eleven evaluable patients across the intravenous and subcutaneous doses thus far, eight patients had a MRD (minimal residual disease negative) CR at 10 to 6 and one patient had this at 10 to 5 sensitivity. 

The observed responses were durable as well as deepened over time. Among responders who were given the recommended phase 2 dose (n = 16), and at a median follow-up of 3.9 months, 94 percent of patients are alive and progression-free. Of those in the subcutaneous cohorts (n = 35), 91 percent of patients are on treatment with ongoing responses; and the observed median follow-up is 6.5 months. 

Patients with the active intravenous and subcutaneous doses (n = 47) remained on the treatment with ongoing responses (94 percent) at a median follow-up of 6.5 months. All the five evaluable patients across the intravenous and subcutaneous cohorts demonstrated sustained minimal residual disease negativity. 

The pharmacokinetic findings favored the recommended phase 2 dose. Regarding the subcutaneous dosing, exposure was dose proportional after the initial treatment dose (80 μg/kg to 3000 μg/kg SC), and 1500 μg/kg subcutaneous was observed to have reduced either peak or trough ratio and maintained exposure over the max EC90. This help in order leads to the chances for less frequent subcutaneous dosing, Garfall added.

The safety profile was identical in the overall as well as recommended phase-2 dose population. Overall, the most common (≥20%) reported adverse events include; anemia, thrombocytopenia, and leukopenia. Nonhematologic all-grade adverse events include; pyrexia, diarrhea, nausea, fatigue, headache, and cough. Grade 3 or higher adverse events include; cough, diarrhea, nausea, and fatigue. 

In the recommended phase-2 dose cohort, hematologic adverse events include; neutropenia, anemia, thrombocytopenia, and leukopenia. Non-hematologic adverse events include; CRS, pyrexia, diarrhea, nausea, fatigue, headache, and cough. There was 1 non hematologic adverse event that was grade 3 or higher, and was fatigue. 

Across all doses, there were basically a couple of dose-limiting toxicities, but no DLTs were at the recommended phase-2 dose. These were grade-4 delirium, appeared at the 20 μg/kg intravenous step-up dose, and grade-4 thrombocytopenia, at the 180 μg/kg intravenous dose. 

Neurotoxicity noted in the 7 patients (5%), 1 (3%) which appeared at the recommended phase-2 dose. Two grade-3 or higher neurotoxicity noted at the intravenous dose, and none of which were reported with subcutaneous dosing.

Injection-site reactions appeared in 32% of patients, 36% noted at the recommended phase-2 dose, all of which were noted as either grade 1 or 2. One treatment-related adverse event, grade 5 pneumonia at 80 μg/kg following 16 cycles, led to death; no treatment related casualties noted at the recommended phase-2 dose.

The CRS noted in 55% of patients overall; the median time to CRS onset was two days (range, 1 to 5 days) and the median duration of CRS was two days (range, 1 to 8).

51% of patients had supportive measures in order to treat CRS: tocilizumab, steroids, low flow oxygen, and single low-dose vasopressor. 

None kind of treatment discontinuations due to CRS noted; CRS was generally confined to the step-up and initial complete doses. CRS appeared in 54%, 57%, and 64% in the intravenous, subcutaneous, and recommended phase-2 dose groups, respectively.

Step-up dosing was considered in order to mitigate the risk of severe CRS, and there were no cases of the grade-3 or higher CRS.

According to Garfall, “The phase-I carried out study remains ongoing, and a phase-II extended study has been initiated, Garfall concluded.