“There was never a night or a problem that could defeat sunrise or hope.”
—Bernard Williams
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on bispecific antibodies such as teclistamab, AMG 701, REGN5458, and talquetamab in the treatment of patients with resistant multiple myeloma. For full details of these study abstracts, visit ashpublications.org.
Anti-BCMA Antibody Platform
ABSTRACT 180: Phase I results of teclistamab, a BCMA (B-cell maturation antigen) x CD3 bispecific antibody in resistant or refractory multiple myeloma (ClinicalTrials.gov identifier NCT03145181).1
Background: Teclistamab (JNJ-64007957) induces T-cell–mediated cytotoxicity against BCMA-expressing myeloma cells. Previously, investigators presented results from a study of teclistamab in resistant or refractory multiple myeloma that included a 67% objective response rate for the 270-μg/kg dose administered intravenously.2
Syed Ali Abutalib, MD
Kenneth C. Anderson, MD
Methods: The primary objective is to identify a recommended phase II dose. As of July 20, 2020, the study included intravenous (n = 84) teclistamab (0.3–720 μg/kg) and subcutaneous (n = 44) teclistamab (80–3,000 μg/kg). Overall, the median patient age was 64 (range = 24–82 years), and the median number of prior lines of therapies was six (range = 2–14). In all, 70% and 38% of the patients are penta-exposed/refractory in the intravenous and subcutaneous arms, respectively.
Results:
Adverse events in more than 20% of patients included anemia, neutropenia, thrombocytopenia, and leukopenia, as well as nonhematologic events of cytokine-release syndrome (3%), pyrexia, diarrhea, cough, fatigue, nausea, back pain, and headache.
Treatment-related grade ≥ 3 adverse events occurred in 39% of patients.
Cytokine-release syndrome events were all grade 1 (n = 51) or 2 (n = 17), and they generally were confined to initial doses.
A total of 5% of patients (all in the intravenous group) had neurotoxicity (2% grade ≥ 3).
Grade 3 or higher infection-related adverse events were reported in 15% of patients (3% treatment-related).
Four grade 5 adverse events were reported (all in the intravenous group and considered to be unrelated to treatment by investigator except for one case of pneumonia).
Overall response rate was 63.8% (30 of 47), including 24 with at least a very good partial response or better and 9 with at least a complete response.
The 1,500-µg/kg subcutaneous dose was selected as the recommended phase II dose; at this dose, six of six patients are in response (three partial responses, one very good partial response, two stringent complete responses) with progressive deepening of responses over time.
Teclistamab treatment in both the intravenous and subcutaneous cohorts led to pharmacodynamic changes supporting its mechanism of action.
Clinical Implications: Teclistamab has a manageable safety profile, which includes low-grade cytokine-release syndrome and low rates of severe infection and neurotoxicity. Deep and durable responses were observed. The encouraging tolerability and efficacy of teclistamab support the planned phase II monotherapy (1,500 g/kg) trial (NCT04557098) and combination with subcutaneous daratumumab regimens (NCT04108195).3 The high response rate and favorable side-effect profile at the recommended phase II dose even in penta-refractory multiple myeloma are promising. Moreover, the ease of use (off-the-shelf availability and subcutaneous administration) is an additional advantage of bispecific BCMA x CD3 antibodies compared with autologous chimeric antigen receptor (CAR) T cells.
ABSTRACT 181: Phase I first-in-human study of AMG 701, an anti-BCMA half-life extended bispecific T-cell engager molecule, in relapsed or refractory multiple myeloma (NCT03287908).4
Methods: Patients with myeloma who were resistant and/or refractory to or intolerant of at least three lines of therapy received AMG 701 intravenous infusions weekly in 4-week cycles until disease progression. A 0.8-mg step dose was added prior to target doses of at least 1.2 mg to prevent severe cytokine-release syndrome. The target dose was achieved by day 8 or sooner with earlier escalation. As of July 2, 2020, 75 patients received AMG 701.
Results:
The most common hematologic adverse events were anemia, neutropenia, and thrombocytopenia.
The most common nonhematologic adverse events were cytokine-release syndrome (61%), diarrhea, fatigue, and fever.
All grade 3 cytokine-release syndrome events (n = 5, 7%) were assessed as dose-limiting toxicities; all were reversible with corticosteroids and tocilizumab, with a median duration of 2 days.
Other dose-limiting toxicities included one case each of transient grade 3 atrial fibrillation, transient grade 3 acidosis, and grade 4 thrombocytopenia.
Serious adverse events (n = 29, 39%) included infections (13), cytokine-release syndrome (7), and asymptomatic pancreatic enzyme rise (2, no imaging changes, 1 treatment-related).
There were four deaths from adverse events reported, none related to AMG 701.
Reversible treatment-related neurotoxicity was seen in six patients, with a median duration of 1 day, all grade 1 or 2, and associated with cytokine-release syndrome in four patients.
The response rate was 36% (16 of 45) at doses of 3 to 12 mg.
With earlier dose escalation with 9 mg, the response rate was 83% (three partial responses, two very good partial responses).
Across the study, responses included four stringent complete responses, one measurable residual disease (MRD, formerly known as minimal residual disease)-negative complete response, six very good partial responses, and six partial responses.
The median (Q1, Q3) time to response was 1.0 month (range = 1.0–1.9 months), the time to best response was 2.8 months (range = 1.0–3.7 months), and the response duration was 3.8 months (range = 1.9–7.4 months), with a maximum duration of 23 months; responses were ongoing at last assessment in 14 of 17 patients.
Clinical Implications: In this ongoing dose escalation, AMG 701 demonstrated a manageable safety profile, encouraging activity, and a favorable pharmacokinetic profile in patients with heavily pretreated relapsed or refractory multiple myeloma, supporting its further evaluation. Moreover, we have recently conducted preclinical studies of AMG 701 combination therapy with lenalidomide and pomalidomide, showing that synergistic cytotoxicity against multiple myeloma cell lines and multiple myeloma patient cells can be achieved, even with low effector T cells, target multiple myeloma cell ratios, and low doses of drugs. Thus, combination therapies may both enhance activity and offer a favorable side-effect profile.5
ABSTRACT 291: Phase I/II, first-in-human study of REGN5458 in 45 patients with relapsed and/or refractory multiple myeloma (NCT03761108).6
Background: REGN5458, a BCMA x CD3 bispecific monoclonal antibody that binds to both BCMA and CD3, targets multiple myeloma cells with T-cell effector function via BCMA. In 2019, investigators presented data showing REGN5458 has an acceptable safety profile with evidence of clinical efficacy in heavily pretreated patients with relapsed and/or refractory myeloma.7
“The ease of use (off-the-shelf availability and subcutaneous administration) is an additional advantage of bispecific BCMA x CD3 antibodies compared with autologous CAR T cells.”— —SYED ALI ABUTALIB, MD, AND KENNETH C. ANDERSON, MD, FASCO
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Methods: Enrolled patients had progressive myeloma after at least three prior lines of systemic therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. About 53.3% patients were penta-refractory. Treatment consisted of weekly subcutaneous doses of REGN5458, followed by a maintenance phase administered every 2 weeks. The median age at enrollment was 64 (range = 41−81 years), and 14 patients (31.1%) were aged 70 or older. The median duration of follow-up was 2.37 months (range = 0.7−12.3 months).
Results:
The most common treatment-related adverse events were cytokine-release syndrome (37.8%), fatigue, nausea, and myalgias.
No patients had grade ≥ 3 cytokine-release syndrome.
Grade ≥ 3 treatment-related neurologic events occurred in one patient (grade 3 syncope 130 days after the first infusion).
Four patients discontinued treatment due to adverse events.
Infection-related adverse events occurred in 46.7% of patients (grade ≥ 3, 20%).
Serious treatment-related adverse events occurred in 22.2% of patients, with the most common due to cytokine-release syndrome (11.1%).
Grade 5 adverse events (all unrelated to the study drug) occurred in three patients: two with sepsis and one with COVID-19 infection.
The overall response rate was 35.6% across all dose levels (60% in the highest dose level), with 81.3% of responders achieving at least a very good partial response; 31.3% had a complete response or a stringent complete response.
A total of 18.8% had a duration of response of at least 8 months.
Clinical Implications: REGN5458 induced deep and durable responses in patients with relapsed and/or refractory multiple myeloma. In this updated analysis, REGN5458 continues to show an acceptable safety profile and durable efficacy in heavily pretreated patients with resistant myeloma. Enrollment in the phase I dose-escalation portion is ongoing, and the phase II portion of the study is recruiting. Although these findings are preliminary, this study shows high response rates at the highest dose levels. The phase II clinical trial will be critical not only to define efficacy, but also to delineate toxicity (especially infections), as maintenance therapy is utilized to prolong response. As with BCMA-directed CAR T cells, optimal strategies to prolong the durability of responses to BCMA x CD3 bispecific monoclonal antibodies will be defined in ongoing and future studies.
Non–BCMA–Bispecific Antibody Platform
ABSTRACT 290: Phase I, first-in-human study of talquetamab, a G protein–coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma (NCT03399799).8
Background: Despite improved outcomes with current treatments, most patients with myeloma will develop refractory disease, highlighting the need for novel treatments. GPRC5D is an orphan receptor whose transcript is highly expressed in primary multiple myeloma cells but has generally limited expression elsewhere, making it an attractive therapeutic target. Talquetamab (JNJ-64407564) binds to GPRC5D and CD3 to induce T-cell–mediated killing of GPRC5D-expressing myeloma cells through the recruitment and activation of T cells. In preclinical models, talquetamab induced cell killing of primary myeloma cells and inhibited tumor formation and growth in myeloma mouse models.
“REGN5458 continues to show an acceptable safety profile and durable efficacy in heavily pretreated patients with resistant myeloma.”— —SYED ALI ABUTALIB, MD, AND KENNETH C. ANDERSON, MD, FASCO
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Methods: Primary objectives are to characterize the safety of talquetamab and to identify a recommended phase II dose. As of July 20, 2020, 137 patients had received talquetamab: 102 by intravenous dosing (0.5–180 μg/kg) and 35 by subcutaneous dosing (5–800 μg/kg). The median patient age was 64 (range = 33–80 years; 31% were ≥ 70 years). The median number of prior therapies was six, with 31% penta-refractory.
Results:
The most frequently reported all-grade adverse events were anemia, neutropenia, lymphopenia, and cytokine-release syndrome (47%).
Cytokine-release syndrome was mostly grade 1 or 2 except for five patients with grade 3 cytokine-release syndrome, which occurred with intravenous dosing; only grade 1 or 2 cytokine-release syndrome was seen with subcutaneous dosing.
Treatment-related neurotoxicity was reported in seven patients (5%), and all resolved or are resolving. The median duration was 2 days [range = 1–9 days]: four had grade 1 or 2 events, and three had grade 3 events.
Of seven patients, six had neurotoxicity that occurred in the context of cytokine-release syndrome, including all three grade 3 events.
Infections were reported in 37% of patients (8% grade 3 or 4).
Two dose-limiting toxicities were observed: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma (7.5 μg/kg intravenous) and grade 3 maculopapular rash (135 μg/kg subcutaneous). The maximum tolerated dose has not been defined.
Intravenous and subcutaneous dosing of talquetamab led to comparable increases in T-cell activation and cytokines.
Overall response rate for intravenous doses of 20 to 180 μg/kg was 78%.
Overall response rate for subcutaneous doses of 135 to 405 μg/kg was 67%.
Responses were noted starting at 1.0 μg/kg, were rapid at a median of 1 month (range = 0.2–3 months), and durable with the median not reached in 36 of 46 patients.
Clinical Implications: GPRC5D is a novel target for myeloma. In the first clinical report of this first-in-class agent, encouraging clinical activity with manageable safety was observed with talquetamab in heavily pretreated patients with relapsed and/or refractory myeloma. A maximum tolerated dose has not been defined, and dose escalation continues, with the study nearing a recommended phase II dose(s). The encouraging clinical activity supports monotherapy development and combination approaches including with another anti-BCMA–bispecific antibody such as teclistamab (NCT04586426). Of note, the BCMA antibody–directed conjugate belantamab mafodotin and the first BCMA-directed CAR T cell (idecel) are already approved by the U.S. Food and Drug Administration to treat relapsed and/or refractory myeloma; moreover, bispecific T-cell engagers targeting BCMA are promising and likely to be approved soon. Although mechanisms of resistance to BCMA-directed therapies are not fully characterized, downregulation of BCMA expression and genetic loss of BCMA have already been described. Immune strategies directed against novel targets such as GPRC5D may offer effective treatment options, even in myeloma refractory to BCMA-directed treatments.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Anderson has been an advisor or consultant for Amgen, Janssen, Pfizer, Sanofi, Oncopeptides, and Precision Biosciences.
REFERENCES
1. Garfall AL, Usmani SZ, Mateos MV, et al: Updated phase 1 results of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 180. Presented December 5, 2020.
2. Usmani SF, Mateos MV, Nahi H, et al: Phase I study of teclistamab, a humanized B-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. 2020 ASCO Virtual Scientific Program. Abstract 100.
3. Pillarisetti K, Powers G, Luistro L, et al: Teclistamab is an active T cell–redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma. Blood Advances 4:4538-4549, 2020.
4. Harrison JS, Minnema MC, Lee HC, et al: A phase 1 first in human study of AMG 701, an anti-B-cell maturation antigen half-life extended BiTE® (bispecific T-cell engager) molecule, in relapsed/refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 181. Presented December 5, 2020.
5. Cho SF, Lin L, Xing L, et al: The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models. Blood Advances 4:4195-4207, 2020.
6. Madduri D, Rosko A, Brayer J, et al: REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with relapsed/refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 291. Presented December 5, 2020.
7. Cooper D, Madduri D, Lentzsch S, et al: Safety and preliminary clinical activity of REGN5458, an anti-BCMA x anti-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Blood 134(suppl 1):3176, 2019.
8. Chari A, Berdeja JG, Oriol A, et al: A phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 290. Presented December 5, 2020.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell and Gene Therapy. Dr. Anderson is Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics and Kraft Family Professor of Medicine at the Harvard Medical School.
