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Emerging Therapies and Novel Approaches Targeting BCMA in Myeloma

Natalie S. Callander, MD
Released: October 26, 2020

Antibody–Drug Conjugates and Bispecific Antibody Constructs

Belantamab Mafodotin: BCMA-Targeted ADC

We now turn our attention to ADCs. Belantamab mafodotin (GSK2857916) is a first-in-class humanized BCMA‑targeted ADC that neutralizes soluble BCMA via multiple mechanisms.[14,15] This therapy carries a cytotoxic agent, monomethyl auristatin F, a microtubule poison that may facilitate antibody-dependent cytotoxicity.

Belantamab mafodotin was granted accelerated FDA approval in August 2020 as therapy for patients with R/R MM who have received ≥ 4 previous therapies, including an anti-CD38 monoclonal antibody, a PI, and an IMiD based on data from the DREAM-2 trial.

Phase I DREAMM-1 Study of Belantamab Mafodotin in R/R MM: Reductions in M Protein or FLC From Baseline

Belantamab mafodotin was initially evaluated in the phase I DREAMM‑1 study conducted in 35 patients with R/R MM, 40% of whom were daratumumab refractory.[16] The ORR in these patients was 60% (95% CI: 42.1% to 76.1%), including 2 patients with stringent CR and 3 with CR. This drug is given via IV infusion every 3 weeks without systemic steroids. Again, this is an impressive response rate.

Phase II DREAMM-2: Belantamab Mafodotin in R/R MM

The DREAMM‑2 study is an open-label, randomized phase II of 2 different doses of belantamab mafodotin in 196 patients with R/R MM after ≥ 3 previous lines of therapy, who were refractory or intolerant to IMiDs, PIs, and CD38 antibodies.[17]

The primary endpoint was ORR, which was 32% with the 2.5 mg/kg every-3-week dose and 34% with the 3.4 mg/kg every-3-week dose. Median PFS was 2.8 months at the lower dose and 3.9 months at the higher dose, and median OS was 14.9 months at the lower dose and 14.0 months at the higher dose. 

Phase II DREAMM-2: Safety

Belantamab mafodotin is associated with keratopathy, a visible corneal irritation that leads to symptoms such as blurring, dry eyes, or even some pain. Grade 3 and 4 keratopathy occurred in 27% and 21%, respectively, of patients in DREAMM-2 across dosing arms. Participants were regularly evaluated by ophthalmologists, and the drug was held if more serious keratopathy developed. Interestingly, during these dose holds, patients did not appear to progress. Careful monitoring and prompt management of any ophthalmic symptoms or keratopathy can help mitigate this AE and allow patients to remain on therapy once symptoms improve. 

Grade 3/4 thrombocytopenia occurred in 20% of patients in the lower dose arm and 33% in the higher dose arm. Grade 3/4 anemia occurred in 20% and 25%, respectively.

DREAMM-6: Study Design (Vd Arm)

The DREAMM‑6 study is an ongoing 2-arm, open-label, dose-escalation/dose-expansion phase I/II study evaluating belantamab mafodotin in combination with bortezomib/dexamethasone or lenalidomide/dexamethasone in patients with R/R MM (Capsule Summary).[18] In Part 1 of the study, 6 patients received 2.5 mg/kg or 3.4 mg/kg belantamab mafodotin with bortezomib/dexamethasone in 21-day cycles. In the dose-escalation phase, 45 patients received one of these regimens, or a similar regimen in which the ADC was split into 3 separate doses, for a maximum of 8 cycles. All arms could then receive single-agent belantamab mafodotin until progressive disease, death, toxicity, or withdrawal of consent. The primary objectives of the study were to assess safety, tolerability, and ORR.

DREAMM-6: Clinical Response

Interim results were available for 18 patients who received belantamab mafodotin with bortezomib/dexamethasone, all of whom had evaluable responses.[18] The ORR among this group was 78% (95% CI: 52.4% to 93.6%), with 50% achieving a VGPR. The most frequent AEs were thrombocytopenia (39%) and keratopathy (81%). All patients required dose interruption or delay. Numerous phase III studies combining belantamab mafodotin with other agents in R/R MM are currently recruiting.[19-21]

MEDI2228: BCMA-Targeted ADC

MEDI2228 is an anti-BCMA antibody that is conjugated to a DNA cross‑linking agent.[22] This compound appears to be preferentially bound to membrane BCMA and seems to be less impeded by soluble BCMA. An ongoing phase I study is assessing dose and toxicity, and we expect to hear more about this agent in the future.

Bispecific Antibody Constructs

Let’s move on to bispecific antibody constructs, starting with BiTE molecules. These are fusion proteins consisting of 2 separate monoclonal antibodies connected by a peptide linker.[23] For example, blinatumomab, approved by the FDA for the treatment of acute lymphoblastic leukemia, is a BiTE molecule consisting of an anti-CD19 antibody and an anti-CD3 antibody. A second form of bispecific antibody construct takes essentially the whole antibody molecule to make a single heterodimeric structure.[24]

AMG 420 in R/R MM: Study Design

AMG 420 is a BiTE molecule that binds to BCMA and CD3 on T-cells. This agent has been evaluated in 42 patients with R/R MM in a phase I study (Capsule Summary).[25] Participants at baseline had progressed after ≥ 2 previous treatment lines (including ≥ 1 each of PI and IMiD) and had no plasma cell leukemia, extramedullary relapse, central nervous system involvement, or previous allogeneic stem cell transplant. AMG 420 was given by continuous infusion for up to 5 cycles, and the primary endpoint was dose-limiting toxicity and maximum tolerated dose.

AMG 420 Response and Safety

The ORR was 31% in all doses, with an ORR of 70% in 10 patients who received 100 µg/day dosing with AMG 420. Of note, 5 patients who received 100 µg/day dosing achieved an MRD-negative response.[25]

The median time to response with AMG 420 was 1 month, with a median duration of response ranging from 8.4-9.0 months. In the patients who achieved MRD-negative CR, the median duration of response was 9.6 months.

The disadvantages of AMG 420 are the infusion schedule and the potential for significant toxicity. Administration is by 4-week continuous infusion likely in a hospital setting, which will be challenging for patients. There were also significant AEs in the phase I study, specifically peripheral neuropathy, which was surprising, and CRS.


Similar to the CAR T-cell therapies, bispecific antibodies can cause CRS, and 38% of patients treated with AMG 420 in the phase I trial developed CRS, although most of the cases were mild (grade 1, n = 13; grade 2, n = 2; grade 3, n = 1).

Another BiTE molecule, AMG 701, is also in development. This compound has been engineered to have an extended serum half-life that may permit weekly dosing. A large phase I/II trial of AMG 701 in patients with R/R MM is underway.[26]

Bispecific BCMA x CD3 Antibody REGN5458

REGN5458 is a bispecific BCMA x CD3 antibody that is given in subcutaneous weekly doses. Findings from a phase I study of REGN5458 in 7 heavily treated patients with primarily medullary and secretory disease have been reported.[27] Participants had received a median of 7 lines of previous systemic therapy, including anti-CD38 therapy, and a response was observed in 4 of the 7 patients. Toxicity was manageable and dose escalation is ongoing. A second compound, with different binding characteristics, REGN5459, is in development.

Teclistamab: BCMA x CD3 Bispecific Antibody

Teclistamab is a humanized IgG-4 bispecific antibody that redirects CD3+ T-cells to BCMA-expressing MM cells, inducing cytotoxicity in preclinical studies.[28,29]

Teclistamab: ORR

A phase I first-in-human study is evaluating the antitumor activity and safety of teclistamab in patients with R/R MM.[30] Doses in this dose-escalation phase ranged from 0.3-720 µg/kg/week. Although efficacy data from the higher-dose arm are not mature, a response rate of 67% was observed among 12 patients receiving the 270-µg/kg dose. At this dose, 7 of the 8 responders were triple-class refractory, and 5 of 8 were pentadrug refractory. Of the 5 patients evaluable for MRD, 4 were negative at a high level of 10‑6, and 2 had MRD-negative CR. The most frequent AEs were CRS and cytopenias. Again, there is likely to be great interest in seeing further data on this molecule.

Phase I Study of CC-93269 in R/R MM (CC-93269-MM-001): Study Design

CC-93269 is another BiTE antibody that binds to 2 different BCMA binding sites and to CD3. Findings from a phase I dose-escalation trial conducted in 30 patients with R/R MM have been reported (Capsule Summary).[31] Participants had received ≥ 3 previous regimens, with progressive disease within 60 days of their last line of therapy, and no previous BCMA-targeted treatment.

CC-93269-MM-001: CRS

Twenty-three of 30 (77%) patients experienced CRS, with one grade 5 event in a patient receiving the 10-mg dose.[31] Of interest, patients developing CRS did so after the first dose of CC-93269. Dexamethasone prophylaxis was administered to patients receiving ≥ 6 mg in later cohorts. So, clearly there is toxicity, but again, the hope is that after the first couple of doses given in hospital, treatment might then move to the outpatient setting.

CC-93269-MM-001: Preliminary Efficacy

Response rates in patients receiving CC-93269 were impressive, with an ORR of 88.9% among 9 patients on the higher dose of 10 mg, including 44.4% with stringent CR/CR.[31]

Conclusion

Thus far, one BCMA-targeted agent, belantamab mafodotin, has been granted accelerated FDA approval and is currently available as a treatment option for patients with heavily pretreated MM (≥ 4 previous therapies, including an IMiD, a PI, and an anti-CD38 antibody). When prescribing belantamab mafodotin, clinicians will access the drug through a REMS program, which will include careful monitoring to preemptively manage any treatment related AEs, such as ocular AEs, that are associated with this agent.

At the early stage of development of most other BCMA targeted agents, significant questions remain including whether 1 molecule within a particular class is superior to another and whether these therapies may be used sequentially. Could a different BCMA‑targeted approach be used as salvage therapy if a patient’s disease progresses, for example, after a CAR T-cell therapy, an ADC, or a BiTE antibody first?

As we have seen in MM over the years, new drugs introduced for R/R disease may eventually become incorporated into combination approaches in earlier lines of therapy or even as upfront therapy. Clinicians are no doubt eager to see these drugs being tested in untreated patients.

Finally, numerous CAR T-cell therapies and ADCs are being compared against standard therapies in randomized phase III trials, and we await findings from those studies in the next few years.[19-21,32,33] This review describes a wide range of BCMA-targeted approaches and therapies that collectively offer great promise for the management of patients with MM.

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