Neparidze Explores Bispecific T-Cell Therapies and Their Sequencing in R/R Multiple Myeloma

Natalia Neparidze, MD

Associate Professor of Internal Medicine (Hematology)

Research Leader, Myeloma Program, Hematology

Yale School of Medicine

New Haven, CT

CASE SUMMARY

• A 63-year-old man was diagnosed with multiple myeloma (IgG-κ) 8 years ago.
• He lives in a rural community .
• Medical history: hypertension controlled with lisinopril
• He now presents with penta-refractory disease progression (4 prior lines of therapy that included autologous stem cell transplant, 1 proteasome inhibitor [PI], 2 immunomodulatory imide drugs [IMiDs], and 1 anti-CD38 antibody).
• ECOG performance status: 2
• Weighs 155 lb (down 20 lb in past 6 months)

Bone Marrow Biopsy

• 80% λ light chain restricted
• Immunohistochemistry: B-cell maturation antigen (BCMA)–positive plasma cells: 63%

Repeat Imaging Study

• PET scan: increased uptake at L4, L5, and bilateral hip

Two Years Later

• The patient presents to their oncologist with bone pain in the lumbar spine region and is post mild stroke: affecting swallowing, requires thickened liquids, and uses cane.
• ECOG performance status: 2
• The patient started on BCMA-targeted bispecific therapy.

What studies validated the use of bispecific T-cell engagers in patients with triple-class refractory multiple myeloma?

NEPARIDZE: One of the landmark studies, MajesTEC-1 [NCT04557098], was a first-in-human phase 1/2 open-label, multicenter, multinational study looking at dose escalation and evaluating the safety, tolerability, and efficacy of single-agent teclistamab [Tecvayli] among patients with triple-class exposed or refractory multiple myeloma. The eligibility criteria included documented progression and measurable disease.

Three or more prior lines of therapy were [required], and they must have had a PI, IMiD, and an anti-CD38 monoclonal antibody. In this study, no prior BCMA-targeted therapy was allowed. The treatment followed the usual dose step-up escalation. It started with, as we do in practice now, 0.06 mg/kg followed by 0.3 mg/kg, and eventually a full treatment dose, which was weekly subcutaneous teclistamab at 1.5 mg/kg. Patients were followed for at least 2 years after the last patient enrollment. This was presented originally at the 2022 American Society of Clinical Oncology [ASCO] Annual Meeting and subsequently published in The New England Journal of Medicine the same year.¹

Overall, 165 patients participated in the study. Of note, there was a substantial number of patients [14.5%] who were [older than 75 years], and they fared just as well. There were [several] patients who had extensive bone marrow involvement with greater than 60% clonal plasma cell involvement [11.3%], and less than 20% of patients had extramedullary disease with evidence of extramedullary plasmacytomas. High-risk cytogenetics were represented in approximately 25% of patients, and other baseline characteristics were as expected for this population. There was a quarter of patients with less than 60 mL/min/1.73 m² estimated glomerular filtration rate. If you look at the prior exposure and refractoriness status…77% were triple-class refractory and approximately one-third were penta-refractory, meaning they were refractory to 2 PIs, 2 IMiDs, and a CD38 monoclonal antibody. So this was a heavily pretreated population.

What were the efficacy and safety findings from MajesTEC-1?

The median time to first response was within a month…. There was a 63% ORR and deep responses, as represented by complete response [CR] and stringent CR [sCR] on the order of 39% [Figure1]. Median progression-free survival [PFS] was 11 months, and median overall survival [OS] was 18 months. There were some responses that…lasted longer than 2 years…in this cohort.

In terms of safety, there were some dose delays and interruptions due to the adverse events [AEs]. [In] fact, 63% of patients required dose interruption due to AEs at some point during the treatment course in this study. This was mostly due to infections. There were several deaths that occurred in the study. Many of them were due to COVID-19…and there were several others. There were [2 deaths due to] severe [Streptococcus pneumoniae], 1 case of hepatic failure, and 1 case of progressive multifocal leukoencephalopathy [PML] that happened during the study. Otherwise, in terms of [the] AE profile, the large majority was represented by hematologic toxicity and cytokine release syndrome [CRS]…with very high prevalence of neutropenia, anemia, thrombocytopenia, and lymphopenia. CRS happened in 72% of patients. Overall, only [1 case of CRS] was higher than grade 2, so a large majority were grade 1 and 2. There were quite a few [cases of] pneumonia [18.2%] and other types of viral infections.

What other trials of BCMA-targeted therapy are important in this setting?

[I will also] review the next landmark study, which was MagnetisMM-1 [NCT03269136]. This was a phase 1 study evaluating another BCMA-targeted bispecific T-cell redirecting antibody, elranatamab [Elrexfio]. This study reported on 55 patients who [were] treated with therapeutically efficacious doses—more than 200 μg/kg in patients with relapsed/refractory multiple myeloma. They were heavily pretreated. Almost all patients were triple-class refractory, with a median of 5 prior lines of therapy, and a substantial portion had high-risk cytogenetics.

Reviewing the safety profile of elranatamab in MagnetisMM-1, it was similar to the prior experience with teclistamab.² There’s a high rate of hematologic toxicity in the form of overall neutropenia. [Most of this was] was grade 3 to 4 neutropenia, as well as [higher-grade] lymphopenia and thrombocytopenia. The CRS rate was initially 87%; after the subsequent modification of the priming plus premedication, the overall incidence of CRS was 67%. It was further mitigated with a priming phase in the phase 2 study, MagnetisMM-3 [NCT04649359]. All cases of CRS were grade 1 to 2. There were no cases of [grade] 3 or 4 CRS. Other AEs [included] fatigue, diarrhea, and decreased appetite…constitutional symptoms were…manageable.

In terms of efficacy, it showed a confirmed ORR of 64%, and the sCR plus CR was 38%. Some responses were durable and ongoing deep responses, with a median duration of response among responders of 17 months and a PFS of almost 12 months. Among all evaluable patients, 62% achieved minimal residual disease [MRD] negativity. Based on these data, elranatamab received FDA approval as of August 2023 for patients with relapsed/refractory multiple myeloma after having received 4 or more lines of therapy, including a prior PI, IMiD, and anti-CD38 monoclonal antibody.³

What additional data support the use of elranatamab?

A phase 2 portion of MagnetisMM-3 followed…. These were patients with triple-class exposed [disease who were] triple-class refractory to at least 1 PI, 1 IMiD, and an anti-CD38 monoclonal antibody. Note that the inclusion criteria were relatively liberal in that creatinine clearance of only 30 mL/min and above was required. Patients with thrombocytopenia were also included in this study, and the absolute neutrophil count target [of at least 1.0 × 10⁹] was reasonable.

In this design, there were 2 cohorts: A and B. Cohort A included only patients who had no prior BCMA-directed therapies…and cohort B treated patients who had received BCMA-targeted therapy, either in the form of [an] antibody-drug conjugate [ADC] or chimeric antigen receptor [CAR] T-cell therapy. Elranatamab was administered in a step-up dose, followed by a full treatment dose of 76 mg subcutaneously. The primary end point of the study was ORR, with [several] secondary end points, including duration of response, CR rate, overall clinical responses, PFS, OS, safety, pharmacokinetics, and negative MRD status.

Reviewing baseline characteristics and prior treatment exposure, approximately one-quarter of patients had high-risk cytogenetics.⁴ Approximately one-third of patients had extramedullary disease and substantial bone marrow involvement. In terms of prior drug exposure, close to 100% were triple-class refractory and 42% were penta-refractory.

The ORR in the entire cohort was 61%. There were many deep responses, with a very good partial response or better on the order of 56%. [Looking at] the variety of degrees of responses, there were impressive durable responses—an average of 15 months—and some responses that were ongoing for more than 25 months.

[For the] overall study population, at [a benchmark of] 15 months, [50.9%] of patients were progression free [95% CI, 40.9%-60.0%]. [Most] patients who had achieved CR…had long-lasting responses. There is some sense of a plateau forming at 89.5% [95% CI, 74.3%-95.9%], and the same is true for the OS curves among patients. The overall study population [had an OS rate of 56.7% at 15 months (95% CI, 47.4%-65.1%)], and patients who achieved CR [had a 92.6% OS rate (95% CI, 78.7%-97.6%]. Clearly, the achievement of the CR by itself is a prognostic marker, which portends better outcomes.

In terms of tolerability and the treatment-emergent AE profile, there were quite a few infectious-related complications, [including] grade 3 adenoviral pneumonias and a case of grade 4 PML. Twenty-eight percent of patients required dose reduction, and…77% of patients required transient dose interruption. In terms of elranatamab-related grade 5 AEs, these were severe adenoviral infections and pneumonia, adenoviral hepatitis leading to fulminant hepatitis, Pseudomonas pneumonia, and 1 case of failure to thrive. Hematologic toxicity, [including] neutropenia, thrombocytopenia, and lymphopenia, was quite prevalent, and CRS occurred in 57% of patients.

What do the studies of T-cell therapies show regarding the sequencing of these therapies?

With the availability of so many T-cell redirected therapies, how much do we know in terms of reusing some of the agents with either the same target or an antigen-switching alternative target? Data were presented by Urvi Patel, PharmD, and the Vanderbilt [University Medical Center] group at the 2023 ASCO Annual Meeting.⁵ This was a comprehensive review of the available data, which included literature, publications in the literature or data available from the ongoing trials, and data presented in the abstract form at the meetings.

The numbers for each one of these agents are small and somewhat hard to interpret, but in patients who received previous BCMA-directed therapy—whether that was a bispecific, an [ADC], or CAR T-cell therapy—if we come back with another BCMA-targeted therapy like teclistamab or elranatamab, there is a chance of approximately 40% to 50% that patients may still respond.⁵

Alternatively, if you do the class switching and come in with a different target like GPRC5D with talquetamab [Talvey], the ORR may be higher.5 The data from the TRIMM-2 study [NCT04108195], which combines talquetamab with daratumumab, appear particularly promising, with an ORR of 72%. But again, the overall numbers are quite small, so it must be interpreted with caution. It is the same thing with FcRH-targeted therapy with cevostamab; there’s an ORR on the order of 56% after prior failure of BCMA-directed therapy. If a patient had prior BCMA-directed therapy in the form of an ADC or bispecific and then secondarily received either [ciltacabtagene autoleucel (Carvykti) or idecabtagene vicleucel (Abecma)], the BCMA CAR T-cell therapies, they are likely to respond on the order of 60% to 70% of cases. Again, more data are needed with longer follow-up, and larger studies are needed to examine these patients.⁵

_REFERENCES

_{1. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478}

_{2. Raje N, Bahlis NJ, Costello C, et al. Elranatamab, a BCMA targeted T-cell engaging bispecific antibody, induces durable clinical and molecular responses for patients with relapsed or refractory multiple myeloma. Blood. 2022;140(suppl 1):388-390. doi:10.1182/blood-2022-166494}

_{3. FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma. FDA. August 14, 2023. Accessed April 2, 2024. https://tinyurl.com/38t58tx3}

_{4. Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9}

_{5. Patel U, Oluwole OO, Kassim A, et al. Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies. J Clin Oncol. 2023;41(suppl 16):e20049. doi:10.1200/JCO.2023.41.16_suppl.e20049}