Linvoseltamab, a new BCMA-targeting bispecific antibody for multiple myeloma: linking new with existing data

Over the past 2 decades, the treatment of multiple myeloma (MM) has dramatically improved. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies (MoAbs) have become the cornerstones of MM therapy in addition to chemotherapy and steroids. This breakthrough in drug development has translated into improved outcomes for MM patients, young and elderly, newly diagnosed and at relapse (1). Because of the availability of different highly active anti-myeloma drugs that can be used in several combinations and sequentially, MM has now gradually been transformed from an acute, life-threatening disease to a more chronic disease with phases of increased disease activity interspaced by deep remissions that can last for many years. Although a growing number of MM patients will no longer die because of myeloma, their disease still remains largely incurable. In addition, patients with high-risk MM, partially defined by unfavorable cytogenetic abnormalities, the presence of extramedullary disease or by an early relapse after first-line therapy, still face a more dismal outcome compared to those without these features (2). MM patients who have been previously treated with at least one PI, one IMiD and a CD38 MoAb are called ‘triple-class exposed’ (TCE). Since many of the anti-myeloma drugs are given until disease progression, the majority of TCE MM patients will also be triple-class refractory (TCR). Those patients face a particularly dismal outcome. This was confirmed in a recent prospective study of 248 TCE patients, of whom 73% were TCR. Overall response rates were only 31%, median progression-free survival (PFS) 4.6 months and overall survival (OS) 13.8 months (3). Moreover, the majority of treatments administered to TCE and TCR MM patients were, until recently, mostly retreatment with the drugs already previously given, emphasizing the unmet medical need for novel therapeutic options (4).

The identification of B-cell maturation antigen (BCMA) as a potential target for MM treatment has fostered the development of several new immunotherapies, including antibody-drug conjugates (ADC), and more recently T-cell redirecting therapies as chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BsAb) (5). The ADC belantamab mafodotin was the first BCMA targeting agent for TCE and TCR MM patients with modest activity in that setting (6), whereas CAR-T and BsAb have now become the real game-changers because of unprecedented clinical activity. Teclistamab (7) and elranatamab (8) are two humanized BsAb targeting BCMA on myeloma cells and CD3 on T-cells. Both agents have been recently approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of TCE and TCR MM.

The recently published paper by Bumma et al. reports the phase I/II data from another BCMAxCD3 targeting BsAb called linvoseltamab (9). The LINKER MM-1 phase I/II study enrolled 282 patients with TCE MM, with the main focus of the publication on the 117 patients receiving the full dose of 200 mg of linvoseltamab. In that cohort, 82% of patients were TCR. After a median follow-up of 14.3 months, the overall response rate in the 200 mg cohort was 71% with an impressive complete response or better rate (≥ CR) of 49.6%. The PFS rate of 89.3% at 12 months is highly promising. Despite these impressive clinical results, one could argue to what extent the MM community is waiting for another BCMA targeting BsAb. The previously published phase 2 studies with teclistamab (MajesTEC-1) (7) and elranatamab (MagnestisMM-3) (8) enrolled a very similar patient population. So how do the LINKER-MM1 efficacy data compare to both studies? The comparative data are summarized in Table 1. In terms of patient selection, all three studies enrolled mostly TCR patients (80% in MajesTEC-1, 97% in MagnetisMM-3). The overall response rates with teclistamab, elranatamab and linvoseltamab were respectively 63%, 61% and 71% with corresponding ≥ CR rates of 45%, 35% and 50%. The reported 1-year PFS of 89.3% with linvoseltamab initially appears favorable compared to the median PFS of 11.3 months with teclistamab and 17.2 months with elranatamab. But does that immediately imply superiority of one agent over the others? Linvoseltamab is a fully human BsAb, whereas teclistamab and elranatamab are humanized and all three target the same antigens (BCMA and CD3). Possible explanations for the difference in the reported clinical activity of teclistamab, elranatamab and linvoseltamab might be the binding to different epitopes in addition to the different dosing regimens. According to the label, the first-in-class BCMA BsAb teclistamab is continued weekly for an additional 6 months in patients achieving ≥ CR (7), whereas elranatamab was switched from weekly to biweekly after 6 months of treatment in patients achieving at least a partial response for a minimum duration of 2 months (8). After step-up dosing, intravenous linvoseltamab was given weekly until week 14, biweekly from weeks 16 to 23 and monthly from week 24 on in patients achieving at least a very good partial response (9). A less dose-dense regimen is not only more patient-friendly, but recent data have emphasized the importance of immune-exhaustion during continued treatment with BsAb (10). In that perspective, the longer intervals between linvoseltamab administrations might contribute to less immune exhaustion and a positive impact on its anti-myeloma efficacy. Interestingly and impressively high ≥ CR rates have been reported with all 3 agents. Deep responses are usually a predictor for response duration in MM. In that regard, the recent 30-month follow-up data with teclistamab revealed a median PFS of 62% and OS of 74% in the ≥ CR cohort (11). These PFS results are comparable with the best results obtained with a BCMA targeting CAR-T cell product in TCE MM patients (12). Just like in the MajesTEC-1 and MagnetisMM-3 trials, patients with high-risk cytogenetic features benefit from linvoseltamab. In contrast, those with a higher tumor load reflected by a high bone marrow plasma cell percentage, more advanced International Staging System (ISS) stage and those with extramedullary disease have a more limited response which could be related to the presence of higher soluble BCMA levels or a less permissive immune micro-environment in the soft tissue plasmacytomas (13,14).

One of the class-specific adverse events associated with the use of T-cell engagers are cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS). Mitigation strategies to prevent CRS and ICANS when using BsAb include step-up dosing and the use of premedications (paracetamol, antihistamine drug, steroids) during the initial treatment phase. CRS was reported in 46% of patients in LINKER-MM1 (9), whereas corresponding percentages were 72% and 56% in MajesTEC-1 (7) and MagnetisMM-3 (8). In all three studies, CRS events remained mostly limited to grade 1 or grade 2 and only very exceptionally grade 3. Linvoseltamab step-up doses were given weekly whereas step-up of teclistamab and elranatamab is usually with an interval of 2 to 3 days between doses, depending on the occurrence of CRS. In many centers patients are still hospitalized during the whole step-up treatment phase which creates a burden for patients, puts additional pressure on the availability of hospital beds and adds a significant cost to this treatment. According to the occurrence and resolution of CRS reported, the step-up dosing of linvoseltamab on day1 and day 8 could limit this hospitalization time. In contrast to the frequency of CRS, ICANS is very rarely seen with BCMA BsAb. Compared with published data on teclistamab and elranatamab, the reported ICANS rates in LINKER-MM1 seem to be a bit higher with 2.6% developing grade 3 ICANS (9). Hematological toxicities can occur with BsAb and reported rates of neutropenia and anemia are comparable between linvoseltamab, elranatamab and teclistamab (7-9). Thrombocytopenia is not reported in the LINKER-MM1 manuscript. One of the major concerns of the use of BsAb in TCE and TCR MM is the increased risk for infection. MM patients already have an intrinsically higher risk for infections, especially when heavily pretreated (15). BCMA-targeting BsAb can cause severe hypogammaglobulinemia, lymphopenia and sometimes neutropenia and therefore put patients at an increased risk for bacterial, viral and opportunistic infections (16). Grade 3 or 4 infections were reported in 36% of patients in LINKER-MM1 (9) compared to 55% and 40% in MajesTEC-1 (7) and MagnetisMM-3 (8), respectively. Mitigation strategies to reduce this high infection risk are prophylactic vaccination whenever possible (17), the use of varicella zoster and Pneumocystis jirovecii prophylaxis, along with immunoglobulin supplementation (18). Also reducing the dosing frequency when a deep anti-myeloma response is reached has been proven to further reduce the infection risk (19).

So where do we go from here? The phase II LINKER-MM1 study adds additional evidence to the clinical value and manageable side effects of BsAb in TCE and TCR MM. All subgroups of patients benefit to some extent and age by itself is not an exclusion if patients are considered fit enough for this type of treatment. So we believe that linvoseltamab will become the third in class BCMA targeting BsAb for TCE MM patients and it is now approved by FDA and EMA. Attractive assets of this compound are its impressive clinical activity, weekly step-up dosing and the less frequent dosing regimen. However, in TCE and TCR MM, BCMA targeting CAR-T cells are still considered as the ‘gold standard’ (12,20,21) but efficacy rates of BsAb, particularly in ≥ CR patients are getting close to the best reported CAR-T data. CAR-T cell treatment still has the advantage of being a ‘one shot’ therapy but worldwide availability is still limited and manufacturing times can be long. Long-term side effects like secondary malignancies and Parkinsonism are, although being very rare, still a concern for patients and physicians (22). Being ‘off the shelf’ products, BsAb are readily and more widely available. If we are able to harness the rapidly expanding pre-clinical knowledge on immune fitness and exhaustion (23) before and during BsAb treatment a more selective and even more effective use of these agents is becoming within reach. Less dose intensive regimens, like the once monthly administration of linvoseltamab in LINKER-MM1 will, together with appropriate prophylactic strategies, further reduce the infection risk.

The journey of advanced immunotherapies in MM has just started with BCMA still being the most commonly target antigen but others like G-protein coupled receptor 5D (GPRC5D) (24) are becoming of growing interest. In addition, several large phase 3 trials are ongoing, or have been fully enrolled, with BsAb used as single agent or in combination in earlier myeloma treatment lines. Overall and most importantly, this is excellent news for MM patients around the world. In that perspective, the future approval of linvoseltamab in relapsed MM will further expand and optimize the use of BCMA targeting BsAb in MM.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-225/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-225/coif). M.D. has received consulting fees from Amgen, BMS, GSK, J&J, Pfizer, Roche, Sanofi and speaker honoraria from Amgen, BMS, GSK, J&J, Pfizer. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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