Amyloid light chain (AL) cardiomyopathy (AL-CM) is a highly aggressive disease with high early mortality without prompt and effective treatment; however, its low prevalence and rapid clinical progression pose significant challenges to randomized controlled trials. As a result, plasma cell–directed management for AL amyloidosis is typically extrapolated from studies of multiple myeloma, and guidance has historically relied on case reports, case series, retrospective cohorts, and expert consensus statements. 1 , 2 , 3
Heart transplantation has emerged as a viable salvage therapy for carefully selected patients with advanced AL-CM without significant extracardiac involvement and adequate hematologic control. Prior expert consensus guidelines emphasize the importance of achieving a hematologic response before transplantation to optimize short- and long-term post–heart transplant outcomes. 3 , 4 However, despite significant advances in AL therapy over the last decade, 5 some patients remain refractory to all plasma cell–directed therapies.
Teclistamab, a novel T cell–redirecting bispecific antibody targeting B-cell maturation antigen, demonstrates remarkable efficacy in refractory multiple myeloma. 6 , 7 Case reports and small series suggest similar promise in AL amyloidosis, 8 , 9 particularly in patients with limited therapeutic options.
In this issue of JACC: Case Reports , Ibrahim et al 10 describe a patient with refractory AL-CM who achieved rapid , minimal residual disease–negative complete hematologic response with teclistamab while in cardiogenic shock, enabling successful heart transplantation. This case expands the limited but growing evidence base supporting innovative approaches in advanced AL-CM.
There were 3 key findings from this report. First, teclistamab effectively achieved a rapid and deep hematologic response in refractory AL amyloidosis with severe AL-CM, consistent with prior reports. 8 , 9 Second, the case demonstrates that a patient presenting in cardiogenic shock on inotropic support, without hematologic disease control at hospital admission, can be stabilized to undergo heart transplantation after rapid inpatient initiation of therapies. This finding underscores the feasibility of urgent transplantation in select patients with AL-CM who would have been previously considered ineligible. Third, there were no peri-transplant complications associated with teclistamab use within 3 months; longer-term outcomes remain unknown.
Conventional plasma cell–directed monoclonal antibodies such as the CD-38 antagonist daratumumab primarily engage components of the innate immune system, including macrophages and natural killer cells. In contrast, teclistamab is a bispecific T-cell engager that recruits the more potent adaptive immune system, binding B-cell maturation antigen on plasma cells and CD3 on cytotoxic T cells to induce direct plasma cell killing. In fact, in the MajesTEC-3 trial, the combination of teclistamab plus daratumumab was superior to daratumumab-based standard regimens, achieving complete responses in 82% vs 32%, respectively, with a median response time of 1.2 months to first response and 6.9 months to complete response. 6
These observations in multiple myeloma provide a biological and clinical rationale for off-label use in AL amyloidosis. In this case report, hematologic response occurred in <2 weeks, highlighting the unique potential of teclistamab for rapid disease control compared with conventional therapies, essential in critically ill patients with AL-CM and cardiogenic shock. This rapid hematologic response facilitates timely eligibility for heart transplantation.
Indications and contraindications for heart transplantation in AL-CM are not strictly established. In a Scientific Statement from the Heart Failure Society of America, a comprehensive multidisciplinary evaluation for extracardiac disease is recommended with particular attention to the presence of gastrointestinal involvement with malnutrition, debilitating peripheral neuropathy, or autonomic dysfunction. 4 In a Mayo Clinic consensus document, the lack of complete remission was considered a potential contraindication to transplantation given uncertainty of disease control and post-transplant recurrence. 3
The availability of teclistamab challenges this paradigm, enabling a more aggressive approach to heart transplantation in patients with cardiogenic shock without established disease control. Furthermore, not only is teclistamab a viable pre-transplant treatment option for patients with AL-CM, but it also offers the hope of heart transplantation for patients in cardiogenic shock without disease control. Given the effectiveness of contemporary plasma cell–directed therapies, including teclistamab, patients with AL-CM, cardiogenic shock, and lack of pre-transplant disease control could be potentially considered for transplantation with deferment of plasma cell–directed therapies to the post-transplant setting.
Nonetheless, despite its promise, there are many unanswered questions regarding the role of teclistamab in AL-CM pre- and post-transplantation. Teclistimab is associated with high rates of toxicity including low-grade cytokine release syndrome (60%), cytopenias (78%), infections (43%), and immune effector cell–associated neurotoxicity syndrome (1%). 6 These adverse events can pose a challenge for patients pre-transplant who are hemodynamically unstable; potentially on temporary mechanical circulatory support and continuous renal replacement therapy; and prone to worsening hemodynamic instability, bleeding, and infections. In addition, the risk of teclistamab on the development of infection and long-term malignancy in the context of post-transplant immunosuppression is unclear. Whether teclistamab may also result in a rebound increase in post-transplant antibodies, particularly new donor-specific antibodies, leading to increased rates of cardiac rejection and allograft vasculopathy, is also not established.
In the gap between clinical trials and patient care, clinicians must use their best judgment and experience, which in this case included avoiding induction immunosuppression and implementing a rapid prednisone taper with addition of monthly intravenous immunoglobulin administration to standard post-transplant infectious prophylaxis. This may have been successful in the short term; however, further evidence from larger cohort studies with longer follow-up would be essential to provide reliable guidance to clinicians implementing teclistamab for patients with AL-CM undergoing heart transplantation.
Although many questions remain regarding the use of teclistamab in AL-CM heart transplant candidates and recipients, this novel and highly effective therapy offers hope for many patients with AL-CM who previously had no options for improvement in quality of life and survival. Whereas randomized controlled trials remain the gold standard for establishing the effectiveness and safety of novel therapies, the rarity and severity of AL-CM, coupled with the low incidence of heart transplantation, means that well-documented case reports continue to play a critical role in advancing the field.
Funding Support and Author Disclosures
Dr Stern has received research support from Intellia Therapeutics and Pfizer, advisor fees from Eidos/BridgeBio and Pfizer, and honoraria from Alnylam Pharmaceuticals. Dr Kittleson has reported that she has no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center .
References
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