Teclistamab in relapsed or refractory AL amyloidosis: a multinational retrospective case series

TO THE EDITOR:

AL amyloidosis is a rare condition characterized by the deposition of misfolded immunoglobulin light chains produced by clonal plasma cells or lymphoplasmacytic cells. Treatment aims at reducing the production of pathogenic free light chains (FLCs) to prevent organ damage. Deep and sustained hematologic response (HemR) correlates with organ function improvement and with survival outcomes.¹ Current guidelines recommend a regimen containing daratumumab, bortezomib, cyclophosphamide, and dexamethasone² for patients with newly diagnosed AL amyloidosis. Although this treatment results in high response rates,³ a proportion of patients are refractory or eventually relapse. The use of immunomodulatory drugs (IMiDs) or carfilzomib can be hampered by kidney injury or cardiovascular issues. Hence, new treatment options for patients with relapsed or refractory (R/R) AL remain an unmet medical need. Teclistamab, a bispecific T-cell engager (BCMA × CD3) antibody, has recently been approved for the treatment of R/R multiple myeloma (MM). Overall response rate in a phase 1 to 2 study of myeloma patients was 63%, with 26.7% reaching minimal residual disease negativity.⁴ Main safety concerns are the occurrence of cytokine release syndrome (CRS), immune cell-associated neurological symptoms (ICANS), and infections. There were no signals related to cardiac or kidney toxicity. Herein, we report data about safety and efficacy from patients with R/R AL treated with teclistamab in a real-life setting.

We retrospectively identified 17 patients with R/R AL from 10 university hospitals (Paris, Limoges, Toulouse, Lille, Poitiers, and Lyon in France; Athens in Greece; Utrecht in The Netherlands; Heidelberg and Essen in Germany) who received at least 1 dose of teclistamab between July 2022 and August 2023. All patients gave informed consent. Teclistamab was administered subcutaneously with the usual step-up dosing: 0.06 mg/kg at day 1, 0.3 mg/kg at day 4, 1.5 mg/kg at day 8, and then 1.5 mg/kg weekly unless otherwise specified. Dexamethasone was administered according to local practice. Data were extracted from patients’ medical records. Diagnosis and staging of AL amyloidosis as well as HemR and organ response assessment were performed according to consensus criteria with complete response (CR) as normal FLC levels with a normal κ/λ ratio and negative serum and urine immunofixation, very good partial response (VGPR) as a difference between involved and uninvolved FLC (dFLC) <40 mg/L, partial response as a dFLC decrease >50%, and no response as all other situations.⁵ We report separately patients in VGPR with a dFLC <40 mg/L and those in VGPR with an involved FLC <10 mg/L, as this threshold has been shown to correlate with outcomes (increased organ response and extended survival).⁶ The Mayo Clinic classification (2004) was used for cardiac assessment.^7,8 Associated symptomatic MM was defined as presence of CRAB criteria (hypercalcemia, renal dysfunction, anemia or bone lesions) or SLiM criteria (≥60% bone marrow plasma cells, free LC ratio >100, or >1 focal lesion >5 mm detected by MRI). Refractoriness was defined as absence of response or progression within 6 months of treatment.

Patient characteristics at teclistamab initiation are summarized in Table 1. Median age was 67 years, with a median time since diagnosis of 4.2 years. Cardiac involvement was present in 16 patients (94%), and kidney involvement was present in 10 (59%). Ten patients (59%) had concomitant symptomatic MM (8 with CRAB criteria, 2 with SLiM criteria). Median number of prior lines of therapy was 4. All patients except 1 had previously received daratumumab, bortezomib, and lenalidomide. Twelve patients (71%) were triple-refractory, and 3 (18%) were penta-refractory. Two patients had received prior anti-BCMA therapy with belantamab mafodotin (1 was refractory and 1 had to discontinue treatment due to ocular toxicity). Three patients with a t(11;14) had received venetoclax, and 2 were refractory.

At the time of evaluation, the median number of cycles received was 3 (range 0.25-10). Fifteen patients (88%) were in VGPR or better (out of 17 patients total) (Figure 1). Seven of 17 (41%) were in CR and 13 of 17 (76%) had a decrease of involved FLC below 10 mg/L. One patient did not respond, and 1 was not evaluable because of early death. Median dFLC at the time of evaluation was 0 mg/L (range 0-1370). Median time to best hematological response was 28 days (range 14-112). Five patients (29%) achieved an organ response (4 cardiac, 1 cardiac, and 1 kidney). Median follow-up was 3 months. None of the patients had a hematological relapse at the time of last follow-up. Two patients (11%) died, 1 from organ progression (initially Mayo 3B) and the other from infection.

Nine patients (53%) had a CRS after teclistamab administration, and all were grade 1. Two patients received tocilizumab. One patient with concurrent past history of unlabeled autoinflammatory syndrome received anakinra due to concomitant ICANS (grade 3) with recovery after 15 days. Serious bacterial infections (grade 3-5) occurred in 5 patients (29%) with 1 death. Viral infections occurred in 5 patients (29%) (influenza, herpes, and unknown), and 1 was grade 3. Two patients discontinued treatment because of adverse events (grade 3 ICANS, grade 5 infection), and 2 discontinued because of CR. Eight patients had schedule modifications: 6 switched to administration every other week instead of weekly, and 2 had delayed administrations due to infectious adverse events. Twelve patients (71%) received immunoglobulin replacement intravenously during the period of the report.

In this cohort of heavily pretreated patients with AL, we report deep and rapid responses, as early as 14 days, with a median time to best HemR of 1 month. Five patients for whom follow-up equals or exceeds 6 months have a sustained response, whether they are still on treatment or not. Longer follow-up is needed for proper assessment of organ responses, but 5 patients already had an organ response.

In daratumumab-exposed R/R AL amyloidosis, BCL2 inhibitor venetoclax is a promising option in the subset of t(11;14) population, with an 88% overall response rate.^9,10 Other regimens are available but show limited efficacy.^11-13 More recently, BCMA-directed therapies such as belantamab mafodotin, an antibody-drug conjugate, resulted in an overall response rate of 60% in the first 25 patients in the ongoing European Myeloma Network phase 2 trial (NCT04617925), with 36% achieving VGPR.¹⁴ A recently updated phase 1/2 clinical trial evaluating an academic anti-BCMA CAR-T HBI0101 was reported in 9 patients with triple-exposed R/R AL (3 of whom were Mayo stage 3a and 1 with stage 3b),¹⁵ with VGPR or better response in 8 patients but 5 deaths due to cardiac failure within 1 year postinfusion.

In our report, adverse event rates are consistent with those reported in a phase 2 R/R MM study, with a 35% rate of severe infections (vs 44.8%) and no grade 3 to 4 CRS (vs 0.6%).⁴ However, we report 1 grade 3 ICANS that occurred after teclistamab administration and hypothesize that the patient’s underlying autoinflammatory syndrome was involved. Severe infections are an important cause of morbidity in patients with AL. To improve safety, potential strategies are to be discussed, including schedule modifications such as spacing out of doses once the patient has reached HemR, fixed duration of treatment, and implementation of systematic immunoglobulin replacement intravenously. Although the number of cases is still limited, we have not registered any toxicity in the heart or kidney, which makes this therapy appear particularly suitable in the context of AL amyloidosis.

Further studies with a larger number of patients and a longer follow-up are warranted to confirm the efficacy and safety anti-BCMA bispecific antibodies in R/R AL amyloidosis.