Elotuzumab in Combination With Dose Reduced IMiDs and Dexamethasone for AL Amyloidosis Patients With Relapsed/Refractory Plasma Cell Dyscrasia and Advanced Organ Involvement

Systemic light chain (AL) amyloidosis is a rare, life-threatening disorder characterized by toxic light chain deposition and multiorgan dysfunction [1, 2]. Standard treatment targets the clonal plasma cells, and daratumumab-based regimens have demonstrated rapid hematologic responses with significant organ recovery [3]. However, with the increasing use of daratumumab in early treatment regimens, there is a growing need for effective therapies for AL patients with double or triple refractory plasma cell disorders. Elotuzumab, a humanized IgG1 monoclonal antibody targeting SLAMF7 on plasma cells and natural killer cells, has been proposed as a promising option in case of daratumumab failure in multiple myeloma, particularly when used in combination with pomalidomide [3]. Although its combination with immunomodulatory drugs (IMiDs) appears promising for AL amyloidosis, data remain scarce, highlighting the need for further investigation to better define its role in patients with advanced organ involvement.

We retrospectively evaluated 33 AL patients with relapsed/refractory plasma cell disorder who were initiated with elotuzumab, dexamethasone, and an IMiD (pomalidomide in 25 patients) between January 2017 and October 2022. Table S1 displays the patient characteristics at initial diagnosis of the AL amyloidosis. All patients had the baseline visit prior to therapy start with elotuzumab and at least one follow-up visit at one of the two institutions, Heidelberg Amyloidosis Center or Hamburg Amyloidosis outpatient clinic (at Onkologicum HOPA). Elotuzumab was administered intravenously according to the manufacturer's prescribing guidelines along with standard premedication including antihistamines and dexamethasone. The initial dexamethasone dose was 20 mg, followed by 8 mg in subsequent treatments, with dose reductions considered in response to toxicity. The initial elotuzumab dose was 10 mg/kg total body weight administered weekly for the first 2 cycles, followed by 10 mg/kg total body weight every 2 weeks (combination with lenalidomide) or 20 mg/kg total body weight every 4 weeks (combination witch pomalidomide) until disease progression or unacceptable toxicities emerged. Additionally, patients orally received pomalidomide and lenalidomide on days 1–21 of each cycle, with median doses of 3 mg (range: 2–4 mg) and 7.5 mg (range: 2.5–15 mg), respectively. As of the data-cutoff date on August 4, 2024, a median of five elotuzumab cycles were administered (range: 2–46). Data acquisition, response evaluation, evaluation of tolerability and adverse events as well as statistical methods are detailed in the supplemental information.

At the start of elotuzumab (Table S2), the cohort exhibited significant organ dysfunction (27% on dialysis; 50% with NT-proBNP > 8500 ng/L) and extensive pretreatment (median of three prior lines, with 79% refractory to proteasome inhibitors, 55% to IMiDs, and 85% to daratumumab). Patients in the pomalidomide group had all prior exposure to daratumumab compared to only 63% of patients in the lenalidomide group and had a lower rate of previous autologous stem cell transplantation compared to the lenalidomide group (Table S2).

Adverse events Grade ≥ 3 occurred in 27% of patients (Table S3), with 57% reporting good or moderate tolerability (Table S4). Elotuzumab was used as last-line therapy in 36% of cases (Table S5). Additionally, 14% of patients resumed elotuzumab after a therapeutic pause with prior satisfactory tolerability and effectiveness. The median time to next treatment was 36 months (including the patients not requiring further therapy), indicating lasting benefit. For those patients switching therapies, common alternatives were venetoclax, daratumumab, melphalan, and belantamab mafodotin. In case the therapy was switched, there was a median interval of 1.5 months to subsequent therapy (Table S5).

Most patients experienced a reduction in dFLC levels, with a −69% change at 6 months and a median nadir of 37 mg/L at 9 months (Figure S1). The best overall hematologic response was achieved by 3 months (32%, intent-to-treat), with some patients showing further improvement at 6 months (Figure 1A,B). Notably, patients refractory to IMiDs before elotuzumab had higher response rates, though this did not improve overall or event-free survival (Figure S2, Tables S6–S8). There was no significant difference in OS and EFS between patients who had or had not been previously exposed to the same IMiD used in combination with elotuzumab (Tables S6–S8).

Four patients achieved an organ response (Table S9)—three with heart response and one with both heart and kidney responses. All organ responders received pomalidomide as an IMiD and achieved a durable very good partial response (VGPR). Due to the small number of evaluable patients, detailed statistical analysis of organ response was not feasible.

Overall survival (OS) and event-free survival (EFS) were evaluated over a median follow-up of 51 months using inverse Kaplan–Meier analysis, with median OS at 37 months and median EFS at 11 months (Figure 1C). Univariate analysis showed that most clinical and biological factors, including translocation (t11;14), gain of 1q21, and proteinuria, were not closely associated with OS or EFS (Table S8). Our analysis revealed no significant difference in OS or EFS between the different IMiDs used in combination with elotuzumab, despite varying severity of organ disease and rates of prior daratumumab exposure (Table S8).

A subgroup of five patients, who were not refractory to daratumumab, experienced no deaths, hinting at a trend toward better OS (Figure S3, Tables S6–S8). This might, at least in part, be caused by a comparably favorable clinical situation and comparably favorable organ involvement of daratumumab non-refractory patients (Table S10). Furthermore, landmark analysis revealed that a very good hematologic response at 6 months (defined as VGPR, low-dFLC PR [2] or CR) extended EFS from 7 to 28 months, though without a corresponding improvement in OS (Figure 1D).

With the growing use of daratumumab in early treatment regimens, effective options are urgently needed for patients with double or triple refractory plasma cell disorders. This retrospective analysis of 33 relapsed/refractory AL amyloidosis patients with advanced organ involvement treated with elotuzumab combined with IMiDs represents the largest systematic evaluation of elotuzumab in AL amyloidosis to date. With a median follow-up of 51 months, the duration of response can be evaluated with confidence.

The patient cohort in this clinically challenging setting of relapsed/refractory AL amyloidosis was characterized by several high-risk features. Almost 40% of patients had high-risk cytogenetics and almost half had a gain1q21. Furthermore, the patients presented severe organ dysfunction, had received extensive prior treatment, and showed refractoriness to proteasome inhibitors, IMiDs, and daratumumab. Due to the severe organ dysfunction, significant dose adjustments were necessary for IMiDs and dexamethasone. Despite these challenges, the tolerability of the elotuzumab and IMiD combination was acceptable, with grade 3 or higher adverse events occurring in 27% of patients and overall tolerability rated as good or moderate in 57%. Adverse drug reactions led to discontinuation in 19% of cases; however, many of these events were likely due to the underlying AL amyloidosis rather than the treatment itself.

In our study, the ORR was comparable to that observed in relapsed/refractory AL patients treated with lenalidomide/dexamethasone [4] and slightly inferior to that observed with pomalidomide/dexamethasone [5]. However, our patient cohort was unfavorable compared to the aforementioned studies, as indicated by a higher number of previous therapies. It is noteworthy that over half of the patients in our cohort were refractory to an IMiD at the start of elotuzumab treatment. Conversely, we observed prolonged OS and EFS compared to the aforementioned studies of AL patients treated with lenalidomide/dexamethasone [4] or pomalidomide/dexamethasone [5]. Interestingly, the patients refractory to an IMiD prior to elotuzumab treatment demonstrated a 19% higher ORR compared to those who were not refractory, and previous exposure to the same IMiD did not adversely affect survival outcomes. These findings suggest that the addition of elotuzumab may enhance the anti-plasmacellular activity of IMiDs in the relapsed/refractory setting. Although patients refractory to daratumumab tended towards worse OS, their EFS was similar to that of non-refractory patients, possibly reflecting differences in baseline clinical conditions and organ involvement.

Limitations of the study include its retrospective nature, lack of a comparison group, potential underreporting of adverse events, and a sample size too small for extensive multivariate analysis to identify prognostic factors.

In conclusion, elotuzumab combined with low-dose IMiDs and dexamethasone may offer the potential for long-lasting hematologic and organ response in heavily pretreated AL amyloidosis patients with advanced disease. Especially patients previously refractory to IMiDs showed acceptable response rates and survival data, making it a valuable treatment option in this difficult-to-treat patient cohort. Nonetheless, only a minority of patients responded, and especially the patients refractory to daratumumab, which is part of the current standard frontline therapy in AL amyloidosis, had inferior outcomes. However, options after failure of frontline daratumumab-based therapy are limited. For select patients, ASCT is possible, while venetoclax shows promise in t(11;14) cases [3]. Emerging immunotherapies, including CART cells and bispecific antibodies, also represent potential alternatives. These strategies require further prospective validation for efficacy and are associated with high costs and usually high risk of significant toxicities and mortality [6].

Validation of this real-world data would be best achieved through prospective studies focusing on elotuzumab and pomalidomide in t(11;14) negative AL patients or those who have relapsed after venetoclax treatment, moving it to second or third-line therapy.

Conceptualization: S.O.S., U.H., T.D. Data curation: T.D., T.H., U.H. Data analysis and visualization: T.D. Interpretation of data: all authors. Writing – original draft preparation: T.D. Writing – critical review and editing: all authors.

The data analysis was approved by the Ethics Committee of the University of Heidelberg and was in accordance with the principles of the Helsinki declaration. All human participants gave written informed consent for retrospective analysis of clinical data.

The authors declare the following conflicts of interest. Tobias Dittrich: none. Timon Hansen: Honoraria: BMS. Consulting or Advisory: BMS. Christoph Richard Kimmich: Honoraria: Amgen, Janssen, Kite/Pharma Gilead, Takeda, Glaxo Smith Kline GmbH & Co, and Sanofi-Aventis Deutschland GmbH. Travel support: Janssen and Kite/Pharma Gilead. Kaya Veelken: none. Anna Jauch: none. Marc S. Raab: Consulting or Advisory: BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie, Takeda. Research Funding: BMS, Janssen, Sanofi, Heidelberg Pharma. Travel support: BMS, Amgen, Janssen. Honoraria: BMS, Janssen, AbbVie, Sanofi. Carsten Müller-Tidow: Research Funding: Pfizer and BiolineRX. Ute Hegenbart: Honoraria: Janssen, Pfizer, Alnylam, Akcea, Prothena, Astra Zeneca. Financial support of congress participation; Janssen, Prothena, Pfizer. Advisory Boards: Pfizer, Prothena, Janssen, Alexion. Financial sponsoring of Amyloidosis Registry: Janssen. Stefan O. Schönland: Research support: Janssen, Prothena and Sanofi. Research cooperation: Neurimmune. Advisory boards: Janssen, Telix and Prothena. Honoraria: AstraZeneca, Alexion, Sobi, Janssen, Takeda, Pfizer and Prothena. Travel and congress participation grants: Janssen, Prothena, Celgene, Binding Site and Jazz.