<scp>Daratumumab, lenalidomide, and dexamethasone</scp> in systemic <scp>light‐chain</scp> amyloidosis: High efficacy, relevant toxicity and main adverse effect of gain 1q21
Authors: Christoph R. Kimmich, Tobias Terzer, Axel Benner, Timon Hansen, Alexander Carpinteiro, Tobias Dittrich, Kaya Veelken, Anna Jauch, Stefanie Huhn, Marco Basset, Hartmut Goldschmidt, Carsten Müller‐Tidow, Stefan O. Schönland, Ute Hegenbart
Journal: American Journal of Hematology (2021)

Daratumumab/dexamethasone (DD) or daratumumab/bortezomib/dexamethasone (DVD) have become standard salvage regimens in systemic light-chain amyloidosis (AL).1 Excellent results have been achieved with the combination of daratumumab/lenalidomide/dexamethasone (DRD) in relapsed/refractory and newly diagnosed multiple myeloma (MM).2 However, in AL the efficacy and toxicity of DRD has not yet been separately assessed. In our retrospective study, we evaluated 44 consecutive AL patients with relevant visceral organ involvement treated with DRD at three specialized centers. Interphase fluorescence in situ hybridization (iFISH) results stem from routine analysis at first diagnosis. All patients with above 10% iFISH-positive cells for ≥3 copies for chromosome 1q21 were classified as gain 1q21 positive. Amplification 1q21 was not analyzed as only one patient had >3 copies. All patients gave written informed consent for their clinical data to be used in accordance with the Declaration of Helsinki. Clinical organ involvement, response assessment, missing data inclusion and statistical evaluation were performed as previously described.3 More detailed information on methods and results can be found within the online only supplement. Daratumumab/dexamethasone was intravenously applied after standard premedication.3 Lenalidomide was taken orally from day 1–21 mainly in dosages of 5 or 10 mg (range 2.5 mg every other day to 25 mg/day) and repeated every 28 days. Treatment was planned as continued therapy without a pre-specified duration. Every patient received prophylactic acyclovir and anticoagulation, usually acetylsalicylic acid 100 mg/day. Antibiotic prophylaxis was not routinely performed. Baseline characteristics (medians with ranges in brackets) showed relevant, but not substantially advanced AL. Daratumumab/lenalidomide/dexamethasone was initiated 8.5 (1–186) months after start of the first line and 1.0 (0–87) months after end of last therapy. Daratumumab/lenalidomide/dexamethasone was utilized as second (n = 27), third (n = 11) or fourth (n = 6) line regimen. Thirteen patients had been treated with lenalidomide in the past, amongst which five were lenalidomide-refractory. Median age was 62 (50–80) years and 70% were male. Baseline bone marrow plasma cell percentage (BMPC) was 18% (4–90). Amongst 31 analyzed patients in 16 cases gain1q21 and in 17 cases t(11;14) was present. The median number of involved organs was two (1–5), namely, heart (77%), kidney (59%), soft tissue (41%), liver (7%), gastrointestinal (GI) tract (23%) and neuropathy (17%). Ahead of DRD, N-terminal prohormone of brain natriuretc peptide (NT-ProBNP) level was 1654 (89–33 341) ng/L, difference between involved and uninvolved serum free light chain (dFLC) was 102 (0–3394) mg/L, estimated glomerular filtration rate (eGFR) in patients not on dialysis was 79 (5–186) mL/min/1.73 m2 and albumin-to-creatinine ratio (ACR) was 33 (0–1034) mg/mmol. Underlying disease was symptomatic MM (n = 5), smoldering MM (n = 35) or a monoclonal gammopathy (n = 4). On the data cutoff date 23 June 2020, after a median follow-up time of 18.2 months, patients had received on median 17 daratumumab infusions (range, 2–38) and four cycles of lenalidomide/dexamethasone (Rd) (range 0.5–24). Fifty-five percent of patients presented with at least one infectious complication, mostly involving respiratory tract (n = 14), skin (n = 4), GI tract (n = 4) or urinary tract (n = 2). Lymphocytopenia was the most common hematologic toxicity with 58% and grade 3/4 in 25%. Apart from a 74-year-old male with neuropathic and cardiac AL (NT-ProBNP 1286 ng/L) dying within the first month of treatment after developing neutropenic sepsis related to pneumonia, no other grade ≥ 3 hematologic toxicities occurred. Another two patients with cardiac AL died early by unknown causes. The following grade 3/4 infectious events occurred: pneumonia (n = 7), large bowel perforation related to colitis (n = 3, location: twice sigmoid, once caecum) and skin abscesses (n = 2). Only the patient with caecum perforation had baseline GI tract involvement. Severe infectious complications mainly occurred within the first three months. Three patients progressed infection-related to dialysis during therapy and another five patients had an eGFR reduction >25% either caused by infection (n = 3) or extensive bleeding. Fatigue, impaired quality of life, was noted in 36% of patients and mainly in combination with infection or congestive heart failure, led to treatment discontinuation or dose reductions. Calculated median hematologic event-free survival (hemEFS) and overall survival (OS) were 17.4 and 29.1 months, respectively. Additionally, to the three early deaths, five patients died related to progressive AL under DD (n = 2), under a next line of therapy (n = 2) or under best supportive care. After 12 months, 84% of patients were alive and 71% had no hematologic event. The following hematologic events occurred as first event: death (n = 5), next-line therapy (n = 10) and hematologic progression (n = 5) with three patients progressing after achieving at least a partial response (PR). On univariable analysis, hemEFS was adversely influenced by dFLC >180 mg/L (HR 2.71, p = .027) and gain 1q21 (HR 9.8, p = .003). ACR >220 mg/mmol showed a trend towards worse hemEFS (HR 2.24, p = .094), whereas translocation t(11;14) did not affect outcome (see Figure 1). Gain 1q21 was simultaneously detected in seven of 17 t(11;14) positive patients. Amongst the 15 patients without gain 1q21 only two hematologic events occurred within the follow-up period: death related to advanced cardiac AL and initiation of a next-line of therapy in an IgD lambda patient with progressively increasing IgD and NT-ProBNP. Exploratory multivariable analysis of the two univariably significant factors in combination with ACR >220 mg/mmol confirmed gain 1q21 as highly significant (HR 8.9, p = .005) and dFLC >180 mg/L as still relevant (HR 3.55, p = .049). Overall response rates (ORR) of 84% (31/37) and 82% (28/34), very good hematologic remission (VGHR) rates of 65% (24/37) and 62% (21/34) as well as complete response (CR) rates of 16% (6/37) and 21% (7/34) were noted after 3/6 months, respectively. All patients without gain 1q21 were in remission at month 3/6 with respective VGHR rates of 87% (13/15) and 86% (12/14). Patients with gain 1q21 also achieved good, but significantly lower ORR and VGHR rates. In univariable analysis, three months VGHR rates were only significantly influenced adversely by dFLC >180 mg/L, gain 1q21 and symptomatic MM, while lambda subtype was beneficial. Compared to baseline, a median NT-ProBNP increase of 12% was measured in 23 patients at month 3 and a median decrease of 4% in 22 patients at month 6 when both values were available. Cardiac responses were present in 19% (6/31) of patients after 3 months, 21% (6/29) after 6 months and 35% (7/20) after 12 months. Renal responses were present in 11% (2/18) after 3 months, 17% (3/18) after 6 months and in 21% (3/14) after 12 months. We did previously detect adverse signals on univariable analysis for gain 1q21 with DD and DVD and can now confirm our findings on multivariable analysis with DRD. Adverse outcome with daratumumab in MM has so far only been reported in combination with GEP70 status.4 In direct comparison to DRD in relapsed/refractory MM, hemEFS was substantially shorter within our cohort, which could be attributed to a shorter duration of combination therapy.2 Extending combination therapy even with very low dosages of lenalidomide (eg, 2.5 mg) might improve results in AL. The hemEFS of 17.4 months seems low compared to results from prospective trials for DD in AL, but has to be put in perspective. A phase 2 trial of patients with comparable cardiac and renal involvement, substantially lower median BMPC (only 3%) reported a median progression free survival (PFS) of 24.8 months, but excluded three early deaths from analysis. Another phase 2 trial achieved a better median PFS (28 months) but had mainly enrolled fit patients with less advanced BM disease.5 Additionally, our DRD cohort seems genetically highly adverse with 52% gain1q21 present in analyzed patients compared to only 25%–30% within our DD/DVD analysis.3 The 27% grade 3/4 infectious complications are consistent with previous data for DRD in MM, however, these infectious complications come at a higher cost for AL patients. The higher rate of lymphocytopenia compared to MM is surprising, whereas other hematologic toxicities were only rarely detected. If you consider all AL patients to be frail MM patients prophylactic antibiotic therapy should be considered. Furthermore, with the substantial rate of lymphocytopenia, low dose cotrimoxazole prophylaxis which provided an additional benefit in MM patients seems to be a good choice.6 Since we did not experience any bowel perforation in a bigger cohort of patients with DD/DVD an association with lenalidomide might be prevalent.3 Note, DFLC >180 mg/L remained relevant even with DRD. Thus, ACR >220 mg/mmol only showed a trend on univariable analysis likely attributed to our gain 1q21-enriched patient population, the additional antineoplastic effect provided by lenalidomide and the sample size. We did again detect low organ response rates with daratumumab in relapse therapy, but did not detect a substantial NT-ProBNP increase with low dose lenalidomide. The following reasons should be considered and ought to be discussed within the amyloidosis community: firstly, NT-ProBNP values ahead of DRD likely represented persisting structural cardiac damage. Secondly, improvement in supportive care has already occurred after first diagnosis and finally, light chain toxicity might be less relevant with lower FLC levels ahead of relapse therapy. Therefore, DRD with low dosages of lenalidomide provided us with excellent response rates and even long-term remission seems possible without gain 1q21. This could make DRD a standard in AL and even a valid (first-line) alternative when daratumumab plus CyBorD is not possible (eg, with neuropathy).1 The unfortunate group with gain 1q21 will likely require further therapy soon, even with DRD. Therefore, the option of a sequential risk-adapted therapy as performed in MM should be discussed with these patients.2 High-dose melphalan in transplant-eligible patients, a proteasome inhibitor in combination with a second agent or venetoclax for t(11;14) patients might be options.1 The authors thank their patients and their families, local hematologists, and hospital staff for their participation in this study. We would like to thank the Deutsche Forschungsgemeinschaft for funding of the Research Unit FOR 2969, projects HE 8472/1-1, HU 2400/1-1, SCHO 1364/2-. Open access funding enabled and organized by Projekt DEAL. H.G. discloses research support from Amgen, BMS, Celgene, Chugai, Dietmar-Hopp-Stiftung, Janssen, John Hopkins University, Molecular Partners, MSD, Mundipharma, Novartis, Sanofi, Takeda; serves on the advisory boards for Adaptive Biotechnology, Amgen, BMS, Celgene, Janssen, Sanofi, Takeda; and has received honoraria from ArtTempi, BMS, Celgene, Chugai, Janssen, Novarti, and Sanofi. C.M.T. has received research funding from Pfizer, Janssen, Daichi and Bioline and serves on advisory boards for Janssen, Bioline and Daichi. T.H. has received travel grants from Janssen, serves on the advisory boards for Janssen, and has received honoraria from Janssen. U.H. has received travel grants from Janssen, Prothena, and Pfizer; served on the advisory boards for Pfizer and Prothena; and has received honoraria from Janssen, Pfizer, Alnylam, and Akcea. S.O.S. has received travel grants from Janssen, MSD, Prothena and Takeda; served on the advisory boards for Janssen and Prothena; has received honoraria from Janssen, Prothena, Pfizer and Takeda; and received research funding from Sanofi and Janssen. C.R.K. has received honoraria from MSD and Gilead. The remaining authors declare no conflict of interest. Contribution: Christoph R. Kimmich, Ute Hegenbart, Stefan O. Schönland undertook conception and design; Christoph R. Kimmich, Tobias Terzer, Kaya Veelken, Alexander Carpinteiro, Marco Basset, Timon Hansen, Hartmut Goldschmidt, Anna Jauch, Carsten Müller-Tidow, Ute Hegenbart and Stefan O. Schönland provided study materials or patients; Christoph R. Kimmich, Marco Basset, Tobias Dittrich, Kaya Veelken, Alexander Carpinteiro, Timon Hansen, Ute Hegenbart, and Stefan O. collected and assembled data; Christoph R. Kimmich, Tobias Terzer, Axel Benner, Marco Basset, Tobias Dittrich, Kaya Veelken, Alexander Carpinteiro, Timon Hansen, Hartmut Goldschmidt, Anna Jauch, Carsten Müller-Tidow, Ute Hegenbart, and Stefan O. Schönland undertook data analysis and interpretation; and all authors wrote the manuscript or revised it critically for important intellectual content. The dataset used and analyzed during the current study are available from the corresponding author on reasonable request. The data that supports the findings of this study are available in the supplementary material of this article Appendix S1: Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.