Title: Daratumumab, lenalidomide and dexamethasone in newly diagnosed systemic light chain amyloidosis patients associated with multiple myeloma
Abstract: Approximately 12%–15% of multiple myeloma (MM) patients develop systemic light chain amyloidosis (AL amyloidosis) during the clinical course.1 Treatment with daratumumab, cyclophosphamide, bortezomib and dexamethasone is becoming a standard of care for systemic AL amyloidosis patients according to the recently published phase-3 ANDROMEDA trial.2 However, patients with coexisting MM have been excluded from the trial. Additionally, MM patients who have organ dysfunction associated with AL amyloidosis are often excluded from prospective MM therapeutic trials. This raises the need for appropriate therapeutic regimens for MM associated systemic AL amyloidosis patients. In the present retrospective cohort study, we analysed the 6 month haematological and organ response of daratumumab, lenalidomide and dexamethasone (DRd), a standard of care for newly diagnosed transplant ineligible MM patients,3 among MM patients with accompanying systemic AL amyloidosis at diagnosis. Data were collected from patients diagnosed with MM (more than 10% of bone marrow plasma cells with myeloma defining events or biomarkers of malignancy) with systemic AL amyloidosis (presence of an amyloid-related systemic syndrome, positive amyloid staining by Congo red in tissues and evidence that the amyloid is light chain-related) according to the International Myeloma Working Group (IMWG) criteria,4 at Kumamoto University Hospital between November 2019 and April 2021. A total of 10 newly diagnosed patients, treated with DRd regimen upfront, were enrolled. All patients were considered autologous stem cell transplant ineligible due to their age or organ dysfunction. The study was approved by the Institutional Review Board of Kumamoto University Hospital and was conducted in accordance with the principles of the Declaration of Helsinki. The patient characteristics of the study are summarized in Table 1. Half of the patients were aged over 75 years old, and 80% of patients were stage 3 or 4 of Mayo 2012 staging system for AL amyloidosis.5 None of the patients were Mayo 2004 stage 3B, which is considered an especially poor prognosis subgroup with a median survival of 3 months.6 Nine out of 10 patients had cardiac amyloidosis according to the criteria of organ involvement in AL amyloidosis.7 Three patients had renal amyloidosis including one case with nephrotic syndrome. All patients initially received intravenous daratumumab (16 mg/kg/week) and were switched to subcutaneous daratumumab (1800 mg/week) after its approval in Japan. Lenalidomide was taken orally from day 1–21 and repeated every 28 days. None of the patients received more than 15 mg of lenalidomide per day, which was adjusted by each physician according to renal function and general conditions. Dexamethasone was given at 20 mg/week to all patients, considering advanced age or heart failure. 1947 (93–4775) (n = 10) 276 (20–689) (n = 10) On the data cut-off (1 December 2021), after a median follow-up time of 11.5 months, patients had received median 8.5 cycles of DRd treatment. Overall haematological response at 6 months from DRd treatment was 90% according to the IMWG uniform response criteria (Figure 1A)8 and 88.9% by the AL amyloidosis haematological response criteria (Figure 1B).9 More than 50% of the patients achieved a haematological response of very good partial response (VGPR) or better, which is known to be associated with significant improvement in survival of systemic AL amyloidosis patients.9 The presence of t(11;14) translocation is known to be associated with low bortezomib sensitivity in AL amyloidosis patients.10 No significant difference in haematological response by DRd treatment was observed between t(11;14) positive and negative cases. Chromosome 1q21 amplification was detected in the single patient without haematological response at 6 months post DRd treatment. Since nine out of 10 patients had cardiac involvement of AL amyloidosis, cardiac response was evaluated at 6 months post treatment. Brain natriuretic peptide (BNP) was used for analysing cardiac response, due to limited access to N-terminal probrain natriuretic peptide (NT-proBNP) at Kumamoto University Hospital. Eight patients had a baseline BNP ≥150 pg/ml and were analysed for cardiac response according to the recently established BNP-based criteria for evaluating cardiac response to treatment in AL amyloidosis.11 Although a previous study reported BNP elevation in AL amyloidosis patients treated with lenalidomide,12 four out of eight patients (50%) achieved cardiac response (Figure 1C) (≥50 pg/ml and ≥30% decrease in BNP).11 Among the three patients with renal amyloidosis, two patients without nephrotic syndrome achieved a renal response, while response of the patient with nephrotic syndrome was stable. On the data cut-off, eight out of 10 patients were still on DRd treatment, and nine patients were alive without disease progression. One patient died of intestinal perforation due to intestinal amyloidosis at 15 months from treatment initiation. The estimated overall survival at 24 months was 80% (Figure 1D). No grade 4 adverse events were observed during DRd treatment. Neutropenia was the most common grade 3 adverse event, which did not lead to treatment discontinuation (Table S1). One patient discontinued treatment after two cycles of DRd due to grade 3 ileus. However, the patient achieved stringent complete response (sCR) by IMWG response criteria without any signs of disease progression after 24 months of treatment initiation. Systemic AL amyloidosis patients coexisting MM have been generally excluded from systemic AL amyloidosis and MM phase-3 trials. Since 12%–15% of MM patients develop systemic AL amyloidosis, appropriate therapeutic regimens for these patients are required. Our present study demonstrated that DRd induces high haematological and cardiac response at 6 months post treatment initiation. Although the patients in our cohort were relatively aged and had advanced stage amyloidosis, the majority were able to continue DRd with limited toxicity. It is noteworthy that the dose of lenalidomide was reduced to a median of 10 mg/day in our cohort. A reduced dose of lenalidomide can be an important factor for treatment continuation, since systemic AL amyloidosis patients are often intolerant to lenalidomide over 15 mg/day.13 One patient without haematological response at 6 months from DRd treatment had chromosome 1q21 amplification. A previous publication reporting the efficacy of DRd regimen against relapsed or refractory systemic AL amyloidosis patients, indicated that the existence of 1q21 amplification may reduce the efficacy of DRd.14 Although the precise mechanisms of low treatment response are unclear, patients with 1q21 amplification may need to consider regimens other than DRd. In conclusion, the DRd regimen can be an effective treatment option for newly diagnosed systemic AL amyloidosis patients associated with MM, who are often excluded from clinical trials. Since the current study is a cohort of small number of patients from a single institute, additional prospective studies by multiple institutes with longer follow up are required for validation. The authors would like to thank all the physicians, nurses, and data managers who contributed to this study. Yawara Kawano has received honoraria from Janssen Pharmaceuticals Inc, Ono Pharmaceutical, Takeda Pharmaceutical Co. Ltd., Bristol Myers Squibb Co., and Sanofi. Masao Matsuoka has received research grants from Kyowa Kirin, Bristol Myers Squibb Co., Sanofi, Shionogi Pharma Co. Ltd., and Eisai. Conception and design: Yawara Kawano, Hiroyuki Hata and Masao Matsuoka. Collection and assembly of data: Yawara Kawano, Hiroyuki Hata, Seiji Takashio, Kenichi Tsujita, Mitsuharu Ueda and Masao Matsuoka. Data analysis: Yawara Kawano and Hiroyuki Hata. Manuscript writing: Yawara Kawano and Hiroyuki Hata. Final approval of manuscript: Yawara Kawano, Hiroyuki Hata, Seiji Takashio, Kenichi Tsujita, Mitsuharu Ueda and Masao Matsuoka. Table S1 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.
Publication Year: 2022
Publication Date: 2022-05-07
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 4
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