Addition of Cyclophosphamide and Higher Doses of Dexamethasone Do Not Improve Outcomes of Patients with AL Amyloidosis Treated with Bortezomib

Abstract

Treatment of AL amyloidosis is based on the elimination of the plasma cell clone that produces the amyloidogenic light chains. Typically, these are indolent clones and plasma cell burden is low, thus, even low dose, low toxicity, regimens may be very effective. Bortezomib is effective in targeting plasma cells. Several series have also shown that bortezomib either as single agent or in combinations, such as bortezomib with dexamethasone (VD) or with the addition of cyclophosphamide (VCD) induce high rates of hematologic CRs and organ responses. Patients with AL are frail due to multisystemic involvement and data from the treatment of frail patients with myeloma, usually elderly ones, have shown that addition of a third agent to VD does not improve outcomes and may increase toxicity. However, VCD is considered as a "standard" regimen for primary therapy of patients with AL, in most centers, but, it is not clear whether the addition of a third drug (cyclophosphamide) to bortezomib/dexamethasone (VD) further and significantly improves efficacy, given the substantial activity of bortezomib itself. Thus, we compared the outcomes of patients with AL amyloidosis who received (VD) or with VD plus a third agent (VCD). The analysis included 101 consecutive patients with biopsy confirmed AL amyloidosis, all diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. All patients received similar supportive care and were treated in two consecutive periods (up to 2010 received VD and after 2011 received VCD). Median age was 65 years, 70% had cardiac and 71% renal involvement; Mayo stage was -1, -2 & -3 in 20%, 47% & 33% while renal stage was -1, -2 and -3 in 22%, 56% & 22% of the patients respectively. Treatment was VD in 59 (58%) and VCD in 42 (42%) patients. Compared to patients who received VCD, patients who received VD were older (median age 67 vs 60.5 years, p=0.024), were more often Mayo stage 3 (42% vs 29%, p=0.03), had lower eGFR (median 54 vs 86 ml/min/1.73 m2) but had similar distribution in renal stages. Heart, renal and nerve involvement were similar between those who received VD vs VCD (p>0.5 for all). According to our institutional guidelines for patients with AL amyloidosis schedule of bortezomib (twice per week vs weekly) and dexamethasone are adjusted to cardiac risk and presence of neuropathy. Weekly bortezomib was given in 41% of patients who received VD and vs 40% with VCD and the starting dose was 1.3 mg/m2 in 90% and 92.5% respectively. The median dose of dexamethasone for all patients was 160 mg/month, but for patients treated with VD was 240 mg/month and was 144 mg/month for those treated with VCD (p=0.01). Early mortality (<3 months from start of therapy) was 22% for patients treated with VD and 8% for patients treated with VCD, but after adjustment for Mayo stage there was no difference, and was 36% vs 29% in patients with Mayo stage 3 disease. On intent to treat a hematologic response was achieved by 72% (CR:25%, VGPR:17% , PR: 30%) and was 68% for patients treated with VD and 78% for VCD (p=0.26); after adjustment for Mayo stage there was still no difference in response rates. Regarding CR+VGPR, it was 47.5% with VD and 35% with VCD. Notably higher doses of dexamethasone or twice-weekly bortezomib schedule were not associated with significantly higher hematologic response rates or CR+VGPR rates. Organ responses occurred in 35% of patients (cardiac in 26%, renal in 42%). For VD, cardiac response rate was 29% and renal response rate was 43%, while for VCD cardiac response was 21% and renal response was 41% (p>0.5 for all comparisons). Median follow up is 3 years and median overall survival (OS) is 34 months. Median OS of patients treated with VD vs VCD was similar (33 vs 36 months, p=0.45). After adjustment for the dose and schedule of bortezomib and dexamethasone, and Mayo stage, still there was no difference in the OS between patients treated with VD vs VCD and no prognostic effect of higher doses of dexamethasone and twice weekly bortezomib was found. In conclusion, our data indicate that bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of a third agent (cyclophosphamide) does not seem to have a profound effect on efficacy and survival. Our data also indicate the limits of bortezomib-based therapies, and new agents either targeting the plasma cell clone (like monoclonal antiCD38) or targeting the amyloid deposits are needed. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

“…Cardiac response was reached in 17% of patients and renal response in 25% of patients 142 . It is not proven that addition of cyclophosphamide to bortezomib‐dexamethasone significantly impacts response or survival 143 . Combinations of novel agents are being reported.…”

Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone

“…This observation is in alignment with a previous analysis from our center showing that the addition of cyclophosphamide to bortezomib/dexamethasone may offer some additional efficacy, but this benefit is not substantial. 8 Taken together, these data indicate that while bortezomib is probably the most effective single drug in patients with AL amyloidosis, the optimal partner has not been defined. In this regard, the addition of daratumumab (or another anti-CD38 antibody) or another targeted therapy (such as venetoclax in patients with t (11;14)) may offer a new opportunity to improve significantly over current bortezomib combinations and is under investigation in a large randomized study (NCT03201965).…”

“…[29][30][31][32] The declaration of complete response (CR) required a normal free light chain (FLC) ratio and a negative immunofixation in at least 2 consecutive measurements. A rigorous assessment protocol following our standard institutional protocol for efficacy and toxicity 8,26,[33][34][35] is followed for all patients treated for AL amyloidosis, including monthly assessment of hematologic and organ response, during the course of active therapy. Toxicity grading is following Common Terminology Criteria for Adverse Events version 4.03 criteria, according to our institution's policy.…”

“…3 Bortezomib, dexamethasone, and cyclophosphamide (CyBorD) [4][5][6] or bortezomib, dexamethasone, and melphalan (BMDex) 7 remain the most commonly used first-line treatments for patients with AL amyloidosis. However, a small retrospective study from our center indicated that in patients with AL amyloidosis, the addition of cyclophosphamide to the bortezomib/dexamethasone (VD) backbone may not improve significantly the efficacy of the regimen, 8 and a better partner for VD may be needed.…”

A comparative study of cyclophosphamide, thalidomide and dexamethasone (CTD) versus bortezomib and dexamethasone (BDex) in light-chain amyloidosis

“…[9][10][11][12][13] A European study showed that the addition of cyclophosphamide to the BDex regimen had no signi cant impact on e cacy. 14 Considering the high activity of bortezomib on plasma cells and the low tumor burden of AL amyloidosis, BDex regimen was recommended for treating newly diagnosed patients not eligible for transplant in Mayo Strati cation of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement published in 2015. 15 Studies conducted in the United Kingdom showed high clonal response rates using cyclophosphamide, thalidomide and dexamethasone (CTD), and this treatment has been used for rst-line therapy for AL amyloidosis over the last decade in the United Kingdom.…”