Abstract
4 min readAbstract The aim of therapy in AL amyloidosis is to rapidly eliminate the production of toxic, amyloidogenic light chains by targeting the plasma cell clone. Especially for patients with advanced cardiac involvement, a rapid hematologic response may be critical, while, the depth of response is important in order to maximize the probability of organ response. Bortezomib with the addition of dexamethasone with either cyclophosphamide (CyBorD) or melphalan (BMDex) remain the most commonly used primary treatment. In myeloma multiple (MM) patients the combinations of bortezomib with an IMiD [thalidomide (VTD) or lenalidomide (VRD)] are very effective and widely used in newly diagnosed patients. In AL amyloidosis the tumor clone is usually of low burden without adverse prognostic features ; thus, the VRD regimen should be particularly effective. However, IMiDs have unique toxicity in patients with AL and their tolerability is poorer than in MM patients and lower doses of IMiDs are commonly used in AL patients. Here we report our experience with a VRD light regimen as primary therapy in consecutive patients with AL amyloidosis. From March 2017, 30 consecutive patients (28 evaluable at the day of this report) treated at the Department of Clinical Therapeutics, Athens, Greece, received bortezomib 1.3 mg/m2 on days 1, 8 & 15, with lenalidomide (starting at 5 to 15 mg, according to age, cardiac and renal function) on days 1-21 and dexamethasone 20 mg weekly, every 28 days for 8 cycles (VRD regimen). Standard and updated criteria for organ involvement and response evaluation and for hematologic response were used. A rigorous assessment following standard institutional protocol for efficacy and toxicity was followed. Among the 30 patients, 71% were males, median age was 65 years (range 46-84); 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000) and per Mayo stage 14%, 54% , 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement with a median eGFR of 59 ml/min/1.73 m2 (range 10-133), renal stage distribution was 13%, 53% and 33% (stages 1, 2 & 3) and no patient required dialysis at the time of initiation of VRD. So far 14 patients have completed the planned 8 cycles, 7 died prior to completion of planned therapy, 1 discontinued per physician's decision and 8 are still on therapy. The starting dose of lenalidomide was 5 mg in 26 (86%), 10 mg in 2 (7%) and 15 mg in 2 (7%) patients. After the first cycle of VRD, 32% patients achieved a VGPR and 29% a PR; after 3 months 76% of evaluable patients (N=17) had a VGPR and 24% a PR, while after 6 cycles ≥VGPR and PR rates (N=15 evaluable) were 94% and 6% respectively. Overall, on intent to treat, the best hematologic response was CR in 24%, VGPR in 48% and PR in 16%, for an ORR of 88% and ≥VGPR of 72%. Median follow up is 10 months and 6 and 12 month survival is 73% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). At 6 month landmark, organ responses were documented in 21% of patients (20% renal and 15% cardiac), but the follow up is still short. Hematologic toxicity was mild (≥Gr3 neutropenia: 4%, anemia: 7%, thrombocytopenia: 7%). Among non hematologic toxicities rash was common (Gr2: 29%, Gr3: 11%, Gr4: 4%); median time to development of rash was 118 days, in 2 patients lenalidomide was discontinued due to rash and in the rest it was continued with the addition of anti-histamines, low dose steroids with or without dose reductions of lenalidomide. Other common AEs included infections (≥Gr3: 11%), constipation (≥Gr3: 11%), neuropathy (Gr2: 18%). Thromboprophylaxis with aspirin was given in 46%, LMWH in 25%, NOACs in 14% and coumadin in 15%. A thromboembolic event (pulmonary embolism) occurred in only one patient with heavy nephrotic syndrome who was receiving LMWH prophylaxis. In total, 43% of patients required lenalidomide dose reduction, 28% discontinued lenalidomide before therapy completion, while, 29% required bortezomib dose reduction and 11% discontinued bortezomib before cycle 8. We conclude that VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy with toxicity that is manageable with appropriate interventions and thromboprophylaxis. Disclosures Kastritis: Prothena: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria.
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