Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial

Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).     

Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial

The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM. Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m(2) weekly for 3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better. The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy.     

A phase II trial of cyclophosphamide,lenalidomide and dexamethasone in previously treated patients with AL amyloidosis

Immune-modulatory drugs are active in immunoglobulin light-chain amyloidosis and the addition of alkylating agents can potentiate their action. In this phase II prospective trial we used cyclophosphamide, lenalidomide and dexamethasone in the treatment of 21 patients who were refractory (n=13, 62%) or relapsed (n=8, 38%) after prior treatment including melphalan in all cases, bortezomib in 4 and thalidomide in 6. Median number of cycles administered was 4 (range 2–9 cycles). Severe adverse events were observed in 57% of patients, most common being neutropenia (29%). The hematologic response rate was 62%, with one complete response and 5 very good partial responses. Overall median survival was three years. The achievement of CR/VGPR was associated with a significant survival advantage. The combination of cyclophosphamide, lenalidomide and dexamethasone is an effective treatment for relapsed/refractory AL amyloidosis, and good quality hematologic response should be the aim of treatment in this setting.(clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00607581","term_id":"NCT00607581"}}NCT00607581)     

Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective,open‐label trial

Given its anti‐angiogenic activity, lenalidomide may have a role in the treatment of POEMS (P eripheral neuropathy, O rganomegaly, E ndocrinopathy, M onoclonal plasma cell disorder and S kin changes) syndrome. This prospective, open‐label, pilot study evaluated the combination of lenalidomide + dexamethasone (RD) in 18 POEMS syndrome patients (13 pre‐treated, 5 newly‐diagnosed but ineligible for high‐dose therapy). Treatment consisted of six cycles of lenalidomide (25 mg/day for 21 days followed by 7 days rest) plus dexamethasone (40 mg/once a week). Patients responding after six cycles continued treatment until progression or unbearable toxicity. The primary endpoint was the proportion of patients with either neurological or clinical improvement. The RD combination was considered as deserving further evaluation if 9 of the first 15 patients responded. Ten responses were observed among the first 15 enrolled patients, meeting the primary endpoint. Fifteen of 18 patients (83%) completed six RD cycles: 13 (72%) patients responded and nine had both clinical and neurological improvement. Among the 15 patients who completed the six RD cycles, four were still on treatment after a 25‐month follow‐up. At 39 months of follow‐up, all patients were alive with a 3‐year progression‐free survival of 59%. No patient discontinued RD for toxicity. Overall, the RD regimen showed a high incidence of prolonged symptoms improvement and was well tolerated in most POEMS patients.     

Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach

The combination of oral melphalan and dexamethasone is considered standard therapy for patients with light-chain amyloidosis ineligible for autologous stem cell transplantation. However, previous trials reported different rates of response and survival, mainly because of the different proportions of high-risk patients. In the present study, including a total of 259 subjects, we treated 119 patients with full-dose melphalan and dexamethasone (dexamethasone 40 mg days 1–4), and 140 patients with advanced cardiac disease with an attenuated dexamethasone schedule (20 mg). Hematologic response rates were 76% in the full-dose group and 51% in the patients receiving the attenuated schedule; the corresponding complete response rates were 31% and 12%, respectively. The median survival was 7.4 years in the full-dose group and 20 months in the attenuated-dose group. Use of high-dose dexamethasone, amino-terminal pro-natriuretic peptide type-B >1800 ng/L, a difference between involved and uninvolved free light chains of >180 mg/L, troponin I >0.07 ng/mL, and response to therapy were independent prognostic determinants. In relapsed/refractory subjects bortezomib combinations granted high hematologic response rates (79% and 63%, respectively), proving the most effective rescue treatment after melphalan and dexamethasone. In summary, melphalan plus dexamethasone was highly effective with minimal toxicity, confirming its central role in the treatment of AL amyloidosis. Future randomized trials will clarify whether bortezomib is best used in frontline combination with melphalan and dexamethasone or as rescue treatment.     

Efficacy of the combination of bortezomib and dexamethasone in systemic AL amyloidosis

Bortezomib–dexamethasone (Btz/Dex) is an active regimen in patients with multiple myeloma and has been used in few patients with amyloidosis. Here, we report a retrospective evaluation of the efficacy and toxicity of Btz/Dex in 26 patients with AL amyloidosis (AL). Eighteen patients (69%) received Btz/Dex as first-line treatment. Organs most frequently involved were kidneys (100%) and heart (35%); five patients (19%) had less than two organs involved. The overall response rate was 54% (14 of 26 patients), with eight patients (31%) achieving a hematologic complete remission (CR). All patients who reached a CR received Btz/Dex as first-line therapy. Median time to response was 7.5 weeks. Improvement in organ function was noticed in three patients (12%). Median progression-free survival (PFS) and overall survival (OS) was 5.0 and 18.7 months, respectively; in CR patients, however, median PFS and OS have not yet been reached. Toxicities were manageable, with hematological side effects being most common. No grade 3/4 neuropathy was observed. Our results confirm the activity of bortezomib/dexamethasone in patients with AL amyloidosis and suggest that patients achieving a CR have a marked benefit for survival.     

Perspectives in treatment of AL amyloidosis

Light chain (AL) amyloidosis is the most frequently diagnosed form of systemic amyloid in the western world. The historically poor prognosis of AL amyloidosis appears to be improving with currently reported median survival of c. 40 months compared to 13 months in the early 1990s when low-dose oral melphalan was the mainstay of treatment. Autologous stem cell transplantation (ASCT) achieves the highest rates of complete clonal response but is confounded by substantial treatment-related mortality in AL amyloidosis unless it is restricted to highly selected patients. Newer chemotherapy regimens appear to have a balance of better safety and respectable efficacy with overall outcomes nearly similar to ASCT, but which may be used more widely. There are few data comparing durability, depth of clonal response, rate of organ response and overall survival following ASCT or chemotherapy, but a recent small, randomized trial did not suggest superiority of ASCT to oral melphalan and dexamethasone. There is a compelling need for further and larger randomized trials in this context. At the same time, various new specific anti-amyloid drugs have shown (in early phase studies or animal models) some very promising results. This review attempts to highlight the challenges, controversies and progress in AL amyloidosis.     

Current treatment of AL amyloidosis

Several effective chemotherapy regimens have been developed during the last decade significantly improving the outlook of patients with AL amyloidosis. Drs. Palladini and Merlini describe our current knowledge in the field and examine future perspectives. See related article on page 1094.Immunoglobulin light chain systemic amyloidosis (AL) is a progressive disease caused by monoclonal light chains with specific mutations that confer a unique propensity to misfold from their native structure to less stable, partially folded intermediates that self-aggregate into oligomers and then into the highly-ordered cross β-sheet structure which defines amyloid fibrils.¹ At least 11 additional proteins, synthesized by different organs (liver, intestine, etc) can cause systemic amyloidoses which can be difficult to distinguish from AL amyloidosis on a clinical basis. These proteins form amyloid deposits that share the common tinctorial, green birefringence under polarized light after staining with Congo red, and ultrastructural features, rigid, non-branching fibril with a distinct diameter of 7.5 to 10 nm (Figure 1). The unequivocal identification of the protein forming the amyloid fibril is essential for the choice of therapy.³ A mistake in protein typing may have catastrophic therapeutic consequences, such as performing an autologous stem cell transplant in a patient with transthyretin amyloidosis who should receive a liver transplant. Proteomics technology has significantly improved the typing of amyloid deposits² and is routinely applied on abdominal fat aspirates at our Center.Open in a separate windowFigure 1.Typing amyloid deposits in subcutaneous adipose tissue. The 10–30 mg fine needle fat aspirate can be used for: (A) Congo red staining and analysis under polarized light showing the diagnostic green birefringence (upper left panel, Nikon Eclipse E600, magnification x 200); (B) for typing the amyloid deposits using electron-microscopy immunohistochemistry, in this case the amyloid fibrils are decorated by a gold- labeled antibody recognizing an anti-κ antibody (central upper panel, TEM Philips CM12, magnification x 22000, gold particles are 15 nm in diameter); and for proteomic analysis by bidimensional- PAGE and mass spectrometry. Comparison with control adipose tissue (C1) allowed location of prominent novel spots (squared in green) in patient (C2). Spots corresponding to fragments or post-translational modifications of the amyloidogenic protein were also observed. Identification of the novel spots, and thus amyloid typing, was obtained by MALDI-TOF mass spectrometry and peptide mass fingerprinting.The amyloidogenic light chains are produced by a bone marrow plasma cell clone usually of limited size, enter the circulation, and target selected organs: heart, kidney, liver, soft tissues and peripheral nervous system, trough specific, but largely undetermined, interactions with local matrix components, such as glycosaminoglycans, and cell membrane constituents. These interactions may promote the formation of light chain oligomers which may represent the main determinant of cell toxicity and the consequent tissue dysfunction. Deposited amyloid fibrils may contribute to organ dysfunction by promoting light chain oligomerization, through increasing macromolecular crowding in the interstitial space,⁴ and by damaging the tissue architecture. The aim of therapy is the prompt reduction/elimination of the supply of newly formed light chains, that feed the formation of oligomers and fibrils, in order to obtain durable improvement of AL amyloidosis-related organ dysfunction and extend survival.⁵Several effective chemotherapy regimens have been developed during the last decade improving significantly the outlook of patients with AL amyloidosis.⁶     

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis

In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.     

Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial

High-dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment-related mortality (TRM) has historically been high. We performed a phase II trial of risk-adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving < or =2 organ systems were assigned to MEL 100, 140, or 200 mg/m(2) with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post-SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4.4%. Thirty-one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention-to-treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow-up of 31 months, 2-year survival was 84% (95% confidence interval: 73%, 94%). Risk-adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.     

Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study

This first prospective phase 2 study of single-agent bortezomib in relapsed primary systemic AL amyloidosis evaluated the recommended (maximum planned) doses identified in phase 1 testing (1.6 mg/m2 once weekly [days 1, 8, 15, and 22; 35-day cycles]; 1.3 mg/m2 twice weekly [days 1, 4, 8, and 11; 21-day cycles]). Among all 70 patients enrolled in the study, 44% had ≥ 3 organs involved, including 73% and 56% with renal and cardiac involvement. In the 1.6 mg/m2 once-weekly and 1.3 mg/m2 twice-weekly groups, the hematologic response rate was 68.8% and 66.7% (37.5% and 24.2% complete responses, respectively); median time to first/best response was 2.1/3.2 and 0.7/1.2 months, and 78.8% and 75.5% had response durations of ≥ 1 year, respectively. One-year hematologic progression-free rates were 72.2% and 74.6%, and 1-year survival rates were 93.8% and 84.0%, respectively. Outcomes appeared similar in patients with cardiac involvement. Among all 70 patients, organ responses included 29% renal and 13% cardiac responses. Rates of grade ≥ 3 toxicities (79% vs 50%) and discontinuations/dose reductions (38%/53% vs 28%/22%) resulting from toxicities appeared higher with 1.3 mg/m2 twice-weekly versus 1.6 mg/m2 once-weekly dosing. Both bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL amyloidosis. This study was registered at www.clinicaltrials.gov as #NCT00298766.     

Lenalidomide and dexamethasone for acute light chain-induced renal failure: a phase II study

We prospectively evaluated the activity and tolerance of lenalidomide-dexamethasone in 35 patients with acute light chain-induced renal failure. The lenalidomide dose was adapted to the estimated glomerular filtration rate and dexamethasone was given at high dose in cycle one and at low dose thereafter. Four patients died within the first two cycles, and five discontinued therapy leaving 26 patients for the per-protocol analysis. Responses were observed in 24/35 (68.6%) patients of the intent-to-treat population. Complete response was noted in seven patients (20%), very good partial response in three patients (8.6%), partial response in 14 patients (40%), and minimal response in one patient (2.9%). Renal response was observed in 16 (45.7%) patients: five (14.2%) achieved complete, four (11.4%) partial and seven (20%) minor renal responses. Five of 13 patients who were dialysis dependent at baseline became dialysis independent. The median time to myeloma and to renal response was 28 days for both parameters, while the median time to best myeloma and best renal response was 92 and 157 days, respectively. The median estimated glomerular filtration rate increased significantly in patients with partial response or better from 17.1 mL/min at baseline to 39.1 mL/min at best response (P=0.001). The median progression-free and overall survival was 5.5 and 21.8 months, respectively, in the intent-to-treat population and 12.1 and 31.4 months, respectively, in the per-protocol group. Infections, cardiotoxicity, anemia and thrombocytopenia were the most frequent toxicities. In conclusion, the lenalidomide-dexamethasone regimen achieved rapid and substantial myeloma and renal responses. The trial was registered under EUDRACT number 2008-006497-15.     

AL型淀粉样变性的治疗

AL型淀粉样变性是由于单克隆浆细胞产生异常折叠轻链在组织器官沉积而导致的一种系统性疾病,通常预后较差.以化疗及干细胞移植治疗为主.本文就近年来治疗方面的进展作一简述.     

Ten-year survivors in AL amyloidosis: characteristics and treatment pattern

Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long-term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis (n = 186) were the subject of this study. Ten-year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10-year survivors compared to those who did not survive to 10 years. All-time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first-line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty-seven percent of the 10-year survivors did not require a second-line therapy. The median treatment-free survival (TFS) among the 10-year survivors was 10·5 years (interquartile range 7·4-12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long-term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.     

Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial

This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m(2), pegylated liposomal doxorubicin 30 mg/m(2), and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.