TEMPI syndrome: difficult to diagnose, "easy" to treat?

TEMPI syndrome is a rare, acquired disorder with multisystemic manifestations. It is classified as a plasma cell disorder and is characterized by telangiectasias, erythrocytosis, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunt. Even though TEMPI's pathophysiology remains elusive, it responds to anti-myeloma therapy indicating that the monoclonal protein or clone plays a key role. We present a challenging case of a 73-year-old man with erythrocytosis and deteriorating renal function with nephrotic-range proteinuria in whom after extensive work up, the diagnosis of TEMPI syndrome was made. He was received treatment with daratumumab-bortezomib-cyclophosphamide and dexamethasone (Dara-VCD) and achieved a hematological and clinical response. We also report preliminary data on a multiplex assay for cytokines and growth factors for two patients with TEMPI syndrome and note lower levels for non-specific innate immunity related cytokines. A direct link between renal impairment and TEMPI syndrome is not currently established; cytokine deregulation could potentially be involved in the ischemic changes observed in the renal biopsy of our patient.

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis.

Growth differentiation factor-15 (GDF-15) improves prognostication in patients with cardiovascular disorders in addition to conventional cardiac markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], troponins [Tns]) and has shown prognostic value in patients with renal diseases. In patients with light chain (AL) amyloidosis, cardiac involvement is the major determinant of prognosis, and cardiac markers define prognosis, whereas biomarkers of renal involvement stratify renal risk. We explored the prognostic importance of serum level of GDF-15 in patients with AL amyloidosis in 2 independent cohorts. The prognostic value of GDF-15 level was initially evaluated in a cohort of 107 consecutive previously untreated patients with AL amyloidosis from Athens, Greece, and was then validated in a second cohort of 202 consecutive previously untreated patients from Pavia, Italy. High GDF-15 level was associated with a higher risk of early death and poor overall survival independently of NT-proBNP and high-sensitivity TnT (hsTnT) or hsTnI levels. At the 6-month landmark, reduction of GDF-15 level ≥25% was associated with improved outcome. GDF-15 level ≥4000 pg/mL was associated with a high risk of progression to dialysis, independently of renal risk defined by estimated glomerular filtration rate and proteinuria, in both cohorts; failure to reduce GDF-15 below this level was associated with increased risk at either the 3- or 6-month landmark, independently of the established renal response or progression criteria. In conclusion, GDF-15 has prognostic implications for different outcomes in patients with AL and adds prognostic information independent of that provided by cardiac and renal risk biomarkers.

Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis.

Cardiac dysfunction determines prognosis in amyloid light-chain (AL) amyloidosis. The heart is the central organ of the vascular system in which endothelium function is critical for the circulatory homeostasis, but there are limited data on endothelial function in AL amyloidosis. von Willebrand factor (VWF) has been considered as a marker of endothelial activation and dysfunction, whereas a disintegrin and metalloproteinase with thrombospondin type-1 repeats 13 (ADAMTS-13) cleaves VWF multimers, but both have been associated with prognosis in cardiovascular disease. We measured the serum levels of VWF (VWF:Ag) and ADAMTS-13 antigens in 111 newly diagnosed patients with AL amyloidosis. The levels of VWF:Ag were significantly higher than in healthy controls; 76% of patients with AL had VWF:Ag levels higher than the upper levels of controls. There was no significant association of VWF:Ag levels with patterns of organ involvement, free light-chain levels, the levels of cardiac biomarkers, or renal dysfunction but correlated with low systolic blood pressure. VWF:Ag levels ≥230.0 U/dL were associated with higher probability of early death and poor survival independently of cardiac biomarkers and low systolic blood pressure (SBP). Moreover, among patients with Mayo stage III or stage IIIB (that is stage III with N-terminal pro-brain natriuretic peptide [NTproBNP] >8500 pg/mL) disease, VWF:Ag identified subgroups of patients with very poor outcome. Low ADAMTS-13 levels correlated with high levels of NTproBNP but had no independent prognostic significance. In conclusion, high VWF:Ag levels, probably representing endothelial dysfunction, are associated with prognosis in patients with AL amyloidosis, independently of other features of the disease or cardiac biomarkers.

Renal outcomes in patients with AL amyloidosis: Prognostic factors, renal response and the impact of therapy.

A staging system for patients with renal AL amyloidosis, based on eGFR (<50 ml/min/1.73 m2 ) and proteinuria (≥5 g/day) at diagnosis, as well as criteria for renal progression (≥25% eGFR reduction) and response (≥30% reduction of proteinuria without renal progression) were recently proposed. We validated these criteria in a cohort of 125 patients with renal AL amyloidosis, mostly treated with bortezomib or lenalidomide. We confirmed the prognostic value of the renal staging system but also identified the limitations of renal progression criteria which are based only on eGFR reduction. We identified the ratio of 24h proteinuria to eGFR as a sensitive marker of renal risk which also accounts for changes in both proteinuria and eGFR: 24h proteinuria/eGFR ratio <30 (in mg/ml/min/1.73 m2 ) was associated with a 2-year progression to dialysis rate of 0% compared to 9% for a ratio of 31-99 and 35% for a ratio ≥100 (P < .001). In landmark analysis, patients who achieved a reduction of this ratio by at least 25% or ≤100 (if initially >100) at 3 months had a 2-year progression to dialysis of 0% vs 24% for patients who either did not reduce to or still had a ratio >100 (P = .001); similar results were obtained by applying the same criteria at 6 months; thus, the evaluation of treatment effect on renal function may be identified early. Furthermore, primary bortezomib-based therapy was more effective than lenalidomide-based therapy, in terms of renal outcomes, especially in patients at intermediate renal risk, but without affecting overall survival.

Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis.

Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)-based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib-treated patients with severe RF (eGFR < 30 ml/min/1.73 m(2) ), of which 31 (37%) required dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11-724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis-independent had longer survival than those remaining on dialysis. In conclusion, VD-based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response.

Long-term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies.

Bortezomib and lenalidomide are increasingly used in patients with AL amyloidosis, but long term data on their use as primary therapy in AL amyloidosis are lacking while early mortality remains significant. Thus, we analyzed the long term outcomes of 85 consecutive unselected patients, which received primary therapy with bortezomib or lenalidomide and we prospectively evaluated a risk adapted strategy based on bortezomib/dexamethasone to reduce early mortality. Twenty-six patients received full-dose bortezomib/dexamethasone, 36 patients lenalidomide with oral cyclophosphamide and low-dose dexamethasone and 23 patients received bortezomib/dexamethasone at a dose and schedule adjusted to the risk of early death. On intent to treat, 67% of patients achieved a hematologic response (24% hemCRs) and 34% an organ response; both were more frequent with bortezomib. An early death occurred in 20%: in 36% of those treated with full-dose bortezomib/dexamethasone, in 22% of lenalidomide-treated patients but only in 4.5% of patients treated with risk-adapted bortezomib/dexamethasone. Activity of full vs. adjusted dose bortezomib/dexamethasone was similar; twice weekly vs. weekly administration of bortezomib also had similar activity. After a median follow up of 57 months, median survival is 47 months and is similar for patients treated with bortezomib vs. lenalidomide-based regimens. However, risk adjusted-bortezomib/dexamethasone was associated with improved 1-year survival vs. full-dose bortezomib/dexamethasone or lenalidomide-based therapy (81% vs. 56% vs. 53%, respectively). In conclusion, risk-adapted bortezomib/dexamethasone may reduce early mortality and preserve activity while long term follow up indicates that remissions obtained with lenalidomide or bortezomib may be durable, even without consolidation with alkylators.

SARS-CoV-2 infection-related deregulation of blood lipids in a patient with -/-LDLR familial homozygous hypercholesterolemia: A case report.

BACKGROUND: The effect of SARS-CoV-2 infection in blood lipids of homozygous familial hypercholesterolemia (HoFH) has not been explored. CASE SUMMARY: We report a case of a 43-year-old male patient with -/-LDLR HoFH with previous history of premature coronary artery disease, coronary artery bypass graft (CABG) and surgical repair of aortic valve stenosis. He presented with an abrupt decrease of his blood lipid levels during acute infection with SARS-CoV2 and subsequently a rebound increase above pre-infection levels, refractory to treatment including LDL-apheresis, statin, ezetimibe and lomitapide up-titration to maximum tolerated doses. Markers of liver stiffness were closely monitored, increased at 9 months and decreased at 18 months after the infection. Potential interactions of hypolipidemic treatment with the viral replication process during the acute phase, as well as therapeutic dilemmas occurring in the post infection period are discussed.

Immune Checkpoint Inhibitors' Associated Renal Toxicity: A Series of 12 Cases.

We present a series of twelve patients, bearing a wide range of solid malignancies, who received either PD-L1 or a combination of PD-L1 and CTLA-4 inhibitors. Following immunotherapy administration, they exhibited the clinical signs indicative of renal toxicity, including increased serum creatinine levels, proteinuria, nephrotic syndrome and/or hematuria. All patients underwent renal biopsy. Results: All cases demonstrated some degree of interstitial inflammation and tubular injury, while in five patients, glomerular alterations consistent with a specific glomerulopathy were also observed: secondary "lupus-like" membranous glomerulopathy in two cases and membranoproliferative glomerulonephritis, IgA glomerulonephritis and secondary AA amyloidosis in each of the remaining three patients. The two patients with "lupus-like" nephritis and the one with amyloidosis experienced nephrotic syndrome, while their creatinine was within normal range. In the remaining nine cases, deterioration of renal function was the main manifestation. Conclusion: Our findings harmonize with bibliographical data that identify tubulointerstitial nephritis as the most frequent histological lesion related to ICIs administration. The preferential involvement of tubulointerstitial tissue could be associated with the reported higher expression levels of PD-L1 on tubular epithelial cells, compared to glomeruli. On the other hand, glomerular involvement is probably a consequence of a systemic immune system reconstruction, induced by immune-checkpoints inhibition.

Clinico-radiologic features and therapeutic strategies in tumefactive demyelination: a retrospective analysis of 50 consecutive cases.

AIMS: Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible therapeutic choices in patients with tumefactive demyelinating lesions (TDLs). METHODS: A retrospective analysis of 50 patients with at least one TDL was performed at an academic neurology center (2008-2020). RESULTS: Our cohort comprised mostly women (33/50) with a mean age of 38 years at TDL onset. The mean follow-up time was 76 months. The mean Expanded Disability Status Scale score at TDL onset and at the latest neurological evaluation was 3.7 and 2.3, respectively. We subcategorized the patients into seven groups based mainly on the clinical/radiological findings and disease course. Group A included patients presenting with a Marburg-like TDL (n = 4). Groups B and C comprised patients presenting with monophasic (n = 7) and recurrent TDLs (n = 12), respectively. Multiple sclerosis (MS) patients who subsequently developed TDL (n = 16) during the disease course were categorized as Group D. Group E comprised patients who initially presented with TDL and subsequently developed a classical relapsing-remitting MS without further evidence of TDL (n = 5). Groups F (n = 2) and G (n = 4) involved MS patients who developed TDL during drug initiation (natalizumab, fingolimod) and cessation (interferon, fingolimod), respectively. Regarding long-term treatments applied after corticosteroid administration in the acute phase, B-cell-directed therapies were shown to be highly effective especially in cases with recurrent TDLs. Cyclophosphamide was spared for more aggressive disease indicated by a poor response to corticosteroids and plasma exchange failure. CONCLUSION: Tumefactive central nervous system demyelination is an heterogenous disease; its stratification into distinct groups according to different phenotypes can establish more efficient treatment strategies, thus improving clinical outcomes in the future.

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease.

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark (p < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.

Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment.

OBJECTIVES: Lenalidomide and dexamethasone (LenDex) is an active regimen for relapsed/refractory multiple myeloma (MM). However, there is limited data for the effect of LenDex on renal impairment (RI) and on renal reversibility. PATIENTS & METHODS: Fifty consecutive patients with relapsed/refractory MM received LenDex in 28-d cycles. Median lines of previous therapies were 2 (range: 1-6). Lenalidomide was administered on days 1-21 according to creatinine clearance (CrCl), while dexamethasone was given at a dose of 40 mg on days 1-4 and 15-18 for the first four cycles and only on days 1-4 thereafter. RESULTS: Twelve patients (24%) had RI at baseline, defined as CrCl < 50 mL/min. Most patients were pretreated with either thalidomide or bortezomib and > 50% of them were refractory to both drugs. At least partial response was documented in 60.5% and 58% of patients with and without RI. Median progression-free survival (PFS) and overall survival (OS) for all patients was 9 and 16 months, respectively. RI was not associated with an inferior PFS or OS. There were no differences in the incidence of adverse events among patients with and without RI. Three of 12 patients with RI (25%) achieved complete renal response and two (16%) achieved minor renal response with LenDex. CONCLUSIONS: We conclude that LenDex is an active treatment even in heavily pretreated MM. With dosing of lenalidomide according to renal function, LenDex can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, LenDex may improve the renal function in approximately 40% of patients with RI.

AChR-and MuSK-positive myasthenia gravis: Double trouble.

This is a report of an early onset AChR-and MuSK-positive myasthenia gravis. The double seropositivity was detected at the onset of the disease and persisted during 3.5 years follow-up despite the chronic immunotherapy and thymectomy. It is the second reported case of this rare immunological coexistence with sufficient follow-up and available clinical details. At the detection of double positive AChR and MuSK Abs, the treating physician often feels unsecure about the optimal treatment strategy and the long-term prognosis. The detailed clinical record and the long observation of these rare cases, are mandatory for best management in clinical practice.

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.

Circulating Soluble Urokinase-Type Plasminogen Activator Receptor Levels Reflect Renal Function in Newly Diagnosed Patients with Multiple Myeloma Treated with Bortezomib-Based Induction.

(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed patients with symptomatic multiple myeloma (NDMM) before and after frontline therapy with bortezomib-based regimens. (2) Methods: We studied 47 NDMM patients (57% males, median age 69.5 years) before the administration of anti-myeloma treatment and at best response to bortezomib-based therapy. suPAR was measured in the serum of all patients and of 24 healthy matched controls, using an immuno-enzymatic assay (ViroGates, Denmark). (3) Results: suPAR levels were elevated in NDMM patients at diagnosis compared to healthy individuals (p < 0.001). suPAR levels strongly correlated with disease stage (p-ANOVA < 0.001). suPAR levels both at diagnosis and at best response negatively correlated with estimated glomerular filtration rate (eGFR) values (p < 0.001). Interestingly, no significance changes in suPAR levels were observed at best response compared to baseline values (p = 0.31) among 18 responding patients with baseline eGFR < 50 mL/min/1.73 m2. (4) Conclusions: SuPAR levels reflect renal function in NDMM patients treated with bortezomib-based induction. Responders may have elevated circulating suPAR levels, possibly reflecting persistent kidney damage, despite their renal response.

Rapamycin for focal segmental glomerulosclerosis: a report of 3 cases.

Corticosteroids and/or cyclosporine constitute the present therapeutic approach for patients with focal segmental glomerulosclerosis (FSGS). The high incidence of side effects for the former and risk of nephrotoxicity combined with the high relapse rate after discontinuation for the latter render their use problematic. Results concerning the role of rapamycin in the treatment of patients with FSGS are conflicting. We describe results for 3 patients treated with a combination of low-dose steroids and rapamycin for FSGS, focusing on the importance of maintaining low drug (rapamycin) levels by using a twice-daily regimen.

Fibroblast growth factor 23 (FGF23) and the kidney.

Phosphate homeostasis in humans is a complex phenomenon involving the interplay of several different organs and circulating hormones. Among the latter, parathyroid hormone (PTh), and vitamin D3 (Vit D3) were thought to be the main regulators of serum phosphate concentration since they mediated the intestinal, renal and bone responses that follow fluctuations in serum phosphate levels. The study of three rare disorders - tumor-induced osteomalacia (TIo), autosomal dominant hypophosphatemic rickets (ADhr) and X-linked hypophosphatemic rickets (XLh) - has offered a completely new insight into phosphate metabolism by unraveling the role of a group of peptides that can directly affect serum phosphate concentration by increasing urinary phosphate excretion. fibroblast growth factor-23 (fGf-23) is the most extensively studied ''phosphatonin''. The production, mechanism of action, effects in various target tissues, and its role in common clinical disorders are the focus of this review.

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

Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.

Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis.

We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2-100) and median number of prior therapies was 1 (range 1-4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.