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The application of high-dose melphalan and autologous stem cell transplant (SCT) to systemic AL amyloidosis (AL) has evolved over the past two decades and remains an important component of therapy for patients with AL. The era of novel agents created the opportunity to provide well -tolerated induction and post-SCT consolidation to AL patients eligible for SCT and the current availability of new monoclonal antibody therapies will likely provide additional opportunities to enhance the outcomes with SCT. In this review, we touch on the history of SCT for AL and examine the data on eligibility, mobilization, induction, risk-adapted melphalan dosing, engraftment, consolidation and maintenance, and long-term outcomes with SCT. We note that induction therapy may deprive some patients of the opportunity to proceed to SCT but is likely needed if the marrow plasmacytosis is > 10%, that risk-adapted melphalan dosing continues to be relevant, and that post-SCT consolidation improves the complete response rate as well as long-term overall survival. The importance of baseline cytogenetics is also highlighted, particularly for patients whose clonal plasma cells are ≤ 10% but harbor the t(11;14), because they may have improved survival with SCT.

In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1–2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician’s choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib–dexamethasone vs 51% with physician’s choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32–0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib–dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.

Abstract Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3–53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06–0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05–0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.

AL amyloidosis is an incurable plasma cell dyscrasia with limited therapeutic options. The pathogenetic mechanism in AL amyloidosis is the deposition of insoluble fibrillary aggregates of misfolded immunoglobulin (Ig) free light chains (FLC) and chaperone proteins in target organs. Therefore, AL amyloidosis is the prototypic, protein-toxicity hematologic disorder. Based on laboratory evidence of increased, constitutive proteotoxic stress, PCs are intrinsically vulnerable to agents that target proteins whose function is to guarantee that nascent polypeptides either reach a functional conformation or are disposed of (proteostasis network). The clinical efficacy of proteasome inhibitors (PIs), such as bortezomib, in the treatment of plasma cell (PC) disorders has provided proof of concept that disrupting protein homeostasis is an effective and generally safe therapeutic approach. Therefore, the intrinsic biology of PC offers us the opportunity to rationally develop therapies that target this distinct proteostasis vulnerability of PC dyscrasias. In this manuscript, we will review the laboratory rationale for the effectiveness of FDA-approved and investigational agents targeting protein homeostasis in AL amyloidosis and related PC disorders.

Increased troponin is associated with poor survival in patients with amyloid light-chain (AL) amyloidosis with cardiac involvement (CAL). The purpose of this investigation was to define the relation between increased troponin and clinical, morphologic, and functional features. The comparative utility of clinical, echocardiographic, and biochemical measurements in predicting survival in CAL was also investigated. One hundred seventeen patients with CAL were divided into 2 groups: normal troponin I (<0.06 ng/ml, n = 42) or increased troponin I (≥0.06 ng/ml, n = 75). Patients in the high troponin I group were older (63 vs 58 years, p = 0.04), with higher B-type natriuretic peptide levels (1,417 vs 936 pg/ml, p = 0.0004). The high troponin I group also had higher echocardiography-determined early/late mitral inflow velocity ratio (2.2 vs 1.4, p = 0.005) and myocardial performance index (0.59 vs 0.45, p = 0.04) and lower stroke index (28 vs 38 ml/beat/m2, p <0.0001) and left atrial systolic force (5.9 vs 8.4 k-dynes, p = 0.037) than the normal troponin group. Median survival was significantly shorter in the high troponin group (11 vs 45 months, p <0.001). At time of CAL diagnosis, univariate predictors of all-cause mortality included increased troponin, older age, male gender, New York Heart Association class III to IV, >2 organs involved, higher B-type natriuretic peptide, lower creatinine clearance, greater ventricular septal thickness, and higher myocardial performance index. However, by multivariate Cox survival analysis, only increased troponin was a significant predictor for all-cause mortality (hazard ratio 3.1, p = 0.002). In conclusion, increased troponin is associated with worse left ventricular and left atrial functions by echocardiography in patients with CAL. Among baseline variables, it is the strongest predictor of all-cause mortality in multivariate analysis. Troponin is a powerful tool in clinical and prognostic assessments of patients with CAL.

Background The monoclonal antibody daratumumab, approved for treating myeloma, targets CD38, a protein on myeloma and also on CD34+ hematopoietic progenitor cells. Because mobilized CD34+ cells are critical for stem cell transplant, we investigated the in vitro activity of daratumumab on mobilized CD34+ cells from myeloma patients with no prior exposure to daratumumab. Methods We determined the number of CD38 molecules per CD34+ cell, and whether daratumumab bound to CD34+ cells, whether C1q bound to daratumumab-coated CD34+ cells and whether daratumumab-related complement-dependent cytotoxicity (CDC) occurred. We also examined CD34+ cell progenitor cell colony capacity in assays with pre-plating incubation of CD34+ cells with daratumumab alone or with daratumumab and the CD59 inhibitory antibody BRIC229, and also assessed CD34+ cell responses to increasing doses of daratumumab in caspase 3/7 activity assays. Results Although 75% of mobilized CD34+ cells co-express CD38, CD38 was minimally present on CD34+ cells compared to Daudi and KG-1 controls, C1q did not bind to daratumumab-coated CD34+ cells, and CDC did not occur. CD34+ cells incubated in complement-rich human serum with daratumumab alone or with daratumumab and BRIC229, and then plated in progenitor cell assays, produced similar numbers of colonies as controls. In progenitor cell assays with cryopreserved or fresh unselected or CD34-selected cells, daratumumab did not affect progenitor cell capacity, and in caspase 3/7 activity assays CD34+ cells were not affected by increasing doses of daratumumab. Conclusion In vitro, daratumumab is not toxic to mobilized CD34+ progenitor cells from myeloma patients.

Two decades ago, a young British woman with systemic immunoglobulin-light-chain (AL) type amyloidosis, hepatomegaly, Howell–Jolly bodies on blood smear, 10% kappa-restricted marrow plasma cells, and a kappa band on urine immunofixation came to Boston for stem-cell transplantation. The kappa light-chain protein was encoded by the IGKV1-16 germline gene, 1 as is the kappa light-chain protein in 17 of 131 AL amyloidosis kappa cases in the Amyloid Light Chain Database (ALBase) (http://albase.bumc.bu.edu); in contrast, kappa protein is encoded by IGKV1-16 in only 1 of 107 myeloma kappa cases in the ALBase (relative risk of amyloidosis, 13.9; 95% confidence interval, 1.9 to 102.7; . . .

Over the past two decades, significant progress has been made in the diagnosis, risk assessment and treatment of patients with multiple myeloma, translating into remarkable improvements in survival outcomes. Yet, cure remains elusive, and almost all patients eventually experience relapse, particularly those with high-risk and refractory disease. Immune-based approaches have emerged as highly effective therapeutic options that have heralded a new era in the treatment of multiple myeloma. Idecabtagene vicleucel (ide-cel) is one such therapy that employs the use of genetically modified autologous T-cells to redirect immune activation in a tumor-directed fashion. It has yielded impressive responses even in patients with poor-risk disease and is the first chimeric antigen receptor (CAR) T-cell therapy to be approved for treatment in relapsed or refractory multiple myeloma. In this review, we examine the design and pharmacokinetics of ide-cel, audit evidence that led to its incorporation into the current treatment paradigm and provide insight into its clinical utilization with a focus on real-life intricacies. Keywords: CAR-T, immunotherapy, multiple myeloma, cytokine release syndrome, neurotoxicity, resistance

Background Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. Methods These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. Results The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. Conclusions A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.