Jithma P. Abeykoon

Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials

Outside of clinical trials, experience with daratumumab‐based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43‐93) years. High‐risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1‐14) and time to first DCT from diagnosis was 4.3 years (range, 0.4‐13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty‐two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and “other” DCTs, respectively. Overall response rate was 47%. Median follow‐up was 5.5 months (95% CI, 4.2‐6.1). Median progression‐free survival (PFS) was 5.5 months (95% CI, 4.2‐7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta‐refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1‐2.4] vs 3.1 [95% CI, 2.1‐NR] vs 5.9 [95% CI, 5.0‐NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1‐6.0] vs 8.2 [95% CI, 4.6‐NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7‐5.9] vs NR [95% CI, NR‐NR]; P = .002). Non‐hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.

New developments in the management of Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a rare, immunoglobulin M -associated lymphoplasmacytic lymphoma. With the recent discoveries of CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) and MYD88 mutations, our understanding of the biology of WM has expanded substantially. While WM still remains incurable, the field is rapidly evolving, and a number of promising agents with significant activity in this malignancy are being evaluated currently. In this review, we discuss the new developments that have occurred in WM over the past 15 years, with a focus on the role of ibrutinib, an oral Bruton’s tyrosine kinase inhibitor that has recently been approved for WM in the United States, Europe, and Canada.

Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenstrom macroglobulinemia

The management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression‐free survival (PFS) and time‐to‐next‐therapy (TTNT) were 32 (95% confidence interval [CI]: 15–51) and 50 (95% CI: 35–60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23–not reached [NR]) and NR (95% CI: 37–NR), respectively. Twenty‐five (86%) of 29 genotyped patients harbored MYD88L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well‐tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed‐duration option, with preliminary data suggesting efficacy independent of the patients’ MYD88 status.

Drugs with anti-oxidant properties can interfere with cell viability measurements by assays that rely on the reducing property of viable cells

Cell viability assays such as Cell Titer Blue and Alamar Blue rely on the reducing property of viable cells to reduce the reagent dye to a product which gives a fluorescent signal. The current manufacture-recommended protocols do not take into account the possibility of the reagent substrate being reduced directly to the fluorescent product by drugs with an anti-oxidant property. After suspecting spurious results while determining the cytotoxic potential of a drug of interest (DOI) with known anti-oxidant property against a renal cell cancer (RCC) cell line, we aimed to establish that drugs with anti-oxidant property can indeed cause false-negative results with the current protocols of these assays by direct reduction of the reagent substrate. We also aimed to counter the same with a simple modification added to the protocol. Through our experiments, we conclusively demonstrate that drugs with anti-oxidant properties can indeed interfere with cell viability measurements by assays that rely on the reducing property of viable cells. A simple modification in the protocol, as elaborated in the manuscript, can prevent spurious results with these otherwise convenient assays.

Reply to Castillo et al.

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Non-tender recurrent scrotal cellulitis

A 45-year-old man with a medical history of diabetes mellitus, dilated cardiomyopathy and obstructive sleep apnoea was hospitalised with recurrent scrotal cellulitis. He had been hospitalised twice within the past 3 months with scrotal oedema and cellulitis, which were managed with antibiotics and diuretics. The physical exam on the current admission was notable for an erythematous, non-tender, warm, indurated skin of the scrotum with a ‘peau d’orange’ appearance (figure 1A) and umbilicated skin …

Daratumumab-based therapy in patients with heavily-pretreated AL amyloidosis

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Primary systemic amyloidosis in patients with Waldenström macroglobulinemia

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Ixazomib: a novel drug for multiple myeloma

ABSTRACT Introduction: Proteasome inhibitors (PIs) have been an integral part of treatment for multiple myeloma (MM) over the past decade. Many newer PIs are being evaluated in pre-clinical and clinical setting, with an aim to improve the safety, efficacy and resistance profile of this class of drugs. Ixazomib is the first oral PI with a robust efficacy and favorable safety profile in MM. Areas covered: This review provides an overview of the (i) pharmacology and dosing of ixazomib, (ii) the efficacy and safety data from clinical studies, (iii) highlight the various novel combinations that have been reported, and (iv) give an overview of the ongoing studies with ixazomib. The review aims to provide a broad overview of the drug and compare and contrast it with the currently available alternatives. Expert commentary: The oral formulation of ixazomib makes it unique in the sense that it is an integral part of the only currently approved oral triplet for relapsed/refractory MM that incorporates both a PI and an immunomodulatory agent. The clinical efficacy, ease of administration, tolerability and synergy with other drug classes make ixazomib a valuable arsenal in the increasingly widening therapeutic armamentarium against MM.

Pompe Disease Could Mimic Exam Findings of Amyloidosis: Two Rare Diagnoses Bona Fide

A 70-year-old female presented with a three-year history of evolving macroglossia causing dysphagia and dysarthria, with proximal muscle weakness. Given the classic physical finding of macroglossia, the patient underwent extensive evaluation for amyloidosis which proved to be negative apart from a bone marrow biopsy which stained positive for transthyretin without amino acid sequence abnormality, thus giving wild-type transthyretin amyloidosis. Since the wild-type transthyretin amyloidosis could not entirely explain her clinical presentation and evaluation, further studies were conducted in a sequential manner, thus leading to a diagnosis of Pompe disease explaining her presenting signs and symptoms including her macroglossia. Through this fascinating case, we attempt to highlight the approach for the diagnoses of two rare diseases in a patient by emphasizing the importance of having a broad differential diagnosis when presented with findings which may have been thought as pathognomonic for certain diseases.