Reece, Donna

AbstractObjectivesApproximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation.MethodsAdult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2‐stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5‐days‐on/2‐days‐off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non‐responding patients, treatment could continue with the addition of low‐dose dexamethasone.ResultsIn total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non‐interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)‐positive group and 3.7 weeks in the t(4;14)‐negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)‐positive group and 34.6% in the t(4;14)‐negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%).ConclusionDovitinib showed no single‐agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)‐positive patients.

SummaryVenous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide‐prednisone to observation for 332 patients with MM post‐autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty‐three patients had biomarker data, including D‐dimer, factor VIII and thrombin anti‐thrombin (TAT) levels collected post‐ASCT at baseline and 2 months after intervention investigating in‐vivo thrombin generation. Differences between the time‐points included a significant reduction over time in D‐dimer, factor VIII and TAT levels in the observation group and sustained elevation of D‐dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide‐prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide‐prednisone arm, with a trend to increase in D‐dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide‐prednisone maintenance therapy post‐ASCT for MM.

SummaryThis single institution, open label Phase I‐II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m2 on day 1, 8, and 15, lenalidomide 25 mg on d 1–21 and prednisone 100 mg every other day in a 28‐d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full‐dose CPR regimen produced no dose‐limiting toxicity and was delivered for a median of 16 months (3·5–65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression‐free survival was 16·1 months [95% confidence interval (CI); 10·9–22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8–36·6 months). Only the beta‐2 microglobulin level at protocol entry correlated with a better survival (P = 0·047). These observations compare favourably with other 2‐ and 3‐ drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients.

SummaryAutologous stem‐cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant‐related mortality rates are high, and a recent randomized trial suggested that non‐transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant‐related mortality occurred in 11·5%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain‐type natriuretic peptide (BNP) >300 pg/ml (17·5 months vs. not‐reached) (P = 0·0004), troponin‐I >0·07 ng/ml (13·5 months vs. not‐reached) (P = 0·00001) and those not achieving a complete haematological response (88 months vs. not‐reached) (P = 0·0345); high BNP and troponin‐I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP <300 pg/ml and/or normal levels of troponin‐I should be considered transplant candidates.

SummaryDexamethasone ± thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T)PACE] is generally reserved as salvage therapy for aggressive multiple myeloma (MM) or plasma cell leukaemia (PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T)PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona. At time of D(T)PACE, 16 patients had PCL and three patients had leptomeningeal disease. Patients were heavily pretreated (median three prior regimens, range 1–12; prior autologous stem cell transplant [ASCT] 33%). Overall response rate was 49% (very‐good partial response 16%, partial response 33%) with stable disease in an additional 36%. Median progression‐free survival (PFS) was 5·5 months (95% confidence interval [CI]:4·3–9·8); overall survival (OS) 14·0 months (95% CI:8·7–19·3). Thirty‐five patients proceeded to ASCT or clinical trial, with median PFS for this subset of 13·4 months (95% CI:7·7–20·1) and OS 20·5 months (95% CI:14·8–63·8). D(T)PACE is an effective salvage therapy for heavily pretreated MM patients. Although the overall response rate of 49% in this poor prognosis cohort is reasonable, the PFS is short, suggesting the best role for D(T)PACE is in bridging to definitive therapy, such as transplantation.

Key Points Thalidomide and prednisone maintenance after transplantation improves progression-free but not overall survival.