F van Rhee

VTD combination therapy with bortezomib–thalidomide–dexamethasone is highly effective in advanced and refractory multiple myeloma

Bortezomib (V) was combined with thalidomide (T) and dexamethasone (D) in a phase I/II trial to determine dose-limiting toxicities (DLTs) and clinical activity of the VTD regimen in 85 patients with advanced and refractory myeloma. The starting dose of V was 1.0 mg/m2 (days 1, 4, 8, 11, every 21 day) with T added from cycle 2 at 50 mg/day, with 50 mg increments per 10 patient cohorts, to a maximum dose of 200 mg. In the absence of DLTs, the same reiteration of T dose increases was applied with a higher dose of V=1.3 mg/m2. D was added with cycle 4 in the absence of partial response (PR). Ninety-two percent had prior autotransplants, 74% had prior T and 76% abnormal cytogenetics. MTD was reached at V=1.3 mg/m2 and T=150 mg. Minor response (MR) was recorded in 79%, and 63% achieved PR including 22% who qualified for near-complete remission. At 4 years, 6% remain event-free and 23% alive. Both OS and EFS were significantly longer in the absence of prior T exposure and when at least MR status was attained. The MMSET/FGFR3 molecular subtype was prognostically favorable, a finding since reported for a VTD-incorporating tandem transplant trial (Total Therapy 3) for untreated patients with myeloma (BJH 2008).

Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: a study of 367 myeloma patients

We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/μl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707–4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005–2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019–2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720–4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081–2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 μ/l (OR=1.129; 95% CI 1.039–1.226; P=0.0069 and OR=1.127; 95% CI 1.038–1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.

Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model.

Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4–6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080–2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065–2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.

Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib

Carfilzomib is a novel, highly selective, tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, which is the proteolytic core particle within the 26S proteasome, as compared with bortezomib, which reversibly inhibits the 20S proteasome.1 In vitro, carfilzomib has demonstrated antiproliferative and proapoptotic activities in solid and hematologic tumor cells.2

Making progress in treating multiple myeloma with total therapies: issue of complete remission and more

Making progress in treating multiple myeloma with total therapies: issue of complete remission and more

Clinical value of molecular subtyping multiple myeloma using gene expression profiling

Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone.

Recovery from neutropenia can be predicted by the immature reticulocyte fraction several days before neutrophil recovery in autologous stem cell transplant recipients

The duration of neutropenia (absolute neutrophil count (ANC) ⩽100/μl) identifies cancer patients at risk for infection. A test that precedes ANC⩾100/μl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC⩾100/μl in 99% of patients after the first Mel-ASCT by (mean±s.d.) 4.23±1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11±1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count⩾100/μl to the time to ANC⩾100/μl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC⩾100/μl.

Renal insufficiency retains adverse prognostic implications despite renal function improvement following Total Therapy for newly diagnosed multiple myeloma

Renal insufficiency (RI) is a frequent complication of multiple myeloma (MM) with negative consequences for patient survival. The improved clinical outcome with successive Total Therapy (TT) protocols was limited to patients without RI. We therefore performed a retrospective analysis of overall survival, progression-free survival and time to progression (TTP) of patients enrolled in TT2 and TT3 in relationship to RI present at baseline and pre-transplant. Glomerular filtration rate was graded in four renal classes (RCs), RC1–RC4 (RC1 ⩾90 ml/min/1.73 m2, RC2 60–89 ml/min/1.73 m2, RC3 30–59 ml/min/1.73 m2 and RC4 <30 ml/min/1.73 m2). RC1–3 had comparable clinical outcomes while RC4 was deleterious, even after improvement to better RC after transplant. Among the 85% of patients with gene expression profiling defined low-risk MM, Cox regression modeling of baseline and pre-transplant features, which also took into consideration RC improvement and MM complete response (CR), identified the presence of metaphase cytogenetic abnormalities and baseline RC4 as independent variables linked to inferior TTP post-transplant, while MM CR reduced the risk of progression and TTP by more than 60%. Failure to improve clinical outcomes despite RI improvement suggested MM-related causes. Although distinguishing RC4 from RC<4, 46 gene probes bore no apparent relationship to MM biology or survival.

Suppression of abnormal karyotype predicts superior survival in multiple myeloma

Cytogenetic studies were performed as part of all diagnostic and surveillance bone marrow examinations in 956 newly diagnosed patients with multiple myeloma (MM) receiving total therapy (TT) protocols and in 1085 previously treated patients enrolled in non-TT protocols. In both groups, cytogenetic abnormalities (CA) were present in one-third at baseline and persisted in 14% prior to first and 10% prior to second transplant (TT, 5%; non-TT, 15%); post-transplant detection rates increased progressively with time, from 7% within 6 months to 21% within 24 months to 28% at relapse. According to multivariate analyses, overall survival was adversely affected by the presence of CA at baseline (hazard ratio (HR)=7.20, P<0.001) and the development of CA both prior to (HR=3.28, P<0.001) and after first transplant (HR=6.24, P<0.001), whereas suppression of CA pretransplant was favorable (HR=0.38, P<0.001). The presence of CA at relapse further distinguished patients with a short median post-relapse survival of only 11 versus 47 months in those without CA (P<0.0001). Post-relapse survival was independently adversely affected by the detection of CA both at baseline (HR=1.35, P=0.044) and relapse (HR=2.47, P<0.001). Collectively, these results underscore the importance of monitoring for CA and attest to the favorable prognostic consequences of CA suppression with effective therapy.

Five gene probes carry most of the discriminatory power of the 70-gene risk model in multiple myeloma

Five gene probes carry most of the discriminatory power of the 70-gene risk model in multiple myeloma