Andrew Winter

Second Autologous Stem Cell Transplantation as Salvage Therapy for Multiple Myeloma: Impact on Progression-Free and Overall Survival

The role of a second autologous stem cell transplant (ASCT) as salvage therapy is unclear, particularly with the availability of novel agents to treat progressive multiple myeloma (MM). We retrospectively reviewed all MM patients who received a second ASCT as salvage therapy at our center from March 1992 to December 2009. Eighty-one MM patients received a second ASCT for relapsed MM. The median time to relapse after first transplant was 39 months (9.83-100). All patients received reinduction therapy before the second ASCT. The high-dose regimen given before the second ASCT consisted of melphalan (MEL) alone in the majority. Complete response, very good partial response, and partial response were seen in 7.7%, 39.7%, and 50%, respectively, at day 100 post-ASCT; the median time to relapse after the second ASCT was 19 months. Early deaths occurred in 2.6%. Median progression-free survival (PFS) based on the time to myeloma relapse after first ASCT was 9.83 months (relapse ≤ 24 months) and 17.3 months (relapse ≥ 24 months) (P < .05). Median overall survival (OS) was 28.47 months (relapse ≤ 24 months) and 71.3 months (relapse >24 months) (P = .006). Second ASCT is a feasible and safe option for salvage therapy in MM. The best outcome was observed in patients whose time to progression was >24 months after first ASCT, as these patients had a subsequent PFS lasting over 1 year and an OS of almost 6 years.

Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution

Autologous 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.

Autologous stem cell transplant for light chain deposition disease: Incorporating bortezomib to the induction therapy

Light chain deposition disease (LCDD) is a rare plasma cell dyscrasia characterized by deposition of immunoglobulin fragments [1]. The kidneys are almost always affected, while heart, liver, and other tissues are occasionally involved [2–4]. Most of the patients present with nephrotic range proteinuria and rapidly deteriorating renal function [5]. The outcome of patients with LCDD is variable. Median time to end-stage renal disease (ESRD) is 2.7 years with 5-year ESRD free survival of 37% [3]. There is no standard treatment for patients with LCDD. Chemotherapy with alkylating agents and steroids has shown modest results [6,7] and high-dose melphalan (HDM) with autologous stem cell transplantation (ASCT) has been used in some patients and has led to improvement of renal function [8–10]. Recently, bortezomib has shown hematologic and organ responses in patients with AL amyloidosis [11,12] and preliminary data indicates that bortezomib may have a protective role of renal parenchyma due to inhibition of NFkB activity [13]. Based on these data, bortezomib has been introduced in the treatment of patients with LCDD who are eligible for ASCT. In this case series, we report six patients with LCDD who underwent ASCT with three receiving induction bortezomib therapy. Between June 2005 and February 2011, six patients with LCDD underwent ASCT at Princess Margaret Hospital. Patient characteristics are shown in Table I. Of the six patients transplanted, 67% (N 5 4) were female. Only one patient had a bone marrow plasma cell count of 15% without evidence of active multiple myeloma. The median number of plasma cells in the bone marrow was 7% (5%–15%). Serum protein electrophoresis showed a monoclonal protein in two patients (IgG kappa). All six patients, however, had elevated serum free light chains and abnormal k to l ratio. Eastern cooperative group performance score was 2 or less in all the patients before undergoing ASCT. Treatment before high-dose therapy and ASCT was recorded. Before transplantation, patients received either dexamethasone alone (N 5 3) or dexamethasone plus bortezomib (N 5 3); dexamethasone was administered at 40 mg/day on days 1–4, 9–12, and 17–20 for variable treatment cycles (ranging from 3 to 6). Bortezomib was administered at 1.3 mg/m once weekly for a median of four cycles. Treatment with bortezomib was well tolerated with only Grade 1 peripheral neuropathy in one patient. No dose reduction or discontinuation was reported. Peripheral blood stem cells were collected using intravenous cyclophosphamide (2.5 g/m) and granulocyte colony stimulating factor. The median number of CD34 cells collected was 5.71 3 10/Kg (range 3.64–8.82) collected within a median of 2 days [1–4]. Five patients were conditioned using melphalan 200 mg/m, and one received melphalan 140 mg/m as per physician discretion. Standard supportive care with prophylactic antibiotics was provided to all patients. Transplanted patients had a median time to higher or equal to ANC 0.5 3 10/L of 13 days (range 11–14). The time to platelets higher or equal to 20 3 10/ L was 14 days (range 13–22). Median time to discharge was 17 days (range 13–30). Treatment related mortality with this approach was 0%. The median number of platelet and packed red blood cell transfusions was 3 apheresis units [1–5] and 4 units [4–8], respectively (similar to that seen in MM and AL transplants at our center) [14]. All patients were admitted to the hospital for ASCT. No patients required temporary or permanent dialysis. The nonhematologic adverse events included: febrile neutropenia (n 5 4), mucositis (n 5 6), nausea requiring antiemetics (n 5 6), and fatigue (n 5 6). Four patients developed fever and blood cultures were persistently reported as negative. According to response criteria cited by light chain amyloidosis [15], four out of six patients achieved a PR, and 2/6 attained SD after induction therapy. Free light chain assays were abnormal in all six patients at diagnosis, and only two patients exhibited a higher than 10 g/L of monoclonal protein in the serum. At Day-100, post ASCT overall response rate was 100%, four patients achieved complete hematological response, one patient exhibited nCR, and one more attained PR. All evaluable patients have derived clinical benefit, including those who achieved less than CR. At 6 months post-ASCT, all six patients showed organ response manifested mainly by decrease of the proteinuria in > 50% (Table I). Patients receiving velcade and dexamethasone induction showed a median time of kidney response of 3 months versus 6 months for the group receiving only dexamethasone (P 5 0.03). No one patient developed Engraftment Syndrome, and no patients

Intermittent granulocyte colony-stimulating factor for neutropenia management in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone

Abstract Neutropenia is a major dose-limiting toxicity associated with lenalidomide in relapsed/refractory multiple myeloma (MM). The optimal dosing schedule of granulocyte colony-stimulating factor (G-CSF) is unclear. We developed an intermittent G-CSF schedule (4–6 doses per cycle) initiated upon onset of grade 3–4 neutropenia. Of 216 patients with relapsed/refractory MM treated at our center with lenalidomide/dexamethasone on an Expanded Access Program, there was a high incidence of grade 3–4 neutropenia (61%) and grade 3–4 infections (37%). Despite intermittent G-CSF use in 117 patients, recurrent grade 3–4 neutropenia was common (59%), and dose reductions were required in 40% of G-CSF recipients, most due to thrombocytopenia. G-CSF recipients had a longer duration on therapy and achieved a higher rate and depth of response. Intermittent G-CSF may be an effective approach for lenalidomide dose-preservation, which may lead to improved outcomes, although it does not prevent infections or thrombocytopenia-related dose limitations.

Oligoclonal and monoclonal bands after single autologous stem cell transplant in patients with multiple myeloma: impact on overall survival and progression-free survival

Abstract Recently, the occurrence of oligoclonal and monoclonal bands (OB/MB) unrelated to the original clone has been reported in patients with multiple myeloma who undergo autologous stem cell transplant (ASCT) and/or receive treatment with novel agents. The aim of our study was to assess the impact of OB/MB occurrence on overall (OS) and progression-free survival (PFS) for patients with MM undergoing single ASCT at our institution. All consecutive patients with documented MM undergoing single ASCT from January 2000 to December 2012 were evaluated. Ninety-nine patients (11.8%) developed OB/MB at day 100 post-ASCT (32.3%, OB and 67.7%, MB). Multivariate analysis identified the development of OBs/MBs as an independent favorable prognostic factor for OS and PFS (p = 0.008 and 0.012, respectively). In conclusion, the occurrence of OB/MB is an important prognostic factor in patients with MM who undergo ASCT. Its impact on clinical outcomes should be prospectively validated and its biological significance further elucidated.