haematologica | 2010; 95 (2) 311In multiple myeloma, peripheral neuropathy has for a long time been considered as mainly secondary to the plasma cell dyscrasia itself. With the advent of new targeted drugs such as thalidomide and bortezomib, the iatrogenic neurotoxicity has become the leading cause of peripheral neuropathy. This review discusses the pathogenesis, incidence, risk factors, diagnosis, characteristics, and management of peripheral neuropathy related to new multiple myeloma drugs, mainly bortezomib and thalidomide. The current knowledge of the pathophysiology of the new forms of peripheral neuropathy is still limited. The mechanisms involved depend on the agents used, patient's medical history, and duration of exposure and/or treatment doses or sequence. Diagnosis of such peripheral neuropathy is often easier than treatment. A full anamnesis and regular clinical evaluation are necessary. Electrophysiological assessments may support the diagnosis, although their contribution remains insufficient. Complex clinical features may require a specialized neurological assessment within the context of a multi-disciplinary approach. Finally, early detection of peripheral neuropathy and the use of dose adjustment algorithms as in the case of bortezomib, should help reduce the side effects while maintaining anti-tumor efficacy.

We investigated efficacy and toxicity of lenalidomide in 24 heavily pretreated myeloma patients with a median age of 59 years (range: 37-70) and relapse after allo-SCT. Lenalidomide was given at a dose of 15 mg (n ¼ 4), or 25 mg (n ¼ 20), orally once daily on day 1 to day 1 every 28 days, with (n ¼ 20) or without (n ¼ 4) DHAP. The median number of lenalidomide cycles was five (range: 2-17). Major side effects were leukopenia (grade 4: 4%, grade 3: 21% and grade 2: 17%) and thrombocytopenia (grade 3: 17% and grade 2: 29%); infectious complications were observed in 50%. Non-hematological toxicity consisted of muscle cramps (n ¼ 9), fatigue (n ¼ 5) and constipation (n ¼ 2). Mild grade I-II GVHD was seen in three patients. Response was achieved in 66%: CR in 8%, VGPR in 8%, PR in 50% and SD in 13%. The median time to progression was 9.7 months (95% confidence interval (CI): 7.5-11.9), and median OS was 19.9 months (95% CI: 17.3-22.5). Immunomonitoring after lenalidomide showed significant increase of activated NK (NKp44 þ ) and T (HLA-DR þ ) cells, as well as regulatory T cells (CD4 þ , CD25 þ , CD127 lo ), supporting an immunomodulating anti-myeloma effect of lenalidomide.

hematopoietic transplantation for hematologic malignancies using post-transplanta-tion cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplanta-tion.

We retrospectively analyzed outcomes of a CD34(+)-selected stem cell boost (SCB) without prior conditioning in 32 patients (male/22; median age of 54 years; range, 20 to 69) with poor graft function, defined as neutrophils ≤1.5 x 10(9)/L, and/or platelets ≤30 x 10(9)/L, and/or hemoglobin ≤8.5 g/dL). The median interval between stem cell transplantation and SCB was 5 months (range, 2 to 228). The median number of CD34(+) and CD3(+) cells were 3.4 x 10(6)/kg (.96 to 8.30) and 9 x 10(3)/kg body weight (range, 2 to 70), respectively. Hematological improvement was observed in 81% of patients and noted after a median of 30 days (range, 14 to 120) after SCB. The recipients of related grafts responded faster than recipients of unrelated grafts (20 versus 30 days, P = .04). The cumulative incidence of acute (grade II to IV) and chronic graft-versus-host disease (GVHD) after SCB was 17% and 26%, respectively. Patients with acute GVHD received a higher median CD3(+) cell dose. The 2-year probability of overall survival was 45%. We suggest that SCB represents an effective approach to improve poor graft function post transplantation, but optimal timing of SCB administration, anti-infective, and GVHD prophylaxis needs further evaluation.

Treatment of multiple myeloma has evolved over the last decade, most notably with the introduction of highly effective novel agents. It is now possible to aim for deep disease responses in a greater number of patients in an attempt to prolong remission duration and survival. Initially introduced in the relapsed setting, the novel agents, namely thalidomide, bortezomib and lenalidomide, are now being increasingly incorporated into upfront treatment strategies, raising questions about the feasibility of 'retreatment' with such agents. Also, in a disease that is characterized by multiple relapses, the 'sequencing' of the different effective options is an important question. In the frontline setting, the first remission is likely to be the period during which patients will enjoy the best quality of life. Thus, the goal should be to achieve a first remission that is the longest possible by using the most effective treatment upfront. At relapse, the challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. The decision will depend on both disease- and patient-related factors. This review aimed to assess the available research data addressing 'retreatment' approaches, drug 'sequencing' and the long-term impact of upfront therapy with novel drugs.

BACKGROUND:The optimal combination of fludarabine, busulfan, and antithymocyte globulin (ATG) for reduced-intensity conditioning (RIC) transplantation has not been established. ATG plays a pivotal role in the prevention of graft-versus-host disease (GvHD), but it is associated with a higher relapse rate and an elevated incidence of infections when high doses are used. METHODS: The authors retrospectively compared 2 different doses of ATG combined with fludarabine and busulfan in 229 adult patients who underwent transplantation at their institution. ATG was administered over 1 day (FBA1) or over 2 days (FBA2) at a daily dose of 2.5 mg/kg. RESULTS: There were 124 patients in the FBA2 cohort and 105 patients in the FBA2 cohorts. Patients in the FBA2 cohort were older and more frequently underwent transplantation from an unrelated donor; 93% of patients in the FBA2 cohort received intravenous busulfan versus only 5% in the FBA1 cohort. The incidence of grade 2 through 4 acute GvHD was 23% in the FBA2 cohort versus 42% in the FBA1 cohort (P ¼ .002); the incidence of grade 3 through 4 acute GvHD was 10% versus 23%, respectively (P ¼ .006); and the incidence of chronic GvHD was 35% versus 69%, respectively (P < .0001). The 2-year rates of overall survival, nonrelapse mortality, and relapse/progression for the FBA1 and FBA2 cohorts were 65% versus 67%, respectively (P ¼ .99), 20% versus 19%, respectively (P ¼ .61), and 30% versus 19%, respectively (P ¼ .09). The results were confirmed in multivariate analysis. CONCLUSIONS: The use of ATG at a dose of 5 mg/kg was correlated significantly with reduced incidence and severity of GvHD without impairing disease control. Taken together, the current results suggest that this conditioning represents a step forward in the optimization of RIC. Cancer 2013;119:986-92.

Allo-SCT is regularly performed in advanced lymphoma. Haploidentical family donors are a valuable source of hematopoietic stem cells and transplants from these donors, using T-repleted grafts, has recently been successfully reported. We report on 49 patients with refractory lymphoma who received T-repleted haploidentical SCT with a non-myeloablative regimen and post-transplant CY. The median time to recover ANC >0.5 × 10e9/L and transfusion independent plt count >20 × 10e9/L was 20 days (range 14-38) and 26 days (range 14-395). The probability to reach ANC >0.5 × 10e9/L at 30 days was 87% and transfusion independent plt count >20 × 10e9/L at 100 days was 87%. The cumulative incidence of grade 2-4 acute GVHD (aGVHD) was 25.6% (95% confidence interval (CI): 12.9-38.3%) and the cumulative incidence of chronic GVHD (cGVHD) was 5.2% (95% CI: 0-12.4%). The median follow-up is 20.6 months (range 12-54), and the projected 2-year OS and PFS were 71 and 63%. The relapse rate was 18.7% (95% CI: 7.6-29.8%) and the median time to relapse was 4.4 months (range 1.1-8.3). At 2 years, cumulative incidence of NRM was 16.3% (95% CI: 5.9-26.8%). T-repleted Haploidentical transplantation with post-infusion CY is a feasible and effective therapy in the poor prognosis of advanced lymphoma patients.

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLAidentical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the 'donor' group could actually proceed to RIC allo-SCT. With a median followup of 36 (range, 21-60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11-55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7-48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56-98%; P ¼ 0.0003) among the nontransplanted patients. In an 'intention-to-treat' analysis, the Kaplan-Meier estimate of PFS was significantly higher in the 'donor' group as compared to the 'no-donor' group (P ¼ 0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15-0.82; P ¼ 0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.