Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].).

Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival, although an overall survival benefit was not observed in all trials. Moreover, follow up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens such as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant has not been extensively evaluated. In the case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that, in young and fit patients, may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets, and chimeric antigen receptor-T cells. Despite encouraging preliminary results, longer follow up and larger patient numbers are needed before the clinical use of these novel therapies can be widely recommended.

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLAmatched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 g/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 g/mL had low (< 50%) donor T-cell chimerism (P ‫؍‬ .03), and 6 patients with MPA Css less than 2.5 g/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P ‫؍‬ .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 g/mL could prevent graft rejection.

Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLAidentical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P ‫؍‬ .001) and event-free survival (EFS) was 2.8 years (P ‫؍‬ .005) for 80 patients with HLAidentical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P ‫؍‬ .02) and EFS was 39 months (P ‫؍‬ .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 highdose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P ‫؍‬ .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study. IntroductionAutologous transplantation has been regarded as the standard of care for young myeloma patients. 1 Recently, "new drugs" such as lenalidomide and bortezomib have prolonged survival. 2,3 Allografting has been considered the only potential cure. 4 However, the high transplant-related mortality (TRM) has limited its use. 5,6 After the observation that donor engraftment could be obtained after reduced-intensity purine analogbased or nonmyeloablative low-dose total body irradiation (TBI)-based conditionings, allografting has become more feasible with acceptable toxicity. [7][8][9] Combining an autograft with a nonmyeloablative conditioning and an allograft has lowered TRM to approximately 15% in myeloma. 10,11 However, role and timing of allografting remain to be determined and convincing evidence that an allograft should routinely be performed is lacking.We report the long-term results of a trial, designed before the introduction of "new drugs," where the treatment assignment of newly diagnosed patients under the age of 66 was based on the presence or absence of an HLA-identical sibling (ClinicalTrials. gov number, NCT00415987). 12 Methods Patients and treatmentsA total of 245 patients were consecutively diagnosed with stage IIA-IIIB myeloma from September 1998 to July 2004 at 5 Italian centers: San Giovanni Battista Hospital, Tosine; University of Udine, Udine; Santa Croce e Carle Hospital, Cuneo; Sant Antonio e Biagio Hospital, Alessandrio; IRCC, Candiole. Of 199 patients, 166 with at least 1 sibling were HLA-typed to search for a potential sibling donor. Written informed consent was obtained from all patients. The study was approved by the 5 Institutional Review Boards according to the Declaration o...

As first salvage regimen, THAL-DEX was superior to CC, as second or third salvage regimen, it was equivalent to CC. THAL-DEX is not myelotoxic. It postpones the delivery of effective salvage chemotherapy. This might explain the survival benefit.

Transformed plasma cells in multiple myeloma (MM) are susceptible to natural killer (NK) cell-mediated killing via engagement of tumor ligands for NK activating receptors or “missing-self” recognition. Similar to other cancers, MM targets may elude NK cell immunosurveillance by reprogramming tumor microenvironment and editing cell surface antigen repertoire. Along disease continuum, these effects collectively result in a progressive decline of NK cell immunity, a phenomenon increasingly recognized as a critical determinant of MM progression. In recent years, unprecedented efforts in drug development and experimental research have brought about emergence of novel therapeutic interventions with the potential to override MM-induced NK cell immunosuppression. These NK-cell enhancing treatment strategies may be identified in two major groups: (1) immunomodulatory biologics and small molecules, namely, immune checkpoint inhibitors, therapeutic antibodies, lenalidomide, and indoleamine 2,3-dioxygenase inhibitors and (2) NK cell therapy, namely, adoptive transfer of unmanipulated and chimeric antigen receptor-engineered NK cells. Here, we summarize the mechanisms responsible for NK cell functional suppression in the context of cancer and, specifically, myeloma. Subsequently, contemporary strategies potentially able to reverse NK dysfunction in MM are discussed.

IntroductionDespite remarkable recent advances in its treatment, multiple myeloma remains incurable. 1 Allografting is still regarded as the only potential cure on account of its well-documented graft-versusmyeloma effect observed in a subset of patients. [2][3][4][5] However, its use remains controversial especially in newly diagnosed patients.In the late 1990s, the introduction of reduced intensity/ nonmyeloablative conditionings greatly renewed the interest in allografting, in particular for diseases such as myeloma where the transplantation-related mortality (TRM) with conventional transplantation regimens had been unacceptably high. [5][6][7] Combining the cytoreductive effect of a high-dose melphalan-based autograft with the graft-versus-myeloma effects of a nonmyeloablative allograft reduced TRM even in elderly, medically unfit myeloma patients. 8,9 Our recent comparison between autografting and nonmyeloablative allografting showed that the latter resulted in longer overall survival (OS) and event-free survival (EFS) in newly diagnosed patients younger than 65 years. 10 Preliminary reports from other groups have confirmed our findings. 11,12 Here, we report on an extended experience consisting of 100 newly diagnosed myeloma patients enrolled in a prospective clinical trial (http://ClinicalTrial.gov; NCT-00702247) and treated with nonmyeloablative allografts as part of their first-line treatment at 15 Italian Bone Marrow Transplantation Units of the Gruppo Italiano Trapianti di Midollo Osseo (GITMO). Methods Patients and donorsFrom July 1999 to June 2005, 100 newly diagnosed myeloma patients younger than 65 years were enrolled in a prospective multicenter trial. Informed consent was obtained upon enrollment in accordance with the An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Inclusion criteria included diagnosis of untreated Durie & Salmon stage IIA to IIIB multiple myeloma or stage I progressed to require therapy; age less than 65 years; Karnofsky performance status greater than 60%; and presence of an human leukocyte antigen (HLA)-identical sibling donor eligible for peripheral blood stem cell (PBSC) donation. Exclusion criteria included prior treatment for myeloma, abnormal cardiac function and chronic respiratory disease defined as systolic ejection fraction less than 35% and carbon monoxide diffusing capacity less than 40% of predicted or need of continuous supplemental oxygen, respectively; serum bilirubins greater than twice normal and alanine amino transferase (ALAT) and/or aspartate amino transferase (ASAT) greater than 4 times normal; poorly controlled hypertension; pregnancy; and seropositivity for HIV. Patients with active nonhematologic malignancies except nonmelanoma skin cancers or who were less than 5 years from the achievement of complete remissi...

Neurologic complications after hematopoietic stem cell transplantation are frequently life-threatening, and their clinical management can be highly challenging. A wide spectrum of causative factors-including drug-related toxicities; infections sustained by virus, bacteria, or invasive molds; metabolic encephalopathy; cerebrovascular disorders; immune-mediated disorders; and disease recurrence-may lead to potentially lethal complications. Moreover, given that some neurologic complications are not uncommonly diagnosed post mortem, their overall incidence is likely to be underestimated. Their prompt recognition and timely treatment are of paramount importance to reduce the risk for transplantation-related death.