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Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies., Competing Interests: Declaration of interests PR-O reports personal fees derived from consulting or advisory board roles from Celgene-BMS, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, and H3Biomedicine; steering committee membership from Celgene-BMS, Regeneron, and Janssen; speaker's bureau fess from Janssen, Celgene-BMS, GSK, Sanofi, and AbbVie; and a travel grant from Pfizer. SU reports grants and personal fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GSK, Merck, Sanofi, and Seagen; speakers’ bureau fees, consulting and advisory board participation, and steering committee membership from Janssen; participation on advisory boards from Karyopharm Therapeutics, Oncopeptides, Secura Bio, SkylineDx, and Takeda; and grants from Moderna, TeneoBio, and Pharmacyclics, outside the submitted work. ADC reports personal fees and participation on advisory boards from GSK; personal fees from Bristol Myers Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, and Legend; personal fees and participation on advisory boards from Genentech/Roche; participation on advisory boards from Novartis, outside the submitted work; and has a patent licensed for Novartis. NWCJvdD reports personal fees from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, Bristol Myers Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier, outside the submitted work. JGP-L reports personal fees from Janssen and GSK, outside the submitted work. MVM reports personal fees from Janssen, Celgene/Bristol Myers Squibb, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron, outside the submitted work. HE reports personal fees and research support from Bristol Myers Squibb/Celgene, Janssen, Sanofi, and GSK; and personal fees from Amgen, Takeda, and Novartis; outside the submitted work. MM reports personal fees from Janssen, Bristol Myers Squibb, WebMD global, GSK, and CDR-Life; and research funding from Siemens and BeiGene; outside the submitted work. BAD reports advisory board participation and consulting fees from COTA and Janssen; personal fees from Multiple Myeloma Research Foundation; honoraria for CME-related activities from Plexus Communications; research funding from Amgen and GSK; and involvement as an independent reviewer of a clinical trial for BMS; outside the submitted work. NP reports research funding and accomodation expenses from Amgen, Bristol Myers Squibb, Janssen, Takeda, and The Binding Site; research funding from Sanofi, and personal fees from Pfizer, outside the submitted work. PJH reports personal fees from Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer, outside the submitted work. W-JC reports personal fees from AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, and Novartis; and grants and personal fees from Bristol Myers Squibb, Janssen, and Novartis, outside the submitted work. GG reports personal fees from and is a shareholder of XNK Therapeutics Sweden, and personal fees from Fujimoto Pharmaceutical corporation, outside the submitted work. FS reports personal fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS, Novartis, SkyliteDX, Pfizer, and Daiki-Sankyo, outside the submitted work. JCY reports personal fees from Janssen, Sanofi, BMS, Regeneron, GSK, Pfizer, Menarini, outside the submitted work. EZ reports personal fees from Janssen, Bristol Myers Squibb, Amgen, and Takeda, outside the submitted work. RP reports personal fees and travel support from GSK and Janssen; and personal fees from Pfizer, AbbVie, Bristol Myers Squibb, and Sanofi, outside the submitted work. CN reports personal fees and participation on advisory boards from Janssen; personal fees from Bristol Myers Squibb, Sanofi, GSK, Pfizer, AstraZeneca, and DKSH; and personal fees and participation on advisory boards from Amgen, outside the submitted work. YL reports grants and personal fees from Janssen; personal fees from Sanofi, NexImmune, Caribou, Bristol Myers Squibb, Regeneron, and Genentech; and personal fees and participation on data safety monitoring boards from Pfizer, outside the submitted work. AC reports personal fees from AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme, outside the submitted work. JM reports personal fees from Amgen, Sanofi, Bristol Myers Squibb, Janssen, and Takeda, outside the submitted work. MC reports personal fees from Janssen, Celgene/Bristol Myers Squibb, GSK, Sanofi, Amgen, Menarini-Stemline, AbbVie, and Pfizer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The presence of minimal residual disease (MRD+) following autologous stem cell transplantation (ASCT) in multiple myeloma represents a poor prognostic factor for progression-free survival (PFS) and overall survival (OS)., Methods: At our department, we recommend lenalidomide maintenance for patients who are MRD+ after ASCT, while MRD-negative (MRD-) patients, after information about the national guidelines, were not advised to follow this regimen., Results: Out of the total 228 patients, 175 received ASCT following first-line induction (MRD- 92 (53%), MRD+ 83 (47%), at 2 months post-ASCT), while 53 underwent ASCT after second-line treatment (MRD- 27 (51%), MRD+ 26 (49%), at the same time point). Comparatively, MRD- patients who did not receive maintenance demonstrated better OS than MRD+ patients who received upfront ASCT and maintenance treatment (96% vs. 86%, p = 0.030, at 3 years). However, nonsignificant difference was found in PFS (76% vs. 62%, at 3 years). Furthermore, second-line ASCT, MRD- non-maintained patients exhibited significantly better PFS than MRD+ (71% vs. 27%, p > 0.001, at 3 years). However, OS was better but nonsignificant (96% vs. 76%, at 3 years). Fluorescence in situ hybridization (FISH) analysis was performed on 141 out of the 228 patients. Of these, 85 (60%) patients were deemed standard risk (SR), and 56 (40%) were classified as high risk (HR). In the SR cohort, MRD- patients exhibited better PFS and OS than MRD+ patients (71% vs. 59% and 100% vs. 85%, respectively). In the HR cohort, the MRD- patients showed superior PFS but similar OS compared to MRD+ patients (66% vs. 42% and 81% vs. 80%, respectively)., Conclusions: Our results indicate that being MRD- is a more crucial prognostic factor for the 3-year PFS and OS than the presence of high-risk cytogenetic markers or undergoing maintenance treatment. The latter appears insufficient, particularly for MRD+ patients following ASCT in the second-line setting, suggesting that these patients may require a more intensive treatment approach., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Despite the effectiveness of newer drugs for the treatment of multiple myeloma (MM), the outcomes are further improved by subsequent autologous stem cell transplantation (ASCT). Data on effectiveness in older patients are limited. We compared outcomes in patients aged 65-75 years depending on whether they were treated with ASCT or not and compared those to outcomes in patients <65 years., Methods: This was a retrospective, single-center study. We compared progression-free survival (PFS) and overall survival (OS) for all MM patients below and above the age of 65 years treated ± ASCT at the Karolinska University Hospital between 2010 and 2020. PFS and OS were calculated by the Kaplan-Meier method. Variables affecting PFS and OS were evaluated using Cox regression model., Results: Both PFS and OS were improved in the group 65-75 years treated +ASCT compared to those treated pharmacologically (p = 0.008 and p < 0.001, respectively). There were no significant differences between patients <65 years and those 65-75 years treated with ASCT., Conclusion: The findings indicate that even patients >65 years should be evaluated as candidates for ASCT. An individualized approach supported by a frailty/geriatric assessment score could assist clinicians to select the appropriate treatment for each patient., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The use of reduced-intensity conditioning (RIC) regimens has decreased the risk of nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). In contrast, disease relapse remains the most frequent cause of treatment failure and death. Owing to both their antimyeloma effect and immunomodulatory properties, novel drugs could improve outcomes after alloSCT. This phase II European Myeloma Network trial was designed to evaluate the combination of alloSCT with novel agents. The study was conducted to evaluate the toxicity and efficacy of RIC intensified with bortezomib (Bz) prior to alloSCT for high-risk (HR) multiple myeloma (MM) patients, as well as the efficacy of post-transplantation maintenance with Bz and lenalidomide (Len). Patients received RIC with Bz on days -9 and -2, fludarabine on days -6 to -4, and melphalan on day -3. Patients who were in complete response (CR) or near CR at day +100 post-transplantation received 6 cycles of Bz every 56 days, and the remaining received Bz, Len, and dexamethasone. Len maintenance was started on day +180 at a dose of 5 mg and continued until relapse or toxicity occurred. Of the 24 patients included, 21 were evaluable on day +100, including 12 in CR, 4 in very good partial response, 3 in partial response, and 2 with relapse or progression. The cumulative incidence (CuI) of relapse was 13.6% (95% confidence interval [CI], 3.2% to 31.3%) at 1 year and 28.5% (95% CI, 11.1% to 48.9%) at 2 years. The CuI of NRM was 21.1% (95% CI, 7.4% to 39.4%) at 2 years. With a median follow-up of 39 months (range, 1 to 67 months), the median event-free survival (EFS) was 29 months, and median overall survival (OS) was not reached. EFS and OS at 3 years were 42.5% (95% CI, 21.9% to 61.7%) and 74.01% (95% CI, 50.9% to 87.5%), respectively. The use of Bz within an RIC regimen allows for a high response rate after alloSCT. Maintenance with Bz and Len is feasible and provides remarkable results in terms of EFS and OS in HR MM patients., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Few approaches have been made toward exploring autologous NK cells in settings of cancer immunotherapy. Here, we demonstrate the feasibility of infusing multiple doses of ex vivo activated and expanded autologous NK cells in patients with multiple myeloma (MM) post-autologous stem cell transplantation. Infused NK cells were detected in circulation up to 4 weeks after the last infusion. Elevations in plasma granzyme B levels were observed following each consecutive NK cell infusion. Moreover, increased granzyme B levels were detected in bone marrow 4 weeks after the last infusion. All measurable patients had objective, detectable responses after NK cell infusions in terms of reduction in M-component and/or minimal residual disease. The present study demonstrates that autologous NK cell-based immunotherapy is feasible in a setting of MM consolidation therapy. It opens up the possibility for usage of autologous NK cells in clinical settings where patients are not readily eligible for allogeneic NK cell-based immunotherapies., Competing Interests: J. Liwing and P.-H.H. are employed by XNK Therapeutics (XNK); H.N., S.M., and M.C. are consulting for XNK; H.-G.L., is a board member of XNK; M.G., B.S., L.W.-J., K.M., G.G., H.-G.L., and E.A. are minority shareholders of XNK. A patent application pertaining to the use of antiviral prophylaxis in the context of autologous NK cell infusions has been filed (WO 2019/211310 A1). The remaining authors have declared that no competing interests exist., (© 2022 The Authors.)

Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma., (© 2021. The Author(s).)

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Novel drugs and drug combinations have improved outcomes for multiple myeloma patients. However, subgroups of patients still have a poor progression-free survival (PFS) and overall survival (OS). In an attempt to identify how the novel drugs affect the outcome in standard-risk and high-risk patients, respectively, we have investigated 715 multiple myeloma (MM) patients who have undergone high dose treatment followed by autologous stem cell transplantation at our center during 1995 - 2020. Outcomes during three time periods, 1995-1999 (period I), 2000-2009 (period II), and 2010-2020 (period III), were compared separately for standard-risk and high-risk patients. Risk stratification was based on chromosome analysis for periods II and III., Results: The whole cohort of patients showed significantly improved OS with time during the three periods being at a median of 5.8, 7.0, and 10.0 years, respectively. There is also a weak tendency for improved PFS, that is, a median of 2.4, 2.6, and 2.9 years, respectively, during the same periods. However, the separate analysis of standard-risk and high-risk patients showed that the overall improvement with time was due to improved standard-risk patients (median OS 8.4 years for the period I and not reached for period II and III). In contrast, no significant improvement was seen in high-risk patients. For patients with del17p, PFS was even worse during period III as compared to period II (median 1.6 vs 3.2 years respectively)., Conclusion: Our results show that the dramatic improvement in outcome for MM patients during the last 20 years only applies for standard-risk patients, while high-risk MM patients still are doing poorly, indicating that the novel drugs developed during this time are preferentially effective in standard-risk patients. New treatment modalities like CAR-T cells, CAR-NK cells, and/or bispecific antibodies should be tried in clinical studies early in the course of the disease, especially in patients with high-risk cytogenetics., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.

Melphalan at a myeloablative dose followed by autologous stem cell transplantation (ASCT) remains the standard of care for transplant-eligible patients with myeloma. However, therapies such as new immunomodulatory drugs and proteasome inhibitors and, more recently, monoclonal antibodies and chimeric antigen receptor T cells are challenging the traditional role of ASCT. Which patients benefit from ASCT? Can its use be delayed until first relapse? The field is moving rapidly as novel agents lead to new patient care strategies. The place of ASCT in this changing landscape will be reviewed and reassessed., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Novel drugs have improved survival for patients with multiple myeloma in recent years. However, the disease is still fatal. Allogeneic stem cell transplantation (Allo) has proven to cure some patients with the disease, but its role is controversial due to relatively high transplant-related toxicity and mortality (nonrelapse mortality, NRM). Using nonmyeloablative reduced-intensity conditioning (RIC), both toxicity and NRM can be reduced, and RICAllo is, therefore, an option for subgroups of patients. Upfront tandem autologous/RICAllo (Auto/RICAllo) was shown to be superior to single Auto or tandem Auto/Auto in both progression-free (PFS) and overall survival (OS) in two prospective studies with long-term follow-up, while three similarly designed studies did not detect a difference. A recent update of pooled patient data from four of these studies showed significantly superior PFS and OS with Auto/RICAllo. Importantly, none of these studies showed inferior results with Auto/RICAllo in patients less than 70 years of age. Auto/RICAllo appears to overcome some poor risk cytogenetic markers. Encouraging results have also been seen in treatment of relapsed patients. Combining Allo with new proteasome inhibitors and immunomodulatory drugs may further improve results. Other encouraging new cell therapies such as with CAR T-cells, NK- and CAR NK-cells may well have a place in combination with RICAllo. Such studies are warranted.

Objectives: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), and its importance as prognostic factor has been controversial. The aim was to analyze its prognostic value., Method: In this retrospective study of 469 newly diagnosed myeloma patients, outcomes in patients with (11;14) and standard risk (t(11;14)SR) or high risk (t(11;14)HR) cytogenetics were compared to outcomes of patients without t(11;14) and SR (non-t(11;14)SR) or HR (non-t(11;14)HR), respectively., Results: Overall progression-free survival (PFS) was shorter in t(11;14)SR than non-t(11;14)SR (median 28.9 vs 35.3 months); however, the difference was not significant (P = .2). Overall survival (OS) did not differ significantly between the groups. In the subgroup of patients that did not receive high-dose treatment, PFS was shorter for t(11;14)SR compared to non-t(11;14)SR, 10.6 vs 24.6 months (P = .01). Although OS were shorter for t(11,14)SR compared to non-t(11;14)SR (5-year OS 41.7% vs 63.8%), the difference was not significant (P = .1). In HDT patients, no significant difference was observed for OS or PFS between those with or without t(11;14)., Conclusion: This study shows that t(11;14) is associated with poorer outcome in MM, particularly in non-high-dose-treated SR patients. It should be considered an intermediate or high-risk marker in these patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: At our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head-to-head in large real-life patient material., Method: A retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high-dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 receiving VCD (351 with, 213 without HDT)., Results: Overall response rate (≥partial response) was higher with VRD compared to VCD in the entire VRD group (98% vs 88%, P < 0.001) and in the non-HDT group (98% vs 79%, P < 0.001). Progression-free survival (PFS) at 18 months was longer with VRD compared to VCD in the entire VRD group, the non-HDT group and the HDT group (88% vs 63%, 82% vs 32% and 91% vs 73%, respectively). Overall survival at 18 months was better for VRD-treated patients in the entire VRD group (95% vs 89%, P = 0.048)., Conclusion: Upfront VRD gives better responses and longer PFS compared to VCD in MM patients with or without subsequent HDT., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Treatment with Daratumumab (Dara), a monoclonal anti-CD38 antibody of IgG1 subtype, is effective in patients with multiple myeloma (MM). However, Dara also impairs the cellular immunity, which in turn may lead to higher susceptibility to infections. The exact link between immune impairment and infectious complications is unclear. In this study, we report that nine out of 23 patients (39%) with progressive MM had infectious complications after Dara treatment. Five of these patients had viral infections, two developed with bacterial infections and two with both bacterial and viral infections. Two of the viral infections were exogenous, i.e. acute respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), while five consisted of reactivations, i.e. one herpes simplex (HSV), 1 varicella-zoster (VZV) and three cytomegalovirus (CMV). Infections were solely seen in patients with partial response or worse. Assessment of circulating lymphocytes indicated a selective depletion of NK cells and viral reactivation after Dara treatment, however this finding does not exclude the multiple components of viral immune-surveillance that may get disabled during this monoclonal treatment in this patient cohort. These results suggest that the use of antiviral and antibacterial prophylaxis and screening of the patients should be considered., Competing Interests: Genmab A/S, and Janssen Biotech, commercial companies, provided support by providing free materials for the study. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single-agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first-line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6-9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow-up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5-not calculable, P < 0.001) with Len. Three-year OS among the total observational study population was 61% (95% CI, 52-69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60-83%) and was significantly lower among those patients who achieved ≥PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short-term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25-26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians.

Chromosomal aberrations have significant prognostic importance in multiple myeloma (MM). However, proteasome inhibitors (PI) and IMiDs may partly overcome the poor prognostic impact of some of them. In this study, we investigated a population-based consecutive cohort newly diagnosed patients with MM admitted during a defined time period to hospitals in Denmark, Norway, and Sweden. The impact of treatment modality on the prognostic importance of specific chromosomal aberration was investigated, with special reference to gain 1q21. The median follow-up of patients still alive at analysis was 40 months for the high-dose (HDT)-treated ones and 29 months for the whole population. Three hundred forty-seven patients with a known 1q21 status were included in this study. The 347 patients were divided into three groups, that is, 119 patients with the 1q21 gain, 105 patients with other aberrations (OA), that is, del(13q), del(17p), t(4,14), and/or (14;16), and 123 patients with no aberrations (NA). The groups were compared in terms of overall survival (OS), time to progression (TTP), and response. The 3-yr OS for patients with gain 1q21 was 60% compared to patients with OA 74% and NO 82% (gain 1q21 vs. NO P < 0.001; gain 1q21 vs. OA P = 0.095). If treated with PI or IMiDs, the 3-yr OS was 58% for patients with gain 1q21 compared to patients with OA 78% and NO 78%, respectively (P = 0.041, P = 0.140). In HDT patients, the 3-yr OS was 69% for patients with gain 1q21 compared to patients with OA 84% and NO 88%, respectively (P < 0.008, P = 0.600). Thus, neither HDT nor using PI or IMiDs could overcome the poor prognostic impact of gain 1q21, while these drugs and HDT seemed to improve OS in patients with OA, approaching the survival in NO. Further, gain 1q21 appears to be one of the most important poor prognostic chromosomal aberrations in multiple myeloma with current treatments. Trials using new drugs or allogeneic transplantation are warranted., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The poor treatment response of acute myeloid leukemia (AML) overexpressing high-risk oncogenes such as EVI1, demands specific animal models for new treatment evaluations. Evi1 is a common site of activating integrations in murine leukemia virus (MLV)-induced AML and in retroviral and lentiviral gene-modified HCS. Still, a model of overt AML induced by Evi1 has not been generated. Cell lines from MLV-induced AML are growth factor-dependent and non-transplantable. Hence, for the leukemia maintenance in the infected animals, a growth factor source such as chronic immune response has been suggested. We have investigated whether these leukemias are transplantable if provided with growth factors. We show that the Evi1(+)DA-3 cells modified to express an intracellular form of GM-CSF, acquired growth factor independence and transplantability and caused an overt leukemia in syngeneic hosts, without increasing serum GM-CSF levels. We propose this as a general approach for modeling different forms of high-risk human AML using similar cell lines.

In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to "best non-HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21).

We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma.

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common first-line treatment for patients with multiple myeloma (MM) under 65 years of age. A second ASCT at first relapse is frequently used but is challenged by the use of novel drugs. We retrospectively studied the outcome of second-line treatment in MM patients from the Nordic countries with relapse after first-line HDT and ASCT. Patients that underwent a second ASCT (n=111) were compared with patients re-treated with conventional cytotoxic drugs only (n=91) or with regimens including novel drugs (proteasome inhibitors and/or immunomodulatory drugs) (n=362) without a second ASCT. For patients receiving a second ASCT median overall survival was 4.0 years compared with 3.3 years (P<0.001) for the group treated with novel drugs and 2.5 years (P<0.001) for those receiving conventional cytotoxic drugs only. A second ASCT also resulted in a significantly longer second time to progression and a significantly longer time to next treatment. We conclude that, irrespective of the addition of novel drugs, MM patients in first relapse after ASCT still appear to benefit from a second ASCT. A second ASCT should be considered for all physically fit patients.

We have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.

Background: Renal impairment is a common feature in multiple myeloma and is considered a poor prognostic factor., Aim: To determine the impact of novel drugs (i.e. bortezomib, lenalidomide and thalidomide) in the treatment of myeloma patients with renal impairment. The primary endpoint was overall survival and secondary endpoints were time to next treatment and response., Methods: The study population included all patients diagnosed with treatment-demanding multiple myeloma January 2000 to June 2011 at 15 Swedish hospitals. Renal impairment was defined as an estimated glomerular filtration rate under 60 mL/min/1.73 m2., Result: The study population consisted of 1538 patients, of which 680 had renal impairment at diagnosis. The median overall survival in patients with renal impairment was 33 months, which was significantly shorter than 52 months in patients with normal renal function (P<0.001). Novel agents in first line improved overall survival (median 60 months) in non-high-dose treated patients with renal impairment (n = 143) as compared to those treated with conventional cytotoxic drugs (n = 411) (median 27 months) (P<0.001). In the multivariate analysis up front treatment with bortezomib was an independent factor for better overall survival in non-high-dose treated renally impaired patients. High-dose treated renally impaired patients had significantly better median overall survival than non-high-dose ones (74 versus 26 months) and novel drugs did not significantly improve survival further in these patients. Patients with renal impairment had both a shorter median time to next treatment and a lower response rate than those with normal renal function. However, novel drugs and high dose treatment lead to a significantly longer time to next treatment and the use of novel agents significantly improved the response rate of these patients., Conclusion: High dose treatment and novel drugs, especially bortezomib, can effectively overcome the negative impact of renal impairment in patients with multiple myeloma.

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment., (© 2013 John Wiley & Sons Ltd.)

Allogeneic transplantation has the potential to cure subgroups of patients with multiple myeloma, but its role is controversial due to high transplant-related mortality. Therefore, myeloablative allogeneic transplantation has fallen out of favor. Allogeneic transplantation using reduced-intensity conditioning (RICallo) has lower transplant-related mortality and may be an option for subgroups of patients. Upfront tandem autologous/RICallo (auto/RICallo) was shown to be superior to single auto or tandem auto/auto in both progression-free and overall survival in two studies with long-term follow-up, while four similarly designed studies with shorter follow-up did not show a significant advantage. All studies included patients less than 70 years of age. No study has shown that the auto/RICallo approach is inferior to auto or auto/auto. There have been indications that poor-risk cytogenetics may be overcome by the auto/RICallo approach. Encouraging results have also been seen in treatment of relapsed patients. Small studies indicate that combining allogeneic transplant with new proteasome inhibitors and immunomodulatory drugs may further improve results. Prospective studies including these drugs for induction, conditioning and post-allogeneic transplant maintenance are warranted and planned. New cell therapies, such as with natural killer cells have shown encouraging results in experimental animals and should be tried in combination with allotransplantation.

The combination of melphalan and prednisone (MP) has been the standard treatment of multiple myeloma (MM). Since the introduction of novel agents, the clinical outcome in MM has improved. Six randomized prospective studies with thalidomide combined with melphalan and prednisone (MPT) compared to MP have been performed, most of them showing that MPT gives a better response rate and median overall survival (OS). Amongst 1843 MM patients admitted to 15 Swedish centres, we selected all patients treated with MP and MPT in first, second, third or fourth line of therapy, in total 888 patients treated with MP and 274 with MPT. Patients were evaluated for response rate, OS and Time to Next Treatment. Multivariate Cox model analysis was made to adjust for different criteria at time for MM-diagnosis. The median OS from beginning of first line of treatment was 2.2/4.2 yrs after MP/MPT respectively, and in second, third and fourth line of treatment 1.8/2.9, 1.4/1.6 and 1.1/1.9 yrs (P < 0.0001, 0.003, 0.74 and 0.235). The relative risk for death in the MPT group vs. the MP group was 0.61 (95% CI: 0.45-0.84) in first and 0.55 (0.38-0.83), P < 0.01) in second line. Treatment with MPT gave a significantly better OS rate after both first and second line of therapy when compared with treatment with MP only., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

Long-term follow-up of prospective studies comparing allogeneic transplantation to autologous transplantation in multiple myeloma is few and controversial. This is an update at a median follow-up of 96 months of the European Group for Blood and Marrow Transplantation Non-Myeloablative Allogeneic stem cell transplantation in Multiple Myeloma (NMAM)2000 study that prospectively compares tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation alone (auto). There are 357 myeloma patients up to age 69 years enrolled. Patients with an HLA-identical sibling were allocated to auto/RICallo (n = 108) and those without to auto alone (n = 249). At 96 months progression-free survival (PFS) and overall survival (OS) were 22% and 49% vs 12% (P = .027) and 36% (P = .030) with auto/RICallo and auto respectively. The corresponding relapse/progression rate (RL) was 60% vs 82% (P = .0002). Non-relapse mortality at 36 months was 13% vs 3% (P = .0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and 47% vs 5% (P = .026), and 31% (P = .154). Long-term outcome in patients with multiple myeloma was better with auto/RICallo as compared with auto only and the auto/RICallo approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation. Follow up longer than 5 years is necessary for correct interpretation of the value of auto/RICallo in multiple myeloma.

Purpose: This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT)., Patients and Methods: Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months)., Results: Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 21%; P 0.001), and the median duration of response was longer (17.9 v 13.4 months; P.04) [corrected].The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia., Conclusion: VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

In this Perspective, we summarize some of the most contentious issues surrounding diagnosis and treatment of myeloma. We outline how a fundamental clash of philosophies, cure versus control, may be at the heart of many of the controversies. From the very definition of the disease to risk stratification to the validity of current clinical trial endpoints, we highlight the major areas of debate and provide alternative viewpoints that have implications for trial design and interpretation, as well as clinical practice.

Purpose: Results of allogeneic stem-cell transplantation (allo) in myeloma are controversial. In this trial autologous stem-cell transplantation (auto) followed by reduced-intensity conditioning matched sibling donor allo (auto-allo) was compared with auto only in previously untreated multiple myeloma., Patients and Methods: In all, 357 patients with myeloma up to age 69 years were enrolled from 2001 to 2005. Patients with an HLA-identical sibling donor were allocated to the auto-allo arm (n = 108) and patients without a matched sibling donor were allocated to the auto arm (n = 249). Single (n = 145) or tandem (n = 104) auto was optional. Conditioning for the auto arm was melphalan 200 mg/m(2); conditioning for the allo arm was total-body irradiation 2 Gy plus fludarabine 30 mg/m(2)/d for 3 days. Median follow-up time was 61 months. Primary end point was progression-free survival., Results: Progression-free survival at 60 months was significantly better with auto-allo than with auto [corrected] alone (35% v 18%; P = .001), as was the risk of death and of relapse in the long term (P = .047 and P = .003, respectively). Overall survival at 60 months was 65% versus 58%, and relapse incidence was 49% versus 78%. Complete remission rates were 51% and 41%, respectively (P = .020). Nonrelapse mortality at 24 months was 12% after auto-allo compared with 3% in the auto group (P < .001). The incidence of grade 2 to 4 acute graft-versus-host disease (GvHD) was 20%, and the incidence of limited and extensive chronic GvHD was 31% and 23%., Conclusion: In patients with previously untreated multiple myeloma, long-term outcome with respect to progression-free survival, overall survival, and relapse rate is superior after auto-allo compared with auto only. Nonrelapse mortality is at a reasonable level in both groups.

The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

Chromosomal aberrations are frequently found in multiple myeloma cells and play a major role in patient outcome and management of the disease. The most important chromosomal aberrations associated with poor outcome are del(17p), t(4;14), t(14;16) and t(14;20). Others that may be associated with adverse prognosis include amp(1)(q21), del(1p32), del(13), del(8p21) and hypodiploidy. Many chromosomal aberrations have no or uncertain impact; for example, t(11;14), t(8;14) and hyperdiploidy. Attempts have been made to overcome the negative prognostic impact of chromosomal aberrations using autologous or allogeneic transplantation or new immunomodulatory drugs such as thalidomide, lenalidomide and the proteasome inhibitor bortezomib, but the results are controversial. Data suggest that allogeneic transplantation and treatment with bortezomib or lenalidomide may help to overcome the negative effect of del(13) on prognosis, whereas bortezomib may have some influence on reducing the impact of del(17p), t(4;14) and t(14;16). Chromosome analysis should always be performed at diagnosis of multiple myeloma to improve the prediction of outcome and to aid treatment decision-making.