Correction: Pomalidomide, bortezomib, and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Allogeneic stem cell transplantation for multiple myeloma: is there a future?

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) relapse and the curability of MM remains limited. Genetically defined high-risk MM represents a subgroup with an aggressive disease course despite novel agents. Allogeneic hematopoietic cell transplantation (allo-SCT) is a potentially curative option in MM that has several advantages including a tumor-free graft, and the potential for sustained immune-mediated disease control. However, historically high treatment-related mortality (TRM) and conflicting reports from prospective studies in the United States and European Union have limited the utilization of this modality. Meanwhile, newer preparative regimens, planned maintenance strategies and improvements in supportive care have led to a decline in TRM and better survival in recent years. The allo-SCT platform also provides additional options of immunotherapy at relapse including donor lymphocyte infusions, immunomodulatory drug maintenance and withdrawal of immune suppression. In this article, we provide an in-depth review of literature for allo-SCT and other immunotherapy options, as well as the authors' approach to using allo-SCT in MM.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Second transplants for multiple myeloma relapsing after a previous autotransplant-reduced-intensity allogeneic vs autologous transplantation.

There is no standard therapy for multiple myeloma relapsing after an autotransplant. We compared the outcomes of a second autotransplant (N=137) with those of an allotransplant (N=152) after non-myeloablative or reduced-intensity conditioning (NST/RIC) in 289 subjects reported to the CIBMTR from 1995 to 2008. NST/RIC recipients were younger (median age 53 vs 56 years; P<0.001) and had a shorter time to progression after their first autotransplant. Non-relapse mortality at 1-year post transplant was higher in the NST/RIC cohort, 13% (95% confidence interval (CI), 8-19) vs 2% (95% CI, 1-5, P0.001). Three-year PFS and OS for the NST/RIC cohort were 6% (95% CI, 3-10%) and 20% (95% CI, 14-27%). Similar outcomes for the autotransplant cohort were 12% (95% CI, 7-19%, P=0.038) and 46% (95% CI, 37-55%, P=0.001). In multivariate analyses, risk of death was higher in NST/RIC recipients (hazard ratio (HR) 2.38 (95% CI, 1.79-3.16), P<0.001), those with Karnofsky performance score<90 (HR 1.96 (95% CI, 1.47-2.62), P<0.001) and transplant before 2004 (HR 1.77 (95% CI, 1.34-2.35) P0.001). In conclusion, NST/RIC was associated with higher TRM and lower survival than an autotransplant. As disease status was not available for most allotransplant recipients, it is not possible to determine which type of transplant is superior after autotransplant failure.

Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group.

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.

Oral antibiotic prophylaxis of early infection in multiple myeloma: a URCC/ECOG randomized phase III study.

Multiple myeloma (MM) is a malignancy of clonal plasma cells, resulting in an increased production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly streptococcal and staphylococcal infections. This study evaluated the impact of prophylactic antibiotics on the incidence of serious bacterial infections (SBIs) during the first 2 months of treatment in patients with newly diagnosed MM. Patients with MM receiving initial chemotherapy were randomized on a 1:1:1 basis to daily ciprofloxacin (C; 500 mg twice daily), trimethoprim-sulfamethoxazole (T; DS twice daily) or observation (O) and evaluated for SBI (Eastern Cooperative Oncology Group ≥grade 3) for the first 2 months of treatment. From July 1998 to January 2008, 212 MM patients were randomized to C (n=69), T (n=76) or O (n=67). The incidence of SBI was comparable among groups: C=12.5%, T=6.8% and O=15.9%; P=0.218. Further, any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, P=0.954). We demonstrate that prophylactic antibiotics did not decrease the incidence of SBI (≥grade 3) within the first 2 months of treatment. We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy.

Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research.

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.

Primary therapy with single agent bortezomib as induction, maintenance and re-induction in patients with high-risk myeloma: results of the ECOG E2A02 trial.

Single agent bortezomib results in response rates of 51% in patients with newly diagnosed multiple myeloma and is touted to be especially effective in high-risk disease. We are the first to prospectively explore single agent bortezomib as primary therapy (induction, maintenance and re-induction) without consolidative autologous stem cell transplant in a cohort selected to have high-risk multiple myeloma. Patients received eight cycles of induction, followed by maintenance bortezomib every other week, indefinitely. Patients relapsing on maintenance had the full induction schedule resumed. On an intention-to-treat basis, the response rate (>or=partial response) was 48%. Among seven patients who progressed on maintenance bortezomib and received re-induction, two responded to the treatment. With a median follow-up of 48.2 months, 1- and 2-year overall survival probabilities were 88% (95% confidence interval (CI) 79-98%) and 76% (95% CI 60-86%), respectively. Median progression-free survival was 7.9 months (95% CI 5.8-12.0). Twenty-three and thirty-four patients had >or=grade 3 hematological and non-hematological toxicity, respectively, with treatment-emergent neuropathy in 7% with motor grade 1-2, 56% with sensory grade 1-2 and 2% with grade 3, and in 14% with neuropathic pain grade 1-2 and 2% with grade 3. In high-risk patients, upfront bortezomib results in response rates that are comparable to those reported for unselected cohorts, but single agent bortezomib is not sufficient as primary therapy.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management.

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.

Cure of multiple myeloma -- more hype, less reality.

Randomized studies have firmly established the role of autologous transplant as initial therapy in multiple myeloma (MM). Indeed, MM has emerged as the commonest indication for autologous SCT in North America. The conceptual basis for high-dose therapy is the goal of complete remission (CR) through steep reduction in tumor burden affected by single and tandem transplants. Careful analysis of the data challenges the notion of CR as a surrogate to success. Intrinsically aggressive MM, defined by known unfavorable biologic risk factors, overrides the benefit of CR. In contrast, subgroups of patients with favorable biological risk factors may achieve prolonged survival, often without ever achieving CR. Unfortunately, even with tandem transplants, there is no plateau in survival curves. To this end, sequential autologous followed by nonmyeloablative allotransplants are a novel attempt at 'curing' myeloma, but the results thus far have failed to show a definite plateau in survival. Given the improvements in supportive care and concomitant reduction in transplant-related mortality, conventional myeloablative allogeneic transplants need to be re-examined as an option in high-risk aggressive myeloma. At the same time, novel antimyeloma therapies, newer risk stratification and staging tools are transforming the treatment algorithm. We examine the changing role of transplantation in myeloma in the context of novel drug therapy, biologic risk stratification and improving supportive care while arguing that the current 'one size fits all' transplant approaches are far from a cure.

The implication of follicular lymphoma patients receiving allogeneic stem cell transplantation from donors carrying t(14;18)-positive cells.

We performed real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood (PB) and/or bone marrow (BM) samples collected pre- and post transplant from 23 recipient-donor pairs receiving allogeneic stem cell transplantation (allo-SCT) for follicular lymphoma (FL). Of 23 donors, 11 had a PB and/or BM sample positive for t(14;18) (BCL2/IGH fusion) at low levels (

Outcome of unrelated transplants in patients with multiple myeloma.

The outcome of patients with multiple myeloma treated with standard therapy is disappointing, with a historical median survival of 3 years. Although high-dose therapy with autologous stem cell transplant has improved treatment outcomes, cure is unlikely. Allogeneic transplant provides a tumor-free graft and a graft-versus-myeloma effect. However, only a minority of patients has a compatible sibling donor. Unrelated hematopoietic stem cell transplant is another option. We analyzed the outcome of patients who received an unrelated bone marrow transplant facilitated by the National Marrow Donor Program (NMDP). Between 1989 and 2000, 71 patients received a myeloablative unrelated transplant for multiple myeloma; 70 patients consented for this analysis. The median recipient age was 44 years. A total of 31% of patients had received a prior autologous transplant. In all, 91% of patients engrafted. The 3-year cumulative incidence estimate of relapse was 34+/-10%. The incidence of Grade II-IV GVHD was 47%. The Kaplan-Meier estimate for overall survival at 5 years was 9+/-7%. The 100-day treatment-related mortality was 42%. In multivariate analysis, only a male donor was a significant predictor for survival. Better strategies are needed to treat patients with multiple myeloma, perhaps by using less-toxic, nonmyeloablative conditioning regimens.

Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: a phase I study.

This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m(2) and advancing by 20 mg/m(2) increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m(2) was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m(2). Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m(2)) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses >/=280 mg/m(2) and was deemed fatal in 1 patient given melphalan 300 mg/m(2). (Another patient with a known cardiomyopathy was given melphalan 220 mg/m(2) and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m(2) died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m(2), and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m(2), an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.

A multicenter phase 2 trial of stem cell transplantation for immunoglobulin light-chain amyloidosis (E4A97): an Eastern Cooperative Oncology Group Study.

Stem cell transplantation was introduced as a new therapeutic modality for amyloidosis. The purpose of the current study was to determine the feasibility and toxicity of stem cell transplantation for amyloidosis in a cooperative group setting in which most participating institutions would have limited experience in managing the disorder. A total of 30 patients with biopsy-proven amyloidosis shown to be immunoglobulin light-chain type were enrolled on this trial. The protocol required mobilization of a minimum of 6 x 10(8) mononuclear cells/kg or 5 x 10(6) CD34(+) cells/kg ideal body weight. These targets had to be achieved within seven collections. Patients with advanced hepatic, renal, or cardiac failure were excluded. End points included objective response rate and overall survival. The secondary end point of the protocol was nonhematologic toxicity. Accrual to the study was faster than expected. The overall response rate (hematologic and organ) was 64%, with three treatment-related deaths. Another patient died before day 30 of sudden cardiac death not treatment related. The median follow-up of surviving patients is 30.3 months. Median survival has not been reached. Stem cell transplantation for selected patients with amyloidosis is feasible in a cooperative group setting. A multicenter phase 3 trial of high-dose therapy is indicated.

Successful treatment of systemic and central nervous system lymphomatoid granulomatosis with rituximab.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder with a mortality rate approaching 60% in the first year. The median survival is 14 months from the time of diagnosis. Although a variety of chemotherapeutic regimens have been utilized, there is no standard treatment. Studies have shown that in most cases the malignant cells are B-cells, which induce massive infiltration of reactive T-lymphocytes in the background. The disease is therefore considered as a T-cell rich B-cell lymphoproliferative disorder. We report a case of LYG with pulmonary, hepatic, central and peripheral nervous system involvement that was successfully treated with the anti-CD20 (B-cell) monoclonal antibody, Rituximab.

Activity of single-agent melphalan 220-300 mg/m2 with amifostine cytoprotection and autologous hematopoietic stem cell support in non-Hodgkin and Hodgkin lymphoma.

High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220-300 mg/m(2) plus amifostine (AF) cytoprotection and AHSCT as part of a phase I-II trial. Median age was 51 years (range 24-62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, 'first-line' AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D +100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL+AF+AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median follow-up in these latter patients of D +1163 (range D +824 to D +1630); one of these patients had a nonmyeloablative allograft as consolidation on D +106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure. Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL+AF+AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens.

Phase I study for poor-prognosis lymphoma: augmentation of the "BEAM" regimen with escalating dose melphalan using amifostine cytoprotection and autologous hematopoietic stem cell transplantation--a preliminary report.

We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting. Our recent experience indicated that the maximum tolerated dose of HD-MEL plus autologous hematopoietic stem cell transplant could be increased from approximately 200 mg/m2 to at least 280 mg/m2 with amifostine. Although a dose-limiting toxicity was not clearly identified, atrial fibrillation was noted in several patients. Phase II trials using this regimen have been reported in lymphoma and myeloma. Nonetheless, it is unlikely that single agent therapy, regardless of dose, will be highly curative in advanced hematologic malignancy. Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma. Patient entry at the starting dose (ie, HD-MEL 140 mg/m2) has been completed without the development of severe regimen-related toxicities. This trial is ongoing.