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Introduction: According to previous data, higher yields of stem-cells collected to support autologous transplantation may predict for improved outcomes. We aimed to assess the association between high stem-cells collection and survival outcomes in multiple myeloma (MM) MATERIALS AND METHODS: We reviewed all patients who underwent autologous transplantation for MM at our center over a 10-year period, and initially used a predefined threshold of 8 × 10 6 /kg used in previous studies., Results: Six hundred twenty-one patients were analyzed. Higher mobilization did not correlate with favorable outcomes post-transplant. The most efficient mobilizers, collecting ≥8 × 10 6 /kg (n = 478) achieved a shorter median progression-free survival (PFS) of 24.1m versus 34.5m in patients collecting 4.5 to 8 × 10 6 /kg (n = 129). A small group (n = 14) collecting ≤4.5 × 10 6 /kg but minimum of 2 × 10 6 /kg to support autologous transplantation exhibited the worst outcomes (median PFS 11.4m). Further analysis of potential confounders identified greater use of bortezomib induction in the lower mobilizers, however, sensitivity analysis in patients receiving bortezomib revealed similar results- worst outcomes to the most efficient mobilizers., Conclusion: Although bortezomib is not considered stem-cell toxic, it may be associated with lower stem cell collection yields. Bortezomib's efficacy at induction may partially explain the improved outcomes, however, other factors may be involved, and are discussed. We can conclude that with our large cohort and long follow-up, high stem-cell mobilization does not appear to predict for a long-term survival advantage., Competing Interests: Disclosure The authors had no conflict of interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Very late relapse (VLR) occurring >5 years after initial diagnosis is an uncommon event in the management of Hodgkin lymphoma (HL). Limited information regarding risk factors and optimal therapy is available., Patients and Methods: We reviewed patients treated for HL at Princess Margaret Cancer Centre, Toronto, Ontario Canada between January 01, 1999 and 31 December 31, 2018., Results: Thirty-two patients experienced VLR. Median time to first relapse was 7.2 years. Most patients were treated with CMT both at initial diagnosis and relapse. Male gender (P = .04) and increased age at initial diagnosis (P = .008; HR 1.09 (95% CI: 1.02-1.15)) were identified as risk factors for inferior survival on univariate analysis. Stage, histology, treatment modality and risk assessment at diagnosis or relapse did not have a significant impact on survival outcomes. ASCT at first relapse had no impact on time to second progression (HR 1.72; 95% CI, 0.35-8.53; P = .51) or overall survival from first relapse (HR 1.55; 95% CI, 0.3-8.03; P = .6)., Conclusion: Our data aligns with the limited information available in VLR HL suggesting the negative impact of age and male gender on this rare event. Additionally, our data did not show benefit of ASCT at first relapse in terms of survival outcomes in this population, though this analysis is limited by small sample size. Further study of optimal therapy to prevent and treat VL in the era of novel agents is critical., Competing Interests: Disclosure The authors declare not conflicts of interest regarding this study., (Copyright © 2023. Published by Elsevier Inc.)

Introduction/background: Daratumumab is an anti-CD38 monoclonal antibody initially approved as a single agent for the treatment of relapsed and refractory multiple myeloma. The infusion-related reactions (IRRs) commonly seen with intravenous daratumumab have been managed by prolonging the first infusion, temporarily stopping/slowing the rate if reactions occur and using adequate pre- and post-infusion medications. Several retrospective studies have evaluated shorter infusions after ≥ 2 prior doses administered at the standard rates. Although the shorter infusions were well-tolerated, patients in these reports were given heterogeneous daratumumab regimens and had often already received multiple doses at the longer standard rates., Patients and Methods: CMRG-009 is a prospective study designed to demonstrate the safety of accelerated daratumumab infusions commencing with the second dose. After an initial dose on Cycle 1 Day consisting of 8 mg/kg over 4 hours, all subsequent doses were given over 90 minutes., Results: No grade 3 IRRs were observed with the 90-minutes infusions. Both the safety profile and anti-myeloma effects were otherwise similar to those observed with other single agent daratumumab studies using longer infusion times., Conclusion: This is the first formal prospective trial using infusion times shorter than the standard schedule directly after an initial 4-hours dose. This rapid infusion protocol has resulted in more efficient resource utilization and has become the standard protocol for the use in all intravenous daratumumab regimens in Canada. This approach has been particularly helpful in shortening chair time during the COVID-19 pandemic and providing a useful alternative in jurisdictions without access to subcutaneous daratumumab., Competing Interests: Disclosure Stakiw J: Research Funding: Roche, Janssen; Honoraria: BMS, Novartis, Amgen, Celgene, Janssen, Lundbeck. Kodad S: None. Leblanc R: Research Funding: Celgene; Honoraria: BMS/Celgene, Janssen, Amgen, Novartis, Takeda. Sebag M: Honoraria: Janssen, Amgen, Takeda, Celgene; Research Funding: Janssen. Hay A: Research Funding: Seattle Genetics, Roche, Janssen, Amgen, Novartis, Celgene, AbbVie, Karyopharm. Kukreti V: Honoraria: Celgene, Amgen, Kyowa Kirin. Cote J: Honoraria: Celgene, Takeda, Janssen, Amgen. Camacho F: Paid Consulting: Janssen, AbbVie, Bausch-Health, Otsuka Canada. Fu M: None. Gul E: None. Reece D: Research funding: Celgene, Janssen, Takeda, Merck, BMS, Millennium; Consultancy: Celgene, Janssen, Amgen, Karyopharm, Takeda; Honoraria: Celgene, Janssen, Amgen, Takeda, Sanofi., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Salvage transplant has been historically considered effective therapy for myeloma patients relapsing after first transplant, if they achieved adequate remission duration. However, the efficacy of novel agent combinations has called this paradigm into question., Materials and Methods: We performed a retrospective analysis in a homogeneously treated cohort of 106 patients undergoing ASCT2 at our institution, all of whom received novel agent-based chemotherapy (immunomodulatory agent [IMiD] and/or proteasome inhibitor [PI]) for both induction and relapse. As an exploratory objective we assessed whether predictive thresholds of progression free survival post first transplant (ASCT1) for benefit post ASCT2 vary with use of IMiD maintenance post ASCT1., Results: The overall response rate (ORR) was 98% post-ASCT2 and treatment-related mortality (TRM) was low at 1.8%. With a median follow-up of 26 months (range 0.5-85) from ASCT2, median overall survival (OS) is estimated at 80 months (95% CI: ≥ 49-months) and median progression-free survival after ASCT2 (PFS2) at 24 months (95% CI 19-39). PFS post first transplant (PFS1) at >/= 50 months was associated with improved OS. Predictors of PFS2 included PFS1 ≤42 months and progression on IMiD-based maintenance post- ASCT1., Conclusion: ASCT2 continues to offer acceptable outcomes for most patients treated within modern day treatment paradigms, with longer PFS after ASCT1 and IMiD non-refractory disease being associated with improved outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Lymphoma is a disease of older patients and while treatment is subtype specific, curative or aggressive intent combination chemotherapy is often recommended. However, there has been limited evidence on which to base treatment decisions for older adults. Our objectives were to assess the utility of risk stratification measures and serial functional tests in predicting chemotherapy toxicity and as well the feasibility of conducting these in older adults undergoing chemotherapy for lymphoproliferative disorders., Materials and Methods: This prospective cohort study recruited lymphoma patients 70 years or older planned for systemic chemotherapy. The Cancer and Aging Research Group (CARG) risk stratification tool and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) were calculated at baseline. The Clinical Frailty Scale (CFS), Charlson Comorbidity Index score, grip strength and gait speed test, and toxicity events, were assessed at baseline and serially throughout treatment. Sarcopenia was calculated on CT scans at baseline, midway through treatment, and 1-month after completion of therapy. The primary endpoint was to assess the feasibility of applying these measures in busy ambulatory clinics. These measures were also correlated with clinical outcomes including ≥grade 3 adverse events (AEs), hospitalizations and emergency department visits, dose changes or delays, and overall survival., Results: In total, 30 patients were enrolled (mean age 78.1 ± 6.4 years), of whom 20 were treated with curative intent. A total of 16 patients (53%) experienced grade ≥3 AEs, 9 (56%) of which led to a chemotherapy delay. On univariable analyses, CFS score, a high CARG score, medium to high CRASH score, and the gait speed were associated with grade ≥3 AEs, while only CFS remained significant on multivariable analysis. On univariable analysis, patients with a medium to high risk CRASH score were more likely than low risk patients to have an unplanned emergency department visit or hospitalization., Conclusions: The CFS seems to predict toxicity in this cohort study, with gait speed, CARG and CRASH scores being potentially additional predictive methods of evaluation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Light chain (AL) amyloidosis and B-cell lymphoma represent 5% to 7% of all AL, Systemic amyloidosis, deposits in sites remote from the underlying lymphoma, and peritumoral amyloidosis deposition is within the immediate vicinity., Materials and Methods: We conducted a retrospectively study to identify and describe AL with B cell lymphoma at Princess Margaret Cancer Center from 01 January 1997 to 31 July 2019., Results: Thirty-five patients with AL and lymphoma, an incidence of 6, 2%, median age of diagnosis of 66 (range 47 to 86), majority male, most had underlying Waldestrom's Macroglobulinemia. 21 patients with peritumoral AL (PAL), and 15 with systemic AL. 42.8% of the patients had major organ involvement. 35% got treatment with Rituximab with alkylator, 20% received proteasome inhibitors, 17% patients were on a watch and wait approach, amyloid response showed very good partial response > 45.8%, and lymphoma ORR was 42.8%, with a median follow up of 31.5 months. A 36 month overall survival (OS) and progression-free survival (PFS) showed worse outcomes for heart involvement OS (P = .002), PFS (0.057) and IgM subtype OS (P = .02), PFS (0.01)., Conclusion: We have shown adverse outcome with IgM AL and to document a differences in OS and PFS not previously reported for PAL., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: The combination of lenalidomide and dexamethasone (Len-Dex) is an established regimen for patients with relapsed or refractory myeloma. To prolong the benefit of this effective regimen, the Myeloma Program at Princess Margaret Cancer Centre has routinely added a third agent, oral cyclophosphamide (Cy) given weekly, to Len-Dex at disease progression., Patients and Methods: In the present report, we describe the cases of 53 patients who had received Len-Dex-Cy for a minimum of 4 weeks from January 2007 to December 2014 after progression with Len-Dex alone. The dose of added Cy ranged from 250 to 500 mg weekly. The median number of previous regimens, including Len-Dex, was 2 (range, 2-4); 80% of patients had undergone previous autologous stem cell transplantation., Results: The overall rate of response equal to or greater than a partial response was 34%, and clinical benefit (stable disease or better) was observed in 87% of the patients. The median duration of Len-Dex-Cy therapy was 6.9 months (range, 0.9-55.1 months). The median progression-free survival was 6.1 months (range, 4.2-8.1 months) from the addition of Cy and 24.1 months (range, 15.9-32.0 months) from start of Len-Dex., Conclusion: The addition of Cy for patients with myeloma developing progression with Len-Dex was an inexpensive option with manageable toxicity that resulted in a clinically meaningful extension of disease control., (Copyright © 2018. Published by Elsevier Inc.)

Background: Translocation t(4;14) has traditionally been classified as a high-risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib., Patients and Methods: We conducted a retrospective study on our patients with t(4;14) multiple myeloma treated with bortezomib-based induction between July 1, 2006 and June 30, 2014 to assess the real-world outcomes of these patients in a tertiary center., Results: Among the 75 patients analyzed, the median PFS was 33.5 months, and the median OS was 69.6 months after a median follow-up of 41 months. Even in the era of novel agents, patients who received frontline autologous stem cell transplant had a better PFS than those who received chemotherapy alone (median PFS, 24.2 months vs. 41.5 months; P = .01). Hypercalcemia at the time of presentation was found to be a significant predictor of progression (hazard ratio [HR], 10.1; 95% confidence interval [CI], 4.0-26.0) and death (HR, 9.4; 95% CI, 3.2-27.8), and co-harboring of del(17p) by fluorescent in situ hybridization with t(4;14) was associated with a significantly inferior OS (HR, 4.0; 95% CI, 1.4-11.4)., Conclusion: Even in the era of novel agents, t(4;14) remains a negative prognostic marker. Frontline autologous stem cell transplant remains as an essential tool when treating these high-risk patients, but further prospective randomized studies are needed to determine the most effective strategy for this patient group., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658)., (© 2017 by The American Society of Hematology.)

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391., (© 2016 by The American Society of Hematology.)

The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to "not reached"). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692)., (© 2016 by The American Society of Hematology.)

Introduction: Cyclophosphamide, bortezomib, and prednisone (CyBorP) is a highly effective, well-tolerated regimen in relapsed/refractory multiple myeloma. CyBorP, originally developed at our center to include weekly bortezomib (Bor) and alternate-day prednisone (P), was recently modified so that weekly dexamethasone (D) replaced prednisone., Patients and Methods: To assess the effectiveness and tolerability of CyBorP/D in real-world practice, we identified 96 relapsed/refractory patients who received ≥ 1 28-day cycle of CyBorP/D, consisting of cyclophosphamide 300 mg/m(2) (days 1, 8, 15, and 22), Bor 1.0 to 1.5 mg/m(2) (days 1, 8, and 15), and either P 50 to 100 mg on alternate days or D 20 to 40 mg weekly between 2007 and 2013., Results: Sixty-six (69%) patients achieved ≥ partial response: 16 with clinical complete response and 25 with very good partial response; 22 others had stable disease. Progression-free and overall survival for all patients were 16.2 months (95% confidence interval [CI], 7.7-20.1 months) and 26.3 months (95% CI, 21.6-81.2 months), respectively. Although 26 patients had prior Bor exposure, there was no difference in progression-free or overall survival versus Bor-naive patients., Conclusion: Toxicities with CyBorP/D were generally mild and manageable. New onset peripheral neuropathy was seen in 13 cases; 9 of 26 patients with pre-existing peripheral neuropathy developed worsening symptoms. No second primary malignancies were observed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way., Patients and Methods: Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured., Results: Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lymphopenia at baseline was common and T cell recovery was significantly delayed., Conclusion: With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Choosing Wisely(®) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely(®) list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely(®) recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts., (© 2014 by The American Society of Hematology. All rights reserved.)

CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766., (© 2014 by The American Society of Hematology.)

Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.

Background: The goal of induction in younger MM patients is to improve performance status and symptoms, enabling autologous stem cell transplantation (ASCT). It is unclear whether intensification of induction regimens improves post transplant outcomes., Patients and Methods: We studied 178 MM patients who received conservative steroid-based induction therapy without novel agents before ASCT between 2000 and 2006 and correlated induction parameters (rapidity of response, need for salvage induction therapy, depth of response) with transplant outcomes., Results: Fifty-three percent of patients achieved at least a partial response by cycle 2 (early responders). Rapidity of induction response did not translate into a significant difference in post transplant progression-free survival (PFS) (20.7 vs. 20.0 months; P = .24) or overall survival (OS) (64.4 vs. 51.3 months, respectively; P = .13). In 41 patients (23%) the first induction regimen failed, but they responded to salvage and proceeded to ASCT. They had inferior PFS (15.6 vs. 21.8 months; P = .008) and OS (43.5 vs. 69.4 months; P = .0004) post transplant compared with those requiring 1 regimen., Conclusion: Rapid response to induction therapy does not correlate with PFS or OS post ASCT when using a conservative steroid-based induction regimen. Patients in whom this initial induction fails have worse post transplant outcomes, thus the upfront use of intensive therapies with novel agents should be considered., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m(2) for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m(2) for cycle 1 and then 27 mg/m(2) for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy-17.1% overall (1 grade 3; no grade 4)-in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.