In the current evolving landscape of myeloma therapies, no recommended salvage strategy exists for patients with relapsed multiple myeloma (MM) after initial successful autologous stem cell transplantation (ASCT) and therapeutic options extend from conventional chemotherapy and novel agents to second autologous and allogeneic transplants. In this article, we summarize the documented evidence about the utilization of second ASCT in patients with relapsed MM after a primary auto-graft and discuss the correct timing for such a salvage approach, the individual characteristics of patients who will benefit more, as well as the therapeutic role of second ASCT in the modern era of forthcoming anti-myeloma treatments. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45–0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33–0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.Leukemia advance online publication, 3 February 2017; doi:10.1038/leu.2016.390. © 2017 The Author(s)

Introduction: Multiple myeloma (MM) is the second most common hematologic malignancy and despite significant outcome improvements with novel agents, the majority of patients will eventually relapse and develop treatment resistance. Immunotherapy is emerging as a promising therapeutic approach in MM. Areas covered: Elotuzumab is a monoclonal antibody directly targeting the SLAMF7 receptor, expressed on normal and malignant plasma cells. Elotuzumab has no meaningful antimyeloma activity when given as monotherapy to patients with relapsed or refractory MM (RRMM). However, it demonstrated significant antimyeloma activity in preclinical studies and when it is combined with other antimyeloma agents (i.e. bortezomib or lenalidomide) in clinical trials, it improved response and clinical outcomes with no additive toxicity. This review provides a brief description of the elotuzumab mechanism of action and an overview on its efficacy in preclinical and clinical trials, including its safety and toxicity profile. Expert commentary: Based on the results of a phase 3 clinical trial (ELOQUENT-2), which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab was approved by FDA in November 2015 for MM patients who received 1–3 prior lines of therapy. Studies with combinations of elotuzumab with other anti-myeloma drugs in different phases of MM are ongoing. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Introduction: Waldenström’s Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM. Recently, the Bruton’s tyrosine kinase inhibitor ibrutinib has been licensed for use in WM with exciting results. Several investigational single agent and combination regimens are being evaluated for response, efficacy and tolerability in phase II clinical trials, including new generation monoclonal antibodies (ofatumumab), immunomodulatory agents (thalidomide and lenalidomide), proteasome inhibitors (bortezomib and carfilzomib), Bruton’s tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), and histone deacetylase inhibitors (panobinostat) both in the setting of newly diagnosed and relapsed/refractory disease. Expert opinion: WM therapeutic approach should be individualized for each patient in accordance to the intensity of the disease characteristics, age, comorbidities, efficacy, tolerability and safety profile of each drug. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Background In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. Methods This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Findings Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58–74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2–6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5–18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66–94), and the estimated 18 month overall survival rate was 97% (95% CI 79–100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3–11·7) increased to 11·4 g/dL (10·9–12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8–13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. Interpretation The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. Funding Pharmacyclics LLC, an AbbVie Company. © 2017 Elsevier Ltd

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Bing Neel syndrome is a rare disease manifestation of Waldenström’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström’s macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation. © 2017 Ferrata Storti Foundation.

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ≥2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (≥2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide. © 2017 Macmillan Publishers Limited, part of Springer Nature.

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m 2 on days 1 and 2 of cycle 1; 27 mg/m 2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ≥3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients. © 2017 Macmillan Publishers Limited, part of Springer Nature.

In the current evolving landscape of myeloma therapies, no recommended salvage strategy exists for patients with relapsed multiple myeloma (MM) after initial successful autologous stem cell transplantation (ASCT) and therapeutic options extend from conventional chemotherapy and novel agents to second autologous and allogeneic transplants. In this article, we summarize the documented evidence about the utilization of second ASCT in patients with relapsed MM after a primary auto-graft and discuss the correct timing for such a salvage approach, the individual characteristics of patients who will benefit more, as well as the therapeutic role of second ASCT in the modern era of forthcoming anti-myeloma treatments. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45–0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33–0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.Leukemia advance online publication, 3 February 2017; doi:10.1038/leu.2016.390. © 2017 The Author(s)

Introduction: Multiple myeloma (MM) is the second most common hematologic malignancy and despite significant outcome improvements with novel agents, the majority of patients will eventually relapse and develop treatment resistance. Immunotherapy is emerging as a promising therapeutic approach in MM. Areas covered: Elotuzumab is a monoclonal antibody directly targeting the SLAMF7 receptor, expressed on normal and malignant plasma cells. Elotuzumab has no meaningful antimyeloma activity when given as monotherapy to patients with relapsed or refractory MM (RRMM). However, it demonstrated significant antimyeloma activity in preclinical studies and when it is combined with other antimyeloma agents (i.e. bortezomib or lenalidomide) in clinical trials, it improved response and clinical outcomes with no additive toxicity. This review provides a brief description of the elotuzumab mechanism of action and an overview on its efficacy in preclinical and clinical trials, including its safety and toxicity profile. Expert commentary: Based on the results of a phase 3 clinical trial (ELOQUENT-2), which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab was approved by FDA in November 2015 for MM patients who received 1–3 prior lines of therapy. Studies with combinations of elotuzumab with other anti-myeloma drugs in different phases of MM are ongoing. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Introduction: Waldenström’s Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM. Recently, the Bruton’s tyrosine kinase inhibitor ibrutinib has been licensed for use in WM with exciting results. Several investigational single agent and combination regimens are being evaluated for response, efficacy and tolerability in phase II clinical trials, including new generation monoclonal antibodies (ofatumumab), immunomodulatory agents (thalidomide and lenalidomide), proteasome inhibitors (bortezomib and carfilzomib), Bruton’s tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), and histone deacetylase inhibitors (panobinostat) both in the setting of newly diagnosed and relapsed/refractory disease. Expert opinion: WM therapeutic approach should be individualized for each patient in accordance to the intensity of the disease characteristics, age, comorbidities, efficacy, tolerability and safety profile of each drug. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Background In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. Methods This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Findings Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58–74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2–6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5–18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66–94), and the estimated 18 month overall survival rate was 97% (95% CI 79–100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3–11·7) increased to 11·4 g/dL (10·9–12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8–13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. Interpretation The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. Funding Pharmacyclics LLC, an AbbVie Company. © 2017 Elsevier Ltd

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Bing Neel syndrome is a rare disease manifestation of Waldenström’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström’s macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation. © 2017 Ferrata Storti Foundation.

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ≥2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (≥2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide. © 2017 Macmillan Publishers Limited, part of Springer Nature.

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m 2 on days 1 and 2 of cycle 1; 27 mg/m 2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ≥3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients. © 2017 Macmillan Publishers Limited, part of Springer Nature.