A phase 1 clinical trial evaluating marizomib,pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

Marizomib (MRZ) is an irreversible, pan‐subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low‐dose dexamethasone (Lo‐DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3–0·5 mg/m²) was administered over 2 h on days 1, 4, 8, 11; POM (3–4 mg) on days 1–21; and Lo‐DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28‐day cycle. Thirty‐eight patients were enrolled that had received a median of 4 (range 1–10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose‐limiting toxicities (DLTs) were observed and 0·5 mg/m² MRZ was determined to be the RP2D. The most common treatment‐related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre‐treated, high‐risk RRMM patients.     

Daratumumab and dexamethasone is safe and effective for triple refractory myeloma patients: final results of the IFM 2014-04 (Etoile du Nord) trial

Single agent daratumumab has shown clinical activity in relapsed, refractory multiple myeloma (RRMM). The Intergroupe Francophone du Myélome 2014-04 trial was designed to further investigate daratumumab in combination with dexamethasone in triple RRMM patients. Patients received daratumumab infusions in combination with weekly dexamethasone until disease progression or unacceptable toxicity. Fifty-seven patients were included in the trial and evaluable for response. The overall response rate and the clinical benefit rate were 33% (n = 19) and 48% (n = 27), respectively. Five (8·8%) patients achieved a very good partial response or better. The median time to response was 4 weeks. For responding patients, the median progression-free survival was 6·6 months, compared to 3·7 months (3·0–5·5) for those with a minimal or stable disease. The median overall survival (OS) for all patients was 16·7 months (11·2–24·0). For responding patients, the median OS was 23·23 months, whereas that of patients with progressive disease was 2·97 months. The incidence of infusion-related reactions was 37%; all cases were manageable and did not lead to dose reduction or permanent treatment discontinuation. These data demonstrate that treatment with daratumumab and dexamethasone results in a meaningful long-term benefit with an acceptable safety profile for patients with triple RRMM.     

Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior-bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.     

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m² and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665)     

Combination therapy with bortezomib,continuous low‐dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients

Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low‐dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re‐induction and maintenance therapy. Secondary endpoints were response to treatment and progression‐free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow‐up was 27·1 (0·46–54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13–43·5) and the median OS was 28·1 months (range 0·13–54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low‐dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.     

Elotuzumab in combination with thalidomide and low‐dose dexamethasone: a phase 2 single‐arm safety study in patients with relapsed/refractory multiple myeloma

Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7–expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50–200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade ≥3 non‐haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade ≥3 non‐haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty‐six (65%) patients had ≥1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression‐free survival was 3·9 months. Median overall survival was 16·3 months and the 1‐year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre‐treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM.     

Safety and efficacy of pomalidomide,dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma

Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration‐approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m² with the latter two drugs administered on days 1, 4, 8 and 11 on a 28‐day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3–29·0 +  months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.     

Impact of treatment variability on survival in immuno‐competent and immuno‐compromised patients with primary central nervous lymphoma

Patients with primary central nervous system lymphoma (PCNSL) treated in the ‘real‐world’ setting do not represent those treated on clinical trials and might not be treated similarly. We studied characteristics and variability in care for 113 newly diagnosed PCNSL patients treated at 5 institutions in the Chicago area between 2000 and 2012. In 111 patients, single modality therapy with a high dose methotrexate (HD‐MTX) regimen +/− rituximab, was most commonly employed (n = 65), and 34 underwent radiotherapy (+/− systemic therapy). Fifty‐eight of 108 patients received rituximab. Twenty‐nine of 110 patients (26%) received intrathecal chemotherapy (ITC). Overall response rate was 80% (47% complete responses). With a median follow‐up of 18·7 months, median overall survival (OS) was 65·2 months. In univariate analysis, HD‐MTX (median OS 72·7 vs. 2·7 months, P < 0·001) and rituximab (median not reached versus 28·4 months, P = 0·005) impacted OS favourably. This significance was sustained regardless of immune status and in multivariate analysis. Whole brain radiotherapy (WBRT) resulted in a trend for improved OS as compared with systemic therapy alone (P = 0·09), while ITC did not impact survival. Clinical practice has evolved to exclude WBRT and ITC while incorporating rituximab with clinical outcomes comparable in immuno‐competent/compromised patients and similar to those achieved in recent clinical trials.     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.     

A randomized phase II study of standard‐dose versus high‐dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B‐cell non‐hodgkin lymphomas: long term results

High‐dose rituximab (HD‐R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single‐arm prospective study of relapsed aggressive B‐cell non‐Hodgkin lymphoma (R‐NHL). We performed a randomized phase 2 study comparing HD‐R versus standard‐dose rituximab (SD‐R) in R‐NHL. Ninety‐three patients were randomized to HD‐R (1000 mg/m²) (n = 42) or SD‐R (375 mg/m²) (n = 51) administered on post‐transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow‐up of 7·92 years, the 5‐year disease‐free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD‐R and SD‐R in 5‐year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08–2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13–3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5‐year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B‐cell NHL, HD‐R provided no DFS or OS advantage over SD‐R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri‐transplant setting remains controversial.     

The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL ‐NOS ) and angioimmunoblastic T‐cell lymphoma (AITL ) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL ‐NOS (n  = 180) or AITL (n  = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS ) and overall survival (OS ) were calculated from the time of first disease progression (FFS 1, OS 1), from second disease progression (FFS 2, OS 2) and from third progression (FFS 3, OS 3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL ‐NOS , 105 AITL ) experienced progression/relapse. In patients with PTCL ‐NOS , the median durations of FFS 1, FFS 2 and FFS 3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL , they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS 1 and OS 1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.     

Salvage therapy using FLT3 inhibitors may improve long‐term outcome of relapsed or refractory AML in patients with FLT3‐ITD

To determine the long‐term efficacy of FLT3 inhibitors (FLT3i) in the salvage setting for relapsed and refractory (rel/ref) acute myeloid leukemia (AML) with FLT3 internal tandem duplication (AML FLT3‐ITD), we conducted a retrospective study of 120 patients with rel/ref AML FLT3‐ITD who received salvage therapy with either FLT3i‐containing regimen (FLT3i group, N = 45) or conventional cytotoxic regimen (conventional group, N = 75). The median overall survival (OS) after the first salvage in the FLT3i group was 6·9 vs. 4·6 months in the conventional group (P = 0·17). The OS was better in the FLT3i group among patients with initial complete remission (CR) duration ≤12 months or with primary refractory disease (6·9 vs. 3·7 months; P < 0·01). The OS was better when FLT3i was combined with cytotoxic agents versus monotherapy (17 vs. 4·8 months; P = 0·017). Multivariate analysis revealed that the use of FLT3i was an independent predictor of OS (hazard ratio 0·58; 95% confidence interval, 0·38–0·88). Incorporating FLT3i into salvage strategies may improve long‐term outcome of patients with AML FLT3‐ITD. Prospective studies to validate this conclusion are warranted.     

Combined intravitreal methotrexate and immunochemotherapy followed by reduced‐dose whole‐brain radiotherapy for newly diagnosed B‐cell primary intraocular lymphoma

Primary intraocular lymphoma (IOL) has a propensity for central nervous system (CNS) relapse within 2 years of initial diagnosis, affecting clinical outcome. To reduce CNS relapse, we performed the combination treatment protocols of intravitreal methotrexate injections, methotrexate‐based systemic induction chemotherapy and consolidation high‐dose cytarabine and reduced‐dose whole brain radiation therapy (rdWBRT, 23·4 Gy) for B‐cell primary IOL with or without newly diagnosed CNS involvement. All patients underwent longitudinal brain magnetic resonance imaging (MRI) and cognitive assessment for evaluation of treatment‐induced leucoencephalopathy. Seventeen patients initiated and 16 completed the protocol treatment. CNS relapse occurred in 2 patients and intraocular relapse in 3. Four‐year progression‐free survival (PFS) was 74·9% and 4‐year overall survival (OS) was 86·3%, with a median follow‐up period of 48·9 months. Of 11 patients without CNS involvement, 1 had CNS relapse and 3 intraocular relapse, and 4‐year PFS and OS was 72·7% and 88·9%, respectively. Although white matter abnormalities shown by MRI were significantly increased at 4 years after rdWBRT, only one patient developed mild cognitive impairment. The combination of intravitreal chemotherapy, prophylactic systemic chemotherapy and rdWBRT for primary IOL showed a potential to reduce CNS relapse rate and improved 4‐year PFS and OS without increase of cognitive dysfunction.     

Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3‐ITD acute myeloid leukaemia in first complete remission

We performed a retrospective study analysing the effect of sorafenib, an oral fms‐Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post‐transplant maintenance in adult patients with FLT3‐internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3‐ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post‐HCT initiation of sorafenib (yes/no) was evaluated as a time‐varying covariate in the overall survival/progression‐free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow‐up was 27·2 months post‐HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post‐HCT; 43 controls were alive without relapse at this cut‐off. Sorafenib patients had improved 2‐year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2‐year PFS (82% vs. 53%, P = 0·0081) and lower 2‐year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). There was no difference in 2‐year non‐relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1‐year chronic graft‐versus‐host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post‐HCT sorafenib in FLT3‐ITD AML, and support further evaluation of post‐HCT FLT3 inhibition.     

Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression‐free survival (PFS) and overall survival (OS) were 8·9 (6·9–11·5) and 30·5 (20·0–36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard‐dose lenalidomide (25 mg) and high‐dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3–4 toxicities were reduced with low‐dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at‐risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.     

A phase 2 study of modified lenalidomide,bortezomib and dexamethasone in transplant‐ineligible multiple myeloma

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m² weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population.     

Phase II study of bortezomib,cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial

We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21‐day cycles of VCD prior to autologous stem‐cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator‐based assessment was 85·4%. Most patients (74%) underwent successful central laboratory‐based molecular cytogenetic analysis. No clinically relevant differences in ORR post‐induction were seen between patients with or without high‐risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow‐up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow‐up, 55·5 months); median progression‐free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high‐risk versus standard‐risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P < 0·0001), and median OS was 54·7 months versus not reached (P = 0·0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long‐term follow‐up, cytogenetic high risk is associated with markedly reduced PFS and OS post‐ASCT.     

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.     

Real‐world use of pomalidomide and dexamethasone in double refractory multiple myeloma suggests benefit in renal impairment and adverse genetics: a multi‐centre UK experience

Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40–89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment. Of 45 patients with fluorescence in situ hybridization results 64% had adverse risk, 19 patients (22·4%) had an estimated glomerular filtration rate <45 ml/min. Grade ≥3 non‐haematological toxicities occurred in 42·4%, and grade ≥3 neutropenia and thrombocytopenia in 38% and 24% respectively, but only 18·8% had dose reductions. The overall response rate was 52·9%. At a median follow‐up of 13·2 months, median progression‐free survival was 5·2 months [95% confidence interval (CI) 4·150–6·238], and median overall survival was 13·7 months (95% CI 11·775–15·707). No significant difference was seen in response, survival or tolerability by renal function, age or cytogenetic risk. This real‐world data support the results seen in published clinical trials.     

Phase 2 study of all-oral ixazomib,cyclophosphamide and low-dose dexamethasone for relapsed/refractory multiple myeloma

There is a need for efficacious, convenient treatments with long-term tolerability for patients with relapsed/refractory multiple myeloma (RRMM). This phase 2 study evaluated the all-oral combination of ixazomib, cyclophosphamide and dexamethasone (ICd). Patients with RRMM received ixazomib 4 mg and cyclophosphamide 300 mg/m² on days 1, 8 and 15, and dexamethasone 40 mg on days 1, 8, 15 and 22 in 28-day cycles. The primary endpoint was overall response rate (ORR). Seventy-eight patients were enrolled (median age 63·5 years). At data cut-off, patients had received a median of 12 treatment cycles; 31% remained on treatment. ORR was 48% [16% very good partial response or better (≥VGPR)]. ORR was 64% and 32% in patients aged ≥65 and <65 years (25% and 16% ≥VGPR), respectively. At a median follow-up of 15·2 months, median progression-free survival (PFS) was 14·2 months, with a trend towards better PFS in patients aged ≥65 years vs. <65 years (median 18·7 months vs. 12·0 months; hazard ratio 0·62, P = 0·14). ICd was well tolerated. The most common treatment-emergent adverse events were diarrhoea (33%), nausea (24%), upper respiratory tract infection (24%), and thrombocytopenia (22%); 10 patients (13%) had peripheral neuropathy (one grade 3). This study is registered at ClinicalTrials.gov (NCT02046070).