Longer‐term follow‐up and outcome by tumour cell proliferation rate (Ki‐67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL‐001(EMERGE) pivotal trial

Patients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.     

Guideline for the laboratory diagnosis of functional iron deficiency

Patients with aggressive non‐Hodgkin lymphoma (NHL) who relapse after autologous stem cell transplantation (ASCT) have a poor prognosis. Additional therapy is often poorly tolerated, and new treatment modalities are needed. This efficacy and safety study was a retrospective analysis of two phase II trials (NHL‐002 and NHL‐003) that studied single‐agent lenalidomide in patients with relapsed/refractory aggressive NHL with prior (n = 87) compared with no prior ASCT (n = 179). The overall response rate in the ASCT group was 39% [14% complete response (CR)], including 29% in patients with diffuse large B‐cell lymphoma, 63% in mantle cell lymphoma, and 60% in transformed lymphoma. The timing of transplant relative to receiving lenalidomide had no effect on outcomes. Median progression‐free survival for the ASCT group was 3·7 months (16·9 months for patients in CR; 7·3 months for partial responders) at a median 12·5‐month follow‐up. Median response duration was 7·9 months. Regardless of prior ASCT, lenalidomide monotherapy was efficacious in heavily pretreated patients with aggressive, relapsed/refractory NHL, with a safety profile that was consistent with prior studies of single‐agent lenalidomide.     

Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory,indolent non‐Hodgkin lymphoma

This phase II study evaluated the safety and efficacy of lenalidomide in combination with rituximab in patients with relapsed/refractory, indolent non‐Hodgkin lymphoma (NHL). Patients were treated with daily lenalidomide in 28‐d cycles and weekly rituximab for 4 weeks. Lenalidomide was continued until progression or unacceptable toxicity. Twenty‐two patients were assessed for FCGR3A polymorphisms. Thirty patients were enrolled; 27 were evaluable for response. The overall response rate (ORR) was 74% including 44% complete responses (CR); median progression‐free survival (PFS) was 12·4 months. The 13 rituximab refractory patients had an ORR of 61·5% (four CR/unconfirmed CR). The ORR was 77% in the 22 follicular lymphoma patients (nine CR/unconfirmed CR). At a median follow‐up time of 43 months, the median duration of response and time to next therapy were 15·4 and 37·4 months, respectively. Most common grade 3/4 adverse events were lymphopenia (45%), neutropenia (55%), fatigue (23%) and hyponatraemia (9%). The ORR and PFS in patients with low‐affinity FCGR3A polymorphisms (F/F and F/V) suggest that lenalidomide may improve the activity of rituximab in these patients. These data suggest that combining lenalidomide with rituximab can produce durable responses with acceptable toxicity in patients with indolent NHL.     

Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with a poor prognosis following first relapse. We present a subgroup analysis of an open-label phase II trial investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL. Oral lenalidomide 25 mg was self-administered once daily on days 1–21 every 28 d for up to 52 weeks, according to tolerability or until disease progression. The primary endpoint was overall response rate (ORR) and secondary endpoints were duration of response, progression-free survival (PFS) and safety. Among 15 patients with MCL with a median disease duration of 5·1 years and a median of four prior treatments, the ORR was 53%. Three patients (20%) had a complete response and 5 (33%) had a partial response. The median duration of response was 13·7 months and median PFS was 5·6 months. Four of five patients who relapsed after transplantation and two of five patients who previously received bortezomib responded to lenalidomide. The most common grade 4 adverse event was thrombocytopenia (13%) and the most common grade 3 adverse events were neutropenia (40%), leucopenia (27%) and thrombocytopenia (20%). In conclusion, oral lenalidomide monotherapy is well tolerated and active in relapsed or refractory MCL.     

A phase 2 study of lenalidomide,rituximab, cyclophosphamide,and dexamethasone (LR‐CD) for untreated low‐grade non‐Hodgkin lymphoma requiring therapy

Patients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m² day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m² days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenström's macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.     

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

In the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history.     

Single‐agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences

We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty‐six patients received lenalidomide 25 mg/d (days 1–21 of a 28‐d cycle) for up to 6 cycles followed by low‐dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0–53·6] and median progression‐free survival (PFS) of 3·9 months (95% CI 0·0–11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3–21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40–60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low‐dose maintenance agent.     

Activity of lenalidomide in mantle cell lymphoma can be explained by NK cell‐mediated cytotoxicity

Lenalidomide is an immunomodulatory agent that has demonstrated clinical benefit for patients with relapsed or refractory mantle cell lymphoma (MCL); however, despite this observed clinical activity, the mechanism of action (MOA) of lenalidomide has not been characterized in this setting. We investigated the MOA of lenalidomide in clinical samples from patients enrolled in the CC‐5013‐MCL‐002 trial (NCT00875667) comparing single‐agent lenalidomide versus investigator's choice single‐agent therapy and validated our findings in pre‐clinical models of MCL. Our results revealed a significant increase in natural killer (NK) cells relative to total lymphocytes in lenalidomide responders compared to non‐responders that was associated with a trend towards prolonged progression‐free survival and overall survival. Clinical response to lenalidomide was independent of baseline tumour microenvironment expression of its molecular target, cereblon, as well as genetic mutations reported to impact clinical response to the Bruton tyrosine kinase inhibitor ibrutinib. Preclinical experiments revealed lenalidomide enhanced NK cell‐mediated cytotoxicity against MCL cells via increased lytic immunological synapse formation and secretion of granzyme B. In contrast, lenalidomide exhibited minimal direct cytotoxic effects against MCL cells. Taken together, these data provide the first insight into the clinical activity of lenalidomide against MCL, revealing a predominately immune‐mediated MOA.     

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.     

Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation

We treated 17 patients with refractory (n = 7) or relapsed lymphoid malignancy (n = 10) following allogeneic HSCT with donor lymphocyte infusions (DLI). Patients with low-grade disease received DLI alone (n = 7) or following radiotherapy (n = 1). Patients with aggressive disease (n = 9) received prior chemotherapy. Nine out of 15 patients receiving DLI from sibling donors responded after one (n = 6), two (n = 2) and three (n = 1) infusions. Both MUD recipients achieved CR after two and three DLI. In all, 10/17 patients achieved CR including 3/4 patients with chronic lymphatic leukaemia (CLL), 4/4 with mantle cell lymphoma (MCL), 3/4 with follicular NHL but 0/5 with aggressive NHL/Richters. The median CD3 cell dose to achieve CR for siblings was 2 x 10(7)/kg. One patient with CLL had a second transplant following DLI-induced aplasia and is in CR at 14 months giving a final CR rate of 64%. Grade II-IV acute GVHD developed in 45% and chronic GVHD in 8/9 evaluable patients. Of the 11 patients finally achieving CR, one patient with MCL relapsed at 18 months post-DLI but all others remain in remission with a median follow-up of 40 months (range 12-64 months). Low-grade NHL and MCL have a high response rate and sustained remissions following DLI. Aggressive disease responds poorly however, despite pre-DLI chemotherapy.     

Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre,single‐arm,phase 2 study

The multicentre, open‐label, two‐stage, single‐arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)‐1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Fifty‐eight patients were enrolled from August 2008–January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5–17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5–6·1) and 16·9 months (95% CI 14·4–29·9), respectively. Grade 3/4 non‐haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.     

A phase I study of lenalidomide plus chemotherapy with mitoxantrone,etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti‐tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose‐escalation study. We enrolled 35 patients using a “3 + 3” design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1‐14 and MEC days 4‐8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1‐10. The dose of lenalidomide was then escalated starting at 5 mg/d (5‐10‐25‐50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1‐10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21‐50%); 30‐day mortality was 6% and 60‐day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12‐month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T‐cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1‐10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.     

Lenalidomide is safe and active in Waldenström macroglobulinemia

Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenström's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV‐WM‐0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow‐up of 36 months, median TTP was 16 months (95% CI 5.5–26), the 5‐year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing. Am. J. Hematol. 90:1055–1059, 2015. © 2015 Wiley Periodicals, Inc.     

Mature results of MM‐011: A phase I/II trial of liposomal doxorubicin,vincristine, dexamethasone,and lenalidomide combination therapy followed by lenalidomide maintenance for relapsed/refractory multiple myeloma

A previous interim report of MM‐011, the first study that combined lenalidomide with anthracycline‐based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long‐term outcomes of all 76 treated patients with follow‐up ≥5 years. This single‐center phase I/II study administered lenalidomide (10 mg on days 1–21 of every 28‐day cycle), intravenous liposomal doxorubicin (40 mg/m² on day 1), dexamethasone (40 mg on days 1–4), and intravenous vincristine (2 mg on day 1). After 4–6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1–7); 49 (64.5%) patients had refractory disease. Forty‐three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment‐related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression‐free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline‐based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM ( ClinicalTrials.gov number, NCT00091624). Am. J. Hematol. 89:349–354, 2014. © 2013 Wiley Periodicals, Inc.     

Abnormal serum free light chain ratio predicts poor overall survival in mantle cell lymphoma

Serum free light Chain (sFLC) ratios have been correlated with survival outcomes in Hodgkin and non‐Hodgkin lymphoma subtypes. This study was undertaken to investigate the prognostic impact of abnormal sFLC ratios in mantle cell lymphoma (MCL). two patient cohorts were analysed for sFLC parameters: a preliminary retrospective cohort and a uniformly treated cohort of 20 relapsed/refractory MCL patients, enrolled in a phase II clinical trial of single agent lenalidomide treatment. 52% of patients had an abnormality of one or more sFLC parameter (71% of the first cohort and 40% of the second cohort). In cohort two, a high baseline SFLC ratio correlated with poorer overall survival (OS) compared to a low/normal ratio (median OS: 1·4 months vs. 19 months respectively; P = 0·001). For patients presenting with an elevated sFLC ratio at trial entry a rise of >35% in the sFLC ratio correlated with disease progression and a sFLC ratio of >2× normal at trial entry correlated with aggressive disease. These data are the first to show a clear clinical correlation between sFLC ratios and survival outcomes in a uniformly treated cohort of MCL patients. We suggest that these markers may be useful in managing patients with MCL in the future.     

The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study

We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty‐one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28‐d cycle. Patients received lenalidomide 25 mg days 1–21 and dexamethasone 20 mg orally days 1–4 and 8–11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow‐up, projected 2‐year progression‐free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1–9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.     

Ifosfamide,epirubicin and etoposide regimen as salvage and mobilizing therapy for relapsed/refractory lymphoma patients

BACKGROUND AND OBJECTIVES: Therapy for relapsed/refractory lymphomas should be based only on drugs not included in the front-line chemotherapy regimens. We adopted the strategy of using salvage chemotherapy to debulk disease and simultaneously mobilize stem cells, using a regimen based on ifosfamide and etoposide, (drugs not usually used for front-line treatment). DESIGN AND METHODS: A three-drug combination of ifosfamide, epirubicin and etoposide (IEV) was used to treat 62 patients with relapsing or refractory aggressive non-Hodgkin's lymphoma (NHL; n=51) or Hodgkin's disease (HD; n=11). Forty-five of the patients were studied for the feasibility of peripheral blood stem cell (PBSC) harvest. RESULTS: The overall and complete response (CR) rates were, respectively, 77% and 32% in the NHL subset and 81% and 45% in the HD subset. Among the 17 patients who achieved CR after IEV but did not have a subsequent transplantation, the median duration of the response was 9 months (range, 2 to 14 months). Mobilization was successful in 33 of 45 (71%) patients. Among the 45 who proceeded to autotransplantation, 27 (60%) were in CR status after the autograft; 23/45 (51%) patients are currently in continuous CR with a median follow-up of 25 months (range, 10-68 months); the relapse-free survival curve shows 83% in this state at 60 months. Twenty-three (37%) patients are currently in continuous CR with a median follow-up of 25 months. Clinical and hematologic toxic effects were mild. INTERPRETATION AND CONCLUSIONS: Our results indicate the efficacy of the IEV regimen in inducing a good remission rate. IEV is a predictable and highly effective mobilization regimen in relapsed/refractory patients with aggressive NHL or HD.     

Bortezomib plus dexamethasone is highly effective in relapsed and refractory myeloma patients but responses are short‐lived

Objectives: Bortezomib has proven to be effective as single agent in myeloma patients. Aim of this study was to evaluate the efficacy and toxicity of bortezomib in combination with dexamethasone in a cohort of multiple myeloma (MM) relapsed/refractory patients treated in a single center. Patients and Methods: In this single center study, 70 patients were treated with bortezomib alone (9) or in combination with dexamethasone (61). Results: Forty‐one patients (59%) achieved at least a partial response (PR), including 7% complete response (CR), 36% very good partial response (VGPR) reaching the best response within four cycles. The duration of response was significantly longer for patients achieving CR/VGPR than for those achieving PR (7.3 vs. 3.8 months, P = 0.03). Likewise, time to progression, time to alternative treatment, and treatment free interval were significantly better for patients obtaining CR/VGPR (6.8, 9.4, 6.5 months respectively) as compared with PR (4.9, 6.3, 2 months respectively). The only dose‐limiting toxicity was peripheral neuropathy (PN), which occurred in 38/70 patients (55%) and was of grade 3–4 in 12 (17%). PN led to a dose reduction or treatment discontinuation in 17 (24%) patients. Complete resolution or improvement of PN occurred in 29/38 (76%) after a median time of 100 d (range: 17–202). Conclusions: Bortezomib in combination with dexamethasone is highly effective in relapsed/refractory MM producing an impressive rate of CR/VGPR, but responses are short‐lived.     

A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide‐containing regimens

Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open‐label, single‐institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide‐refractory patients. Patients were considered lenalidomide‐refractory if they had no clinical response (<minimal response) on a previous lenalidomide‐containing regimen (lenalidomide non‐responsive) or if they had progressive disease on or within 60 days of discontinuing a previous lenalidomide‐containing regimen (lenalidomide relapsed/refractory). Patients received oral vorinostat 400 mg days 1–7 and 15–21, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15 and 22 in 28‐day cycles. Twenty‐five patients were enrolled, median age was 65 years and patients had received a median of 5 prior regimens. The overall response rate was 24% (6 partial responses) and clinical benefit rate (≥stable disease) was 80%. Median time to a partial response was 1·9 months and median duration of response was 3·3 months. Median progression‐free survival was 5·3 months. Most common grade 3/4 adverse events were neutropenia (48%), thrombocytopenia (32%), anaemia (20%) and gastrointestinal toxicities (16%). In this heavily pre‐treated population, vorinostat in combination with lenalidomide and dexamethasone was active in lenalidomide‐refractory patients.     

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.