Search

The article focuses on a research which aims to evaluate the efficacy of bendamustine, dexamethasone and thalidomide in relapsed or refractory multiple myeloma patients following lenalidomide and bortezomib therapy or who were ineligible to receive such drugs as measured by the rate of response in terms of overall response rate. It also aims to assess the tolerability and toxicity and evaluate the time to treatment failure, overall survival, and disease-free survival.

Introduction: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE‐MM1. Objectives and Methods: We conducted a retrospective–prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. Results: At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high‐risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)‐exposed (including both Len‐sensitive and Len‐refractory pts), and 22% were Len‐refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non‐hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1‐2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow‐up of 38 m, median PFS (mPFS) was 16 m and the 1‐year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len‐naïve (NR), age ≥70 (20 m). In pts exposed to Len, non‐refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len‐refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). Conclusion: IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len‐sensitive, independent of age, and cytogenetic risk. [ABSTRACT FROM AUTHOR]

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3–4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting. [ABSTRACT FROM AUTHOR]

Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk. The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18–65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, patients were stratified according to International Staging System stage (I vs II/III) and age (<60 years vs 60–65 years) and randomly assigned (1:1:1) to KRd plus autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m2 and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m2 on days 1 and 2 of cycle 1, followed by 36 mg/m2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m2 intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1–21; cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction–consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m2 was administered intravenously on days 1–2 and days 15–16, every 28 days for up to 2 years, and lenalidomide 10 mg was administered orally on days 1–21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov , NCT02203643. Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46–56). 4-year progression-free survival was 71% (95% CI 64–78) in patients with zero HRCA, 60% (95% CI 52–69) in patients with one HRCA, and 39% (95% CI 30–50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90–1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74–3·75]); p<0·0001) across the induction–intensification–consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34–2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91–98) in patients with zero HRCA, 83% (95% CI 76–90) in patients with one HRCA, and 63% (95% CI 54–74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22–5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24–13·18]; p<0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53–4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33–42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74–88) in patients with zero HRCA, 68% (95% CI 59–78) in patients with one HRCA, and 53% (95% CI 42–67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01–2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60–4·69], p=0·0003) than in patients with zero HRCA. This preplanned analysis of the FORTE trial showed that carfilzomib-based induction–intensification–consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need. Amgen and Celgene/Bristol Myers Squibb. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the case of two patients affected by Hodgkin's lymphoma (HL) who successfully underwent bendamustine as a salvage treatment for relapse after allogeneic bone marrow transplantation (allo-SCT).

We report on the case of a young woman with a diagnosis of amyloidosis who developed severe portal and splenic venous thrombosis shortly after hormonal follicle stimulation therapy for oocyte preservation. The clinical implications are discussed. [ABSTRACT FROM AUTHOR]

Background: High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone.Methods: We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1-21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m(2)) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 × 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m(2), days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1-21]) or two courses of high-dose melphalan (200 mg/m(2)) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1-21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831.Findings: 389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52·0 months (IQR 30·4-57·6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28·6 months [95% CI 20·6-36·7] vs 43·3 months [33·2-52·2]; hazard ratio [HR] for the first 24 months 2·51, 95% CI 1·60-3·94; p<0·0001). Progression-free survival did not differ between maintenance treatments (median 37·5 months [95% CI 27·8-not evaluable] with lenalidomide plus prednisone vs 28·5 months [22·5-46·5] with lenalidomide alone; HR 0·84, 95% CI 0·59-1·20; p=0·34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high-dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects.Interpretation: Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide.Funding: Celgene. [ABSTRACT FROM AUTHOR]

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m2) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ⩾70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age. [ABSTRACT FROM AUTHOR]

The article focuses on a study which evaluated the effectiveness and safety of the addition of bortezomib to thalidomide plus dexamethasone (TD) (VTD) against TD alone as induction therapy prior to double analogous stem-cell transplantation in multiple myeloma. Patients at the Grupo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Myeloma Network hospitals were selected. Results indicate that patients eligible for transplant, induction and consolidation therapy with VTD improved clinical outcomes compared to patients receiving only TD therapy.

ITF2357, an orally effective member of the family of histone deacetylase inhibitors, is a potent inducer of apoptosis and death of multiple myeloma (MM) cells. We performed a phase-II, multiple-dose clinical trial in 19 patients with relapsed or progressive MM to determine the maximum tolerated dose (MTD) of ITF2357 administered twice daily for four consecutive days every week for 4 weeks (i.e., first cycle). The first six patients received 150 mg ITF2357 twice daily. Since two of them experienced a dose-limiting toxicity (DLT) during the first cycle, the subsequent patients received 100 mg ITF2357 twice daily. This was the MTD, as only one DLT occurred. Up to 12 weeks (i.e., three cycles) of treatment were scheduled. Oral dexamethasone was allowed to a maximum weekly amount of 20 mg. Median duration of treatment was 6 weeks, ranging from two (two patients) to 12 weeks (five patients). Four patients suffered from serious adverse events. Three patients experienced grade 3–4 gastro-intestinal toxicity and three had transient electrocardiographic abnormalities. Thrombocytopenia occurred in all but one patient (grade 3–4 in ten patients). At last follow-up, five patients were in stable disease, five had disease progression, and nine had died all of progressive MM. In conclusion, when given at a dose of 100 mg twice daily alone or combined with dexamethasone, ITF2357 proved tolerable but showed a modest clinical benefit in advanced MM. [ABSTRACT FROM AUTHOR]

Summary. This study investigated whether T-cell receptor excision circles (TRECs) are a prognostic marker for the outcome of myeloma patients undergoing a tandem autologous peripheral blood stem cell transplantation (PBSCT). Twenty-five patients were enrolled. Samples were obtained at study enrolment, after conventional therapy, between first and second transplantation and 3, 6, 12 and 24 months after the second PBSCT. TRECs were quantified using real-time polymerase chain reaction. A high variation in TREC levels was found at diagnosis (median TREC level 136/10[sup 5] peripheral blood mononuclear cells (PBMCs); range 1–1729), suggesting individual differences in thymic output of naive T cells. Patients with more than 136 TRECs/10[sup 5] P BMCs at diagnosis had a statistically significant better overall survival (P = 0·05) and event-free survival (P = 0·045), whereas low TREC levels correlated with a higher incidence of infectious complications. Median TREC values were lowest after the first PBSCT (52/10[sup 5] PBMCs) and reached the baseline 12 months after the second transplantation. Patients with high TREC levels after the second PBSCT had a significantly higher probability of being in complete or partial remission 30 months after the second PBSCT. TREC levels were not correlated with β[sub 2] -microglobulin and C-reactive protein levels at diagnosis. These data suggest that TRECs could be a relevant prognostic factor for patients who receive high-dose chemotherapy and autologous PBSCT. [ABSTRACT FROM AUTHOR]