Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the accumulation of a monoclonal PC population in the bone marrow (BM). Cannabidiol (CBD) is a non-psychoactive cannabinoid with antitumoural activities, and the transient receptor potential vanilloid type-2 (TRPV2) channel has been reported as a potential CBD receptor. TRPV2 activation by CBD decreases proliferation and increases susceptibility to drug-induced cell death in human cancer cells. However, no functional role has been ascribed to CBD and TRPV2 in MM. In this study, we identified the presence of heterogeneous CD1381TRPV21 and CD1381TRPV22 PC populations in MM patients, whereas only the CD1381 TRPV22 population was present in RPMI8226 and U266 MM cell lines. Because bortezomib (BORT) is commonly used in MM treatment, we investigated the effects of CBD and BORT in CD1381TRPV22 MM cells and in MM cell lines transfected with TRPV2 (CD1381TRPV21). These results showed that CBD by itself or in synergy with BORT strongly inhibited growth, arrested cell cycle progression and induced MM cells death by regulating the ERK, AKT and NF-jB pathways with major effects in TRPV21 cells. These data provide a rationale for using CBD to increase the activity of proteasome inhibitors in MM.Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells (PCs) and their accumulation in the bone marrow (BM). 1 MM displays enormous genomic instability and marked variation in clinical characteristics and patient survival. 1 In recent years, immunomodulatory drugs, proteasome inhibitors and other specific therapies have been developed to target myeloma cells and/or the BM microenvironment. 2 In addition, a number of new inhibitory agents targeting farnesyltransferase, mitogen-activated protein kinases (MAPKs), protein kinase B (AKT) and cell cycle proteins (e.g., cyclin D1 and D2) are currently under investigation for the treatment of relapsed/refractory MM in preclinical and clinical studies. 3 Bortezomib (BORT), a 26S proteasome inhibitor, is used to treat relapsed and refractory MM patients, but the molecular mechanisms responsible for the favourable outcome of this treatment remain unclear. 4,5 Although the initial overall rate of response to BORT is promising, the vast majority of patients who respond to this therapy develop resistance over time. 1,2 Key words: multiple myeloma, cannabidiol, transient receptor potential vanilloid type 2, bortezomib Abbreviations: Abs: antibodies; AKT: protein kinase B; BM: bone marrow; BORT: bortezomib; BrdU: 5-bromo-2-deoxyuridine; CBD: cannabidiol; Dw m : mitochondrial transmembrane potential; ERK: extracellular signal-related kinase; FACS: fluorescence activated cell sorting; FBS: foetal bovine serum; FISH: fluorescence in situ hybridisation; GAPDH: glyceraldehydes-3-phosphate dehydrogenase; MM: multiple myeloma; NAC: N-acetyl cysteine; pAKT: phospho protein kinase B; PC: plasma cell; pERK: phospho extracellular signalrelated kinase; ROS: reactive oxygen species; RP...

Learning Objectives: After completing this course, the reader will be able to: Demonstrate the proper use of a simplified comprehensive geriatric analysis, including activities of daily living (ADL), Mini‐Mental State Evaluation (MMSE), Cumulative Illness Rating Scale–Geriatrics (CIRS‐G), and geriatric syndromes (multidimensional geriatric assessment [MGA]). Maintaining a tailored anthracycline‐based therapy, describe alternative treatment in elderly diffuse large B‐cell lymphoma (DLBCL) patients unfit for the standard chemotherapy. This article is available for continuing medical education credit at http://CME.TheOncologist.com Background. Elderly patients with diffuse large B‐cell lymphoma (DLBCL) are a heterogeneous population; clinical trials have evaluated a minority of these patients. Patients and Methods. Ninety‐one elderly patients with DLBCL received tailored treatment based on a comprehensive geriatric assessment (CGA). Three groups were identified: I, fit patients; II, patients with comorbidities; III, frail patients. Group I received 21‐day cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP‐21), group II received R‐CHOP‐21 with liposomal doxorubicin, and group III received 21‐day cycles of reduced‐dose CHOP. Fifty‐four patients (59%) were allocated to group I, 22 (25%) were allocated to group II, and 15 (16%) were allocated to group III. Results. The complete response (CR) rates were 81.5% in group I, 64% in group II, and 60% in group III. With a median follow‐up of 57 months, 42 patients are alive, with 41 in continuous CR: 31 patients (57%) in group I, seven patients (32%) in group II, and four patients (20%) in group III. The 5‐year overall survival, event‐free survival, and disease‐free survival rates in all patients were 46%, 31%, and 41%, respectively. Multivariate analysis selected group I assignment as the main significant prognostic factor for outcome. Conclusions. This approach in an unselected population of elderly DLBCL patients shows that treatment tailored according to a CGA allows the evaluation of elderly patients who are currently excluded from clinical trials.

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

We present the results of a phase 2 study using thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) in the treatment of 50 patients older than 65 years with newly diagnosed multiple myeloma. Thalidomide 100 mg was administered orally at bedtime continuously, dexamethasone 40 mg was administered orally on days 1 to 4 and 9 to 12, and pegylated liposomal doxorubicin 40 mg/m 2 was administered intravenously on day 1 over the 28-day cycle. Response was assessed according to the EBMT criteria. Seventeen (34%) patients achieved CR, 7 (14%) nCR, 5 (10%) VGPR, 15 (30%) PR, and 5 (10%) MR, resulting in an ORR of 98%. Only 1 patient (2%) presented progressive disease. Time to progression (TTP), event-free survival (EFS), and overall survival (OS) projected at 3 years were 60%, 57%, and 74%, respectively, and these parameters were significantly higher in those patients achieving a response of at least VGPR versus those who did not. Grade 3 and 4 nonhematologic adverse events were constipation (10%), fatigue (6%), tremors (4%), mucositis (4%), and palmar-plantar erythrodysesthesia (2%). Grade 3 and 4 neutropenia occurred in 12% of patients. Grade 3 and 4 infections and thromboembolic accidents were observed in 22% and 14% of patients, respectively. In the treatment of elderly patients with newly diagnosed multiple myeloma, ThaDD is a very effective regimen with manageable toxicity.

We evaluated the toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet) when substituted for conventional doxorubicin in the CHOP-21 regimen in the treatment of frail elderly patients with aggressive non-Hodgkin lymphoma. Twenty frail patients (median age, 73 years), as defined by Balducci et al., with diffuse large B cell or grade IIIb follicular lymphoma, either at diagnosis (15 patients) or relapsed (five patients), were prospectively enrolled. Nine out of 20 (45%) had a World Health Organisation (WHO) performance status > or =2. Fifteen out of 20 patients (75%) had an International Prognostic Index (IPI) score > or =3. Thirteen out of 20 (65%) evaluable patients obtained a complete response. Five additional patients (25%) achieved a partial response. With a median follow-up of 24 months (range 18-27), 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. Toxicity was mainly hematological with grade 3/4 neutropenia in 26% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III-IV WHO toxicity (one fatal pulmonary embolism, one congestive, and one ischemic heart failure) while receiving R-COMP chemotherapy. In conclusion, R-COMP-21 is an effective regimen with promising response rates for frail and elderly patients with aggressive non-Hodgkin lymphoma.