Patrizia Caraffa

Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study

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.

Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma

Abstract The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma

Proteasome inhibition represents one of the more important therapeutic targets in the treatment of multiple myeloma (MM), since by suppressing nuclear factor-κB activity, which promotes myelomagenesis, it makes plasma cells susceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor approved for MM therapy, has been shown to increase response rate and improve outcome in patients with relapsed/refractory disease and in the frontline setting, particularly when combined with immunomodulatory drugs and alkylating agents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM. Ixazomib has shown improved pharmacokinetic and pharmacodynamic parameters compared with bortezomib, in addition to similar efficacy in the control of myeloma growth and prevention of bone loss. Ixazomib was found to overcome bortezomib resistance and to trigger synergistic antimyeloma activity with dexamethasone, lenalidomide, and histone deacetylase inhibitors. Phase I/II studies using ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested antitumor activity of the single agent, but more promising results have been obtained with the combination of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a single agent, showing important activity in this difficult-to-treat plasma-cell dyscrasia. More frequent side effects observed during administration of ixazomib were thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas severe peripheral neuropathy was rare. Here, we review the chemical characteristics of ixazomib, as well as its mechanism of action and results from preclinical and clinical trials.

Pomalidomide for the treatment of relapsed- refractory multiple myeloma: a review of biological and clinical data

Despite the improvements thanks to the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs), nearly all myeloma patients eventually become refractory to these drugs. Consequently, the outcome of these patients is very poor. Pomalidomide is a new IMiD with a similar structure to the commonly used IMiD thalidomide and lenalidomide. Pomalidomide exhibited more potent anti-myeloma activity and a similar favorable safety profile compared with thalidomide and lenalidomide. In Phase I–II studies pomalidomide plus low-dose dexamethasone demonstrated activity in myeloma patients refractory to both bortezomib and IMiDs. Based on the results of a Phase III trial, the FDA and EMA agencies granted accelerated approval to pomalidomide, which is now considered a new effective strategy for relapsed and/or refractory myeloma patients. Very promising results were obtained when pomalidomide-dexamethasone was used in combination with other compounds. This review provides updated information about pharmacokinetics, mechanism of action, resistance, clinical efficacy and safety of pomalidomide.

Infection complications in an unselected cohort of patients with multiple myeloma treated with lenalidomide combinations.

To the Editor: Immunomodulatory drugs (IMiDs) exert various effects on the immune system, altering cytokine production, regulating T-cell costimulation, and enhancing NK cell cytotoxicity. Particularly, IMiDs inhibit tumor necrosis factor-alpha (TNF-alfa), playing an important role in immune response against bacterial and virus infections (1). Moreover, lenalidomide causes myelosuppression, mainly neutropenia, that is an important risk factor for infections. We retrospectively assessed the incidence, type, and major factors affecting infections in a population of 127 patients with multiple myeloma (MM) receiving lenalidomide-based regimens. We studied the following parameters as possible major factors: sex, disease status (newly diagnosed vs. relapsed/refractory), monoclonal component level (>3 gr/dL vs. 3 gr/dL), age (>65 yr vs. 65 yr), leukopenia or thrombocytopenia prior to the start of therapy (yes vs. no), renal failure (yes vs. no), Lenalidomide (L)–dexametasone (d) 40 mg weekly vs. L plus chemotherapy, PS 2 vs. <2, prior to the lines of therapy ( 3 vs. <3), International Scoring System (ISS) (II–III vs. I). Median age was 67 yr (40– 88) and 53.5% were older than 65 yr. Fifty-four patients (42.5%) had newly diagnosed MM and four of these received an autologous peripheral blood stem cells transplantation (APBSCT) upfront, whereas the remaining 73 (57.5%) had relapsed/refractory disease. Among this group, 67% of patients received more than one line of therapy and 26% underwent APBSCT prior to lenalidomide. ISS stage 2–3 and renal failure were recognized in 54.5% and 8.5% of patients, respectively; 15% had an ECOG PS 2. Overall, 80 patients (63%) received L-d and 47 (37%) lenalidomide combined with steroids and chemotherapy. Median number of lenalidomide courses was 6 (1–28); 34.7% of patients developed severe neutropenia (26% grade 3 and 8.7% grade 4), while of the nine patients with renal impairment, two developed neutropenia 3. Nearly all patients (95%) received trimethoprim–sulfamethoxazole (TMP-SFZ) as infections prophylaxis and 31% granulocyte colony-stimulating factor according to guidelines (2). Twenty-six patients (20.5%) developed infections, resulting in grade 1–2 in eight patients (6%) and 3–4 in the remaining 18 (14%). Two deaths (1.5%) because of infections were observed. Type of infections was pneumonia in 15 (58%), upper respiratory tract in 3 (11.5%), Fever of Unknown Origin (FUO) in 3 (11.5%), septic shock by gram-negative microorganisms in 2 (8%), cholecystitis in 2 (8%), and Varicella Zoster Virus in one (4%). Risk of grade 3–5 infection was 16% at 12 months; 62.5%, 69%, and 94% of infections occurred at 3, 4, and 6 months, respectively. Among all the parameters evaluated in univariate and multivariate analysis, only ISS resulted as factor affecting severe infection development (Fig. 1). Particularly, the risk of grade 3–5 infections at 6 months was 18% in patients with ISS 2–3, compared with 6% in those with ISS 1 (P = 0.034). A trend for a longer Progression Free Survival (PFS) in patients without infection (median PFS = 8 vs. 16 months in patients with or without infections, respectively, P = 0.064) was documented; however, Overall survival (OS) of patients developing infections was significantly shorter, compared to patients who did not develop infections (median OS = 26 vs. 33 months; P = 0.001). Multivariate analysis adjusted for age, PS, ISS, renal function, and ther-