Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.

Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.

This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1-7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.

Cutaneous legionellosis: case report and review of the medical literature.

Discrete nodules developed on the leg of a 27-year-old immunosuppressed woman after an allogeneic stem cell transplant. Biopsy and culture grew Legionella pneumophila serogroup 8. On day 7 of azithromycin treatment, respiratory distress and abnormal liver transaminases developed, and the patient died on day 14. Review of the medical literature identified 19 reports of Legionella species-associated skin or soft tissue infections (total of 20 patients, 13 with confirmed infection). Manifestations of the 13 confirmed cases included erythematous macular rash (n = 7), erythema after thoracentesis (n = 1), abscess formation (n = 4), respiratory symptoms (n = 6), and abnormal chest radiographs (n = 8). Six required surgical exploration and débridement, and 7 were immunocompromised. Rash and respiratory infection improved with antibiotics in 10, but 3 died. Immunosuppression may predispose transplant recipients to Legionella infections. Diagnostic biopsies may facilitate appropriate treatment.

Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma.

In this report, we provide a comprehensive review on the preclinical and clinical investigations conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed, MEDLINE, ASH, ASCO annual symposium abstracts and http://clinicaltrials.gov/ for the purpose of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in relapsed/refractory MM. MM is the second most common hematological malignancy in the US. Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs, and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the anti-myeloma armamentarium is widely anticipated to have a significant impact on the overall clinical outcome of advanced stage relapsed and refractory MM patients.

Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis.

Trials comparing efficacy of melphalan prednisone (MP) with MP plus thalidomide in transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. Although there is agreement regarding improved response rates (RRs) and higher toxicity with the addition of thalidomide to MP, the impact on progression free survival (PFS) and overall survival (OS) is less clear. We performed a meta-analysis comparing efficacy of melphalan, prednisone and thalidomide (MPT) and MP by pooling results on RR, PFS and OS reported in all the identified randomized controlled trials (RCTs) under a random effects model. Overall, six prospective RCTs, with data extractable from five published trials (n=1571) [corrected] were identified. The pooled odds ratio of responding to therapy with MPT vs MP was 3.39 (P<0.001, 95% CI: 2.24-5.12). The pooled hazard ratios for PFS and OS were and 0.68 (P<0.001; 95% CI: 0.55-0.82) and 0.80 (P=0.07; 95% CI: 0.63-1.02), respectively, in favor of MPT. The odds ratios for high grade peripheral neuropathy and deep venous thrombosis were 6.6 and 2.4, respectively, in favour of MP. There was significant heterogeneity among the RCTs. Our meta-analysis demonstrates that in previously untreated, transplant ineligible, elderly myeloma patients, the addition of T to MP results in significantly improved RR and PFS with a trend towards improvement in OS compared with MP alone, but at a cost of significantly greater toxicity.

Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM).

Patients with multiple myeloma progressing on current therapies have limited treatment options. Pomalidomide (CC4047), an immunomodulatory drug, has significant activity in relapsed myeloma and previous studies suggest activity in lenalidomide refractory disease. To better define its efficacy in this group, we treated a cohort of lenalidomide refractory patients. Pomalidomide was given orally (2 mg) daily, continuously in 28-day cycles along with dexamethasone (40 mg) given weekly. Responses were assessed by the International Myeloma Working Group Criteria. Thirty-four patients were enrolled. The best response was very good partial response in 3 (9%), partial response (PR) in 8 (23%), best responses (MR) in 5 (15%), stable disease in 12 (35%) and progressive disease in 6 (18%), for an overall response rate of 47%. Of the 14 patients that were considered high risk, 8 (57%) had responses including 4 PR and 4 MR. The median time to response was 2 months and response duration was 9.1 months, respectively. The median overall survival was 13.9 months. Toxicity was primarily hematologic, with grade 3 or 4 toxicity seen in 18 patients (53%) consisting of anemia (12%), thrombocytopenia (9%) and neutropenia (26%). The combination of pomalidomide and dexamethasone (Pom/dex) is highly active and well tolerated in patients with lenalidomide-refractory myeloma.

Safety and efficacy results from an international expanded access programme to bortezomib for patients with relapsed and/or refractory multiple myeloma: a subset analysis of the Australian and New Zealand data of 111 patients.

BACKGROUND: Bortezomib has been shown to be a safe and efficacious for the treatment of relapsed and refractory multiple myeloma (MM). Here we report a subset analysis of Australian and New Zealand data from the International Extended Access Programme for bortezomib. METHODS: Patients with more than or equal to two prior lines of therapy were given bortezomib 1.3 mg/m(2) (i.v. bolus days 1, 4, 8, 11) for up to eight 21-day cycles (C). Dexamethasone, 20 mg/day p. o. on the day of, and day after, bortezomib was added after C2 for progressive disease or after C4 for stable disease. Efficacy was assessed using modified Southwest Oncology Group criteria in the intent-to-treat group. Results were compared between the Australian and New Zealand and international cohort. RESULTS: One hundred and eleven patients from 16 centres (55% men, median age 61.9 years) had a median of 5.2 +/- 2.8 treatment cycles of bortezomib. Among them, 82% had > or =3 prior therapies. Grade 3-4 treatment-related adverse events were reported in 57 patients (52%); the most common were thrombocytopenia (25.7%), anaemia (8.3%), peripheral neuropathy (7.3%) and diarrhoea (7.3%). Responses were evaluable in 106 patients: 22% achieved a best response of complete response/response and 20% partial response (overall response rate of 42%). Median times to first and best responses were 42 days and 69 days, respectively. Compared with the international cohort, the cohorts from Australian and New Zealand showed inferior overall response rates (54 vs 42%, P = 0.001), possibly due to heavier pretreatment (82% greater than or equal to three prior therapies vs 68%, P < 0.001). CONCLUSION: Our analysis confirms that bortezomib is safe and effective in relapsed and refractory MM in a real-life clinical setting.

Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial.

We have studied a three-drug combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) on a 28-day cycle in the treatment of newly diagnosed multiple myeloma (MM) patients to assess response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with MM received bortezomib 1.3 mg/m(2) intravenously on days 1, 4, 8 and 11, cyclophosphamide 300 mg/m(2) orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1-4, 9-12 and 17-20 on a 28-day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (>or= partial response) was 88%, with 61% of very good partial response or better (>or=VGPR) and 39% of complete/near complete response (CR/nCR). For the 28 patients who completed all four cycles of therapy, the CR/nCR rate was 46% and VGPR rate was 71%. All patients undergoing stem cell harvest had a successful collection. Twenty-three patients underwent stem cell transplantation (SCT) and are evaluable through day 100 with CR/nCR documented in 70% and >or=VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed MM with manageable toxicity.

Predictors of mortality in patients undergoing autologous hematopoietic cell transplantation admitted to the intensive care unit.

Between January 2001 and July 2006, 1013 patients received autologous hematopoietic cell transplants (AHCT) at Canada's largest transplant center. In this retrospective cohort study of AHCT patients admitted to the intensive care unit (ICU), we describe the outcomes following ICU admission and the variables measured in the first 24 h of ICU admission associated with overall ICU mortality. Results indicate a 3.3% ICU admission rate (n=34) with 13 deaths (1% overall mortality rate, 38% in ICU mortality rate). The worst outcome was in AL amyloid patients of whom 28% were admitted to the ICU, with an ICU mortality rate of 55%. The Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score in the first 24 h were statistically associated with mortality by univariate analysis. Other variables measured at 24 h and associated with ICU mortality included multiorgan failure, mechanical ventilation, inotropic support >4 h and Gram-negative sepsis. Our data indicate that ICU admission in the autotransplant population is rare and that it is influenced by underlying diagnosis, with AL amyloid patients having the highest risk. Our observations may assist clinical decision-making regarding the continuation of intensive care delivered 24 h after ICU admission.