Early mortality in myeloma patients treated with first-generation novel agents thalidomide, lenalidomide, bortezomib at diagnosis: A pooled analysis.

INTRODUCTION: Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity. METHODS: We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib. RESULTS: During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients <80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death. CONCLUSION: First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.

Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study.

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.

Bortezomib-Induced Muscle Toxicity in Multiple Myeloma.

Multiple myeloma (MM) accounts for ∼13% of all hematologic malignancies. Bortezomib treatment is effective in MM, but can be complicated with neurological side effects. We describe a patient with symptomatic MM who had a reversible metabolic myopathy associated with bortezomib administration and pathologically characterized by excessive storage of lipid droplets together with mitochondrial abnormalities. In a single-center prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, 7 developed muscular signs and/or symptoms. The myopathy was characterized by a proximal muscle weakness involving lower limbs and was an early complication. Complete resolution of muscle weakness occurred after treatment discontinuation. Conversely, none of the patients who received a treatment without bortezomib developed muscular symptoms. Experimental studies demonstrate that in primary human myoblasts bortezomib at low concentrations leads to excessive storage of lipid droplets together with structural mitochondrial abnormalities, recapitulating the pathologic findings observed in patient's muscle. Our data suggest that patients treated with bortezomib should be monitored for muscular signs and/or symptoms and muscle weakness should alert the clinician to the possibility of myopathy. Bortezomib-induced metabolic myopathy is a potentially reversible entity with important implications for management and treatment of patients with MM.

Bortezomib, Thalidomide and Lenalidomide: Have They Really Changed the Outcome of Multiple Myeloma?

Treatment of multiple myeloma (MM) has significantly improved, although the disease remains incurable. Prospective clinical trials evaluating the impact on outcome of new drugs such as proteasome inhibitors or immunomodulating agents are limited since they are not able to reflect the clinical routine and available retrospective data are not detailed enough to directly evaluate the value of new drugs. To address these information gaps, we performed a retrospective real-life analysis. We retrospectively assessed 949 patients treated for multiple myeloma or plasma cell leukemia at three Italian cancer centers in the years 1979-2014. Clinical features at the time of diagnosis were consistent with what was observed in clinical routine. A total of 39% of patients underwent high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). The median overall survival (OS) of the whole group was 5.4 years and ranged from 3.4 years for patients who did not receive at least one of the new drugs compared to 5.9 years in the other patients (p<0.001). The improvement in OS due to administration of new drugs was also observed among different prognostic sub-groups such as age, Durie and Salmon stage, international staging system and renal impairment. Availability of new drugs significantly improved survival of patients who underwent ASCT and also those who did not. In conclusion, we provided evidence that the advent of the new drugs drastically improved the outcome of patients with MM, also in cases with poor risk at the time of diagnosis. ASCT is still of major importance in the treatment of this disease. Nevertheless, MM remains incurable and new therapeutic approaches are warranted.

Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease.

BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM). METHODS: Forty-three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m(2) intravenously on day 1 and fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses. RESULTS: The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow-up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the ß2-microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long-lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow-up. CONCLUSIONS: The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good-quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration.