Improving Health Outcomes Through Treatment Sequencing Optimization in Multiple Myeloma: A Simulation Model in Transplant-Ineligible Patients.

OBJECTIVES: Patients with multiple myeloma often require multiple treatment lines. The order in which treatments are sequenced has impact on clinical outcomes. This study aimed to estimate progression-free survival (PFS) and overall survival (OS) with common treatment sequences used in Portugal and the incremental benefit of an optimal sequence in transplant-ineligible patients with multiple myeloma. METHODS: A state-transition sequential model with a five-health state conceptual structure was developed to simulate and compare survival outcomes between treatment sequences up to four lines of treatments. Data sources included randomized clinical trials and indirect treatment comparisons. A panel of Portuguese hematologists listed four most common treatment sequences and optimal sequence of choice in transplant-ineligible patients. RESULTS: Our simulation estimated an OS between 6.1 and 7.8 years using the most common sequences, with VMP + DRd + Pd + Kd as the most effective (7.8 years). Optimal sequence of choice (DRd + PVd + Kd + Vd) achieved OS of 9.8 years and may extend OS in 2.0-3.7 years vs. most common sequences (26%-61% increase). This benefit was mostly explained by extended PFS in the first line of treatment. CONCLUSION: Model results demonstrate that choosing the most effective treatment upfront is crucial in delaying disease progression thus yielding better survival outcomes in transplant-ineligible patients. There was a clear survival benefit in using daratumumab-based regimens in first line. This modelling exercise highlights the need to raise awareness around the impact of sequencing strategies to improve patient's outcomes.

Consensus guidelines for the optimal management of adverse events in newly diagnosed, transplant-ineligible patients receiving melphalan and prednisone in combination with thalidomide (MPT) for the treatment of multiple myeloma.

Thalidomide has received approval from the European Agency for the Evaluation of Medicinal Products for the treatment of newly diagnosed multiple myeloma (MM) patients older than 65 years or ineligible for transplant. The results of five phase III trials assessing thalidomide in combination with melphalan and prednisone (MPT) have demonstrated significantly improved response rates compared with melphalan and prednisone (MP) alone. Additionally, two of these studies showed that survival was extended by approximately 18 months in patients treated with MPT compared with MP alone. Thalidomide, in combination with MP, is associated with adverse events (AEs) including peripheral neuropathy and venous thromboembolism. In order to optimize the efficacy of MPT, a good awareness of these AEs is imperative. This manuscript outlines both evidence- and consensus-based recommendations discussed by a panel of experts, to provide a practical guide for physicians addressing the effective management of newly diagnosed, transplant-ineligible MM patients receiving thalidomide therapy.

Congenital amegakaryocytic thrombocytopenia--report of a new c-mpl gene missense mutation.

A 44-month old girl with congenital amegakaryocytic thrombocytopenia, already with pancytopenia, underwent an unrelated allogeneic cord blood transplantation with recovery of normal blood cell counts. The patient was a compound heterozygote for two c-mpl missense mutations inherited from both parents, one of them, a G578A exon 4 mutation leading to a cysteine to tyrosine replacement of codon 193, previously unreported.

Large-volume leukaphereses may be more efficient than standard-volume leukaphereses for collection of peripheral blood progenitor cells.

To overcome the need for multiple leukaphereses to collect enough PBPC for autologous transplantation, large-volume leukaphereses (LVL) are used to process multiple blood volumes per session. We compared the efficiency of CD34+ cell collection by LVL (n = 63; median blood volumes processed 11.1) with that of standard-volume leukaphereses (SVL) (n = 38; median blood volumes processed 1.9). To achieve this in patients with different peripheral blood concentrations of CD34+ cells, we analyzed the ratio of CD34+ cells collected per unit of blood volume processed, divided by the number of CD34+ cells in total blood volume at the beginning of apheresis. For LVL, 30% (9%-323%) of circulating CD34+ cells were collected per blood volume compared with 42% (7%-144%) for SVL (p = 0.02). However, in LVL patients, peripheral blood CD34+ cells/L decreased a median of 54% during LVL (similar data for SVL not available). The number of CD34+ cells collected per blood volume processed after 4 and 8 blood volumes and at the end of LVL were 0.32 (0.01-2.05), 0.24 (0.01-1.68), and 0.22 (0.01-2.40) x 10(6) CD34+ cells/kg, respectively (p = 0.0007), despite the 54% decrease in peripheral blood CD34+ cells/L throughout LVL. A median 66% decrease in the platelet count was also observed during LVL. Thus, LVL may be more efficient than SVL for PBPC collection, allowing, in most patients, the collection in one LVL of sufficient PBPC to support autologous transplantation.