Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma.

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.

A new route for the efficient metalation of unfunctionalized aromatics.

The synthesis and isolation of a novel bimetallic species formed by reacting two equivalents of TMPLi with CuCl in the presence of Et2O are reported. X-ray crystallography reveals the Et2O-free tetranuclear aggregate (TMPCu)2(TMPLi)2 1, which formally results from the catenation of dimers of TMPLi and TMPCu. NMR spectroscopy confirms that, upon dissolution in hydrocarbon media, the crystals fail to form a conventional Gilman cuprate dimer. Instead they exhibit a spectrum which is consistent with that recently proposed for an isomer of dimeric Gilman cuprate. Moreover, while pre-isolated Gilman cuprate is inert to benzene solvent, this new isomer smoothly affects aromatic deprotonation to give mainly Ph(TMP)3Cu2Li2 3, which is formally a heterodimer of Gilman cuprate TMPCu(µ-TMP)Li 2 and PhCu(µ-TMP)Li 4. Attempts to synthesise 3 through explicit combination of pre-isolated 2 and 4 were successful; additionally, this permitted the preparation of Ph(TMP)3Cu3Li 5 and Ph(TMP)3CuLi3 7 when 4 was combined in 1 : 2 ratios with TMPCu or TMPLi, respectively. 5 was characterised as metallacyclic in the solid-state, its structural features resembling those in 3 but with reduced Li-π interactions. It also proved possible to perform Cu/Li exchange on 5 (using t BuOCu) to give a novel mixed organo(amido)copper species Ph(TMP)3Cu4 6. Remarkably, the unprecedented reactivity of 1 towards benzene is reproduced by heating a 1 : 1 mixture of TMPLi and TMPCu in the same solvent; this gives predominantly 3. On the other hand, mixtures which are rich in either Cu or Li can lead to the selective in situ formation of 5 or 7. Though crystallographic data on 7 could not be obtained, DFT calculations accurately corroborated the observed structures of 3 and 5 and could be used to support 7 having the same structure type, albeit with enhanced Li-π interactions. This was consistent with NMR spectroscopic data. However, in contrast to 3 and 5, for which 2D NMR spectroscopy indicated only conformational changes, 7 was additionally found to exhibit fluxionality in a manner consistent with a dissociative process.