Clinical characteristics of patients with relapsed multiple myeloma.

AbstractAlthough survival outcomes have improved over the last decade for patients with multiple myeloma (MM), few patients remain free of disease and most inevitably relapse. Selecting a treatment for patients with relapsed MM is challenging given the number and diversity of regimens patients may have previously received, which can affect subsequent therapeutic choices. Importantly, a number of patient- and disease-related factors can also have an effect on treatment choice, treatment efficacy, and tolerability; thus, an understanding of the heterogeneity of patients in the setting of relapsed MM is important for appropriate treatment selection. Here, we review select patient and disease characteristics reported in key interventional and observational studies in relapsed MM (including age, sex, race, and the presence of high-risk disease, renal impairment, or peripheral neuropathy at baseline) to examine common and disparate features of patients with relapsed MM. As therapeutic regimens can have varying efficacy and/or tolerability in patients depending on these factors, we also provide treatment recommendations for patients with select baseline characteristics

Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities

Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase–inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI–sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ?CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene

How lenalidomide is changing the treatment of patients with multiple myeloma

Lenalidomide is a distinct second-generation immunomodulatory drug with multiple anticancer and immunomodulatory effects against hematologic malignancies, in particular multiple myeloma (MM). Dexamethasone synergistically enhances the anticancer effects of lenalidomide, and the combination of lenalidomide and dexamethasone (Len/Dex) is approved for the treatment of patients with relapsed and/or refractory MM. Results from pivotal phase III trials in this setting have demonstrated that Len/Dex extends overall survival compared with dexamethasone alone. Optimal clinical benefits are seen when Len/Dex is initiated at first relapse and continued, beyond best treatment response, until disease progression. Lenalidomide based regimens are also effective as induction therapy in patients with newly diagnosed MM. Importantly, lenalidomide has a predictable and manageable tolerability profile, with minimal neurotoxicity, allowing long-term administration. As the paradigm of myeloma disease continues to change, future studies will determine the efficacy of lenalidomide in novel combinations with potentially complimentary agents. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Clinical characteristics of patients with relapsed multiple myeloma

Although survival outcomes have improved over the last decade for patients with multiple myeloma (MM), few patients remain free of disease and most inevitably relapse. Selecting a treatment for patients with relapsed MM is challenging given the number and diversity of regimens patients may have previously received, which can affect subsequent therapeutic choices. Importantly, a number of patient- and disease-related factors can also have an effect on treatment choice, treatment efficacy, and tolerability; thus, an understanding of the heterogeneity of patients in the setting of relapsed MM is important for appropriate treatment selection. Here, we review select patient and disease characteristics reported in key interventional and observational studies in relapsed MM (including age, sex, race, and the presence of high-risk disease, renal impairment, or peripheral neuropathy at baseline) to examine common and disparate features of patients with relapsed MM. As therapeutic regimens can have varying efficacy and/or tolerability in patients depending on these factors, we also provide treatment recommendations for patients with select baseline characteristics. © 2015 The Authors