Elias Anaissie

Clinical activity of arsenic trioxide for the treatment of multiple myeloma

Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described impressive results with arsenic trioxide in patients with de novo, relapsed, and refractory acute promyelocytic leukemia (APL). Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States. Investigations of this agent have demonstrated that its efficacy in APL and preclinical tumor models is dependent upon a number of mechanisms, including induction of apoptosis, effects on cellular differentiation, cell cycling, and tumor angiogenesis. Subsequent preclinical studies showed significant activity of arsenic trioxide in multiple myeloma (MM). Based on this, in a phase II trial, we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM, refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM.

VTD combination therapy with bortezomib–thalidomide–dexamethasone is highly effective in advanced and refractory multiple myeloma

Bortezomib (V) was combined with thalidomide (T) and dexamethasone (D) in a phase I/II trial to determine dose-limiting toxicities (DLTs) and clinical activity of the VTD regimen in 85 patients with advanced and refractory myeloma. The starting dose of V was 1.0u2009mg/m2 (days 1, 4, 8, 11, every 21 day) with T added from cycle 2 at 50u2009mg/day, with 50u2009mg increments per 10 patient cohorts, to a maximum dose of 200u2009mg. In the absence of DLTs, the same reiteration of T dose increases was applied with a higher dose of V=1.3u2009mg/m2. D was added with cycle 4 in the absence of partial response (PR). Ninety-two percent had prior autotransplants, 74% had prior T and 76% abnormal cytogenetics. MTD was reached at V=1.3u2009mg/m2 and T=150u2009mg. Minor response (MR) was recorded in 79%, and 63% achieved PR including 22% who qualified for near-complete remission. At 4 years, 6% remain event-free and 23% alive. Both OS and EFS were significantly longer in the absence of prior T exposure and when at least MR status was attained. The MMSET/FGFR3 molecular subtype was prognostically favorable, a finding since reported for a VTD-incorporating tandem transplant trial (Total Therapy 3) for untreated patients with myeloma (BJH 2008).

Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3

Prognostic implications of 3 imaging tools, metastatic bone survey, magnetic resonance imaging, and positron emission tomography (PET), were evaluated in 2 consecutive Total Therapy 3 trials for newly diagnosed myeloma. Data including PET at baseline and on day 7 of induction as well as standard prognostic factors were available in 302 patients of whom 277 also had gene expression profiling (GEP)-derived risk information. According to multivariate analysis, more than 3 focal lesions on day 7 imparted inferior overall survival and progression-free survival, overall and in the subset with GEP-risk data. GEP high-risk designation retained independent significance for all 3 end points examined. Thus, the presence of > 3 focal lesions on day 7 PET follow-up may be exploited toward early therapy change, especially for the 15% of patients with GEP-defined high-risk disease with a median overall survival expectation of 2 years. This trial was registered at www.clinicaltrials.gov as #NCT00081939 and # NCT00572169.

MicroRNA theragnostics for the clinical management of multiple myeloma

Theragnostics represent cutting-edge, multi-disciplinary strategies that combine diagnostics with therapeutics in order to generate personalized therapies that improve patient outcome. In oncology, the approach is aimed at more accurate diagnosis of cancer, optimization of patient selection to identify those most likely to benefit from a specific therapy and to generate effective therapeutics that enhance patient survival. MicroRNAs (miRNAs) are master regulators of the human genome that orchestrate myriad cellular pathways to control growth during physiologic and pathologic conditions. Compelling evidence shows that miRNA deregulation promotes events linked to tumor initiation, metastasis and drug resistance as seen in multiple myeloma (MM), an invariably fatal hematologic malignancy. miRNAs are readily detected in body fluids, for example, serum, plasma, urine, as well as circulating tumor cells to demonstrate their potential as readily accessible, non-invasive diagnostic and prognostic biomarkers and potential therapeutics. Specific miRNAs are aberrantly expressed early in myelomagenesis and may more readily detect high-risk disease than current methods. Although only recently discovered miRNAs have rapidly advanced from preclinical studies to evaluation in human clinical trials. The development of miRNA theragnostics should provide widely applicable tools for the targeted delivery of personalized medicines to improve the outcome of patients with MM.

Future directions in the clinical management of amyloid light-chain amyloidosis

Abstract Amyloid light-chain (AL) amyloidosis results from extracellular deposition of fibril-forming monoclonal immunoglobulin light chains (LCs) usually secreted by a plasma cell (PC) clone. Misfolded LCs deposit as unique fibrils leading to organ failure and eventually death. Survival for untreated patients remains poor, and restrictive cardiomyopathy, nephrotic syndrome or hepatic failure greatly worsen outcome. Conventional chemotherapy and novel therapy with immunomodulatory drugs or proteasome inhibitors (PIs) eradicate PCs but generate adverse toxicities, and sustained responses are limited. Moreover, only 20% of patients with AL amyloidosis are eligible for stem cell transplant. The molecular events deregulated in AL amyloidosis remain undefined, and effective therapies based upon the biology of the disease are lacking. Impressive hematologic response rates obtained with bortezomib provide practice-changing data to advocate their introduction early in the treatment course. Bortezomib and the emerging second-generation PIs alone or combined with dexamethasone and alkylating agents may enhance hematologic and organ responses in AL amyloidosis.

Targeting the Proteasome Pathway for the Treatment of Solid Tumors

The ubiquitin-proteasome system (UPS) is a highly complex protein network that maintains proteostasis and cell viability through the targeted and timely turnover of selected substrates. The proteasome serves as the catalytic core of the UPS to precisely recognize and efficiently execute the rapid ATP-dependent removal of ubiquitinated proteins. Small-molecule pharmacologic inhibitors exploit the pivotal role of the proteasome in cellular metabolism as a molecular vulnerability in cancer cells to promote the selective cytotoxicity of tumor cells. Proteasome inhibitors (PIs) have yielded durable clinically responses that dramatically improve the survival of patients diagnosed with the invariably fatal hematologic malignancy multiple myeloma (MM). Success of the PI bortezomib in the treatment of the hematologic malignancy MM has emerged as the standard of care and catapulted the UPS into a position of prominence as a model system in cancer biology and drug development. However, advancement of PIs to improve the treatment of patients with solid tumors has been far more challenging and less successful. Clinical assessment of second-generation PIs progresses as well as pharmacologics to intervene at other points within the UPS is being explored for both hematologic and solid tumors. Agents to target non-proteolytic activities associated with the proteasome are emerging as are agents to inhibit Ub-binding proteins. New approaches to unravel the UPS should advance its utilization as a drug development platform in mechanism-based anticancer strategies that include PIs as monotherapy or in synergistic combinations that improve the outcome of patients with solid tumors.