Faculty Bibliography

The first of the so-called "novel agents" (thalidomide, lenalidomide, and bortezomib), thalidomide has demonstrated activity as a single agent and in combination with other agents in patients with relapsed and/or refractory MM. The combination of melphalan, prednisone, and thalidomide (MPT) has become a standard treatment option for newly diagnosed patients who are ineligible for high-dose chemotherapy with autologous stem cell transplantation (ASCT). For patients intending to undergo ASCT, the combination of thalidomide, dexamethasone and cyclophosphamide can be used as a non-myelosuppressive induction regimen. Treatment with thalidomide is associated with an increased risk of developing peripheral neuropathy, which can be managed with dose reductions and discontinuation, and venous thromboembolism, which warrants thromboprophylaxis. While its adverse event profile may preclude prolonged use as maintenance therapy, thalidomide is an effective and well-tolerated salvage therapy option. Ongoing trials continue to evaluate novel thalidomide-based regimens to further optimize the use of thalidomide in the management of MM.

Multiple myeloma (MM) cells rely on protein homeostatic mechanisms for survival. These mechanisms could be therapeutically targeted via modulation of the heat shock response. We studied the roles of Hsp72 and Hsc70, and show that the two major cytoplasmic Hsp70s play a key role in regulating protein homeostasis and controlling multiple oncogenic pathways in MM, and their inhibition can lead to myeloma cell death. Our study provides further evidence that targeting Hsp70 represents a novel therapeutic approach which may be effective in the treatment of MM.

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.

Significant benefits for zoledronic acid (ZOL) over clodronate acid (CLO) were seen in the Medical Research Council Myeloma IX randomized trial. ZOL significantly reduced skeletal-related events (SREs), and improved progression-free survival and overall survival (OS), making it the bisphosphonate of choice for newly diagnosed myeloma patients. In this analysis of Myeloma IX data, we have investigated the impact of response on bone disease in 1111 transplant-eligible patients. At posttransplant day 100, complete response (CR) was seen in 48% of patients, very good partial response (VGPR) in 20%, and partial response (PR) in 23%. For patients in VGPR or less, ZOL was superior to CLO in reducing SREs (P = .048), whereas for patients in CR, both agents were equivalent (P = .83). For OS, ZOL was associated with a significant benefit in patients in PR (P = .0091). No difference in OS was seen with patients in CR (P = .91) or VGPR (P = .74). These findings indicate that response category posttransplant may influence the impact of bisphosphonate therapy.

PURPOSE/OBJECTIVE:Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years). EXPERIMENTAL DESIGN/METHODS:At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide-vincristine-doxorubicin-dexamethasone (CVAD) or cyclophosphamide-thalidomide-dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan-prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics. RESULTS:Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01). CONCLUSIONS:Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.

Neutropenia is a hematologic adverse event characterized by an absolute neutrophil count (ANC) lower than 1500 cells/mL. This reduction may be due to decreased neutrophil production, accelerated use, a shift in compartments of neutrophils, or a combination of these factors. Neutropenia is often associated with infections, which are major causes of morbidity and mortality in patients with cancer. In patients with multiple myeloma, the novel agents thalidomide, lenalidomide, and bortezomib have improved outcome, but chemotherapy-related neutropenia should be carefully considered. Chemotherapy-related high-risk factors for severe neutropenia include regimens with an expected neutropenia rate of > 50%, such as the 3-drug combinations including lenalidomide plus alkylating agents or doxorubicin, whereas low-risk regimens include combinations of the novel agents with dexamethasone alone. Patient characteristics, disease stage, type of current and previous treatment, and ANC < 1000 cells/mL at baseline are additional factors that define the risk of severe neutropenia. Granulocyte-colony stimulating factor (G-CSF) should be used to manage chemotherapy-related neutropenia so that patients may stay on treatment for a longer time and benefit from it. Primary G-CSF prophylaxis should be used when high-risk regimens are administered or when low/intermediate-risk regimens are used and additional risk factors are present. Reactive G-CSF treatment is indicated when patients undergoing low-risk chemotherapy experience grade 3/4 neutropenia. If ANC restores to > 1000 cells/mL, therapy can be resumed with no dose modifications. In case of persistence of severe neutropenia, treatment should be delayed until ANC reaches > 1000 cells/mL, and dose reductions are necessary.

OBJECTIVES/OBJECTIVE:To measure apparent diffusion coefficient (ADC) values in patients with active myeloma and remission and to determine whether changes differ in those responding/progressing on treatment. The relationship between changes in marrow fat and ADC was also explored. METHODS:20 patients were recruited. T(1 )weighted, T(2) weighted, short tau inversion-recovery, diffusion-weighted and two-point Dixon MRI of the lumbar spine and pelvis were performed at baseline, 4-6 weeks and 20 weeks. RESULTS:ADC values of active disease (mean 761.2 ± 255×10(-6) mm(2) s(-1)) were significantly higher (p=0.047) than marrow in remission (mean 601.8 ± 459×10(-6) mm(2) s(-1)). Changes in ADC in responders showed a significant increase at 4-6 weeks (p=0.005) but no significant change between baseline and 20 weeks (p=0.733). ADCs in progressing and stable patients did not change significantly between either time point. Pearson's correlation coefficient between change in fat fraction and change in the number of pixels with an ADC of ≤655×10(-6) mm(2) s(-1) was 0.924, indicating a significant correlation (p<0.001). CONCLUSION/CONCLUSIONS:ADC values in active myeloma are significantly higher than marrow in remission, indicating the potential for diffusion-weighted MRI to quantify the transition from active disease to remission and vice versa. This study confirms significant changes in ADC in patients responding to treatment and indirect evidence from two-point Dixon MRI suggests that these changes are influenced by changes in marrow fat. ADVANCES IN KNOWLEDGE/CONCLUSIONS:ADC of active myeloma is significantly higher than marrow in remission; the direction of ADC changes on treatment is dependent on the timing of measurements and is influenced by changes in marrow fat.

The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.