Erica L. Campagnaro

Phase II Trial of Combination Therapy With Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone in Patients With Newly Diagnosed Myeloma

PURPOSE This single-center, open-label, phase II trial evaluated the bortezomib, pegylated liposomal doxorubicin (PLD), and dexamethasone combination regimen (VDD) as initial treatment for patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS Enrolled patients (N = 40) received up to six 3-week cycles of treatment with bortezomib 1.3 mg/m(2) intravenously (IV) on days 1, 4, 8, and 11; PLD 30 mg/m(2) IV on day 4; and dexamethasone 20 to 40 mg daily as specified in the study design. The primary end point was the complete/near-complete response (CR/nCR) rate after six cycles. Secondary end points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The impact of VDD on stem-cell mobilization and collection also was evaluated. RESULTS After six cycles, the ORR was 85.0% (CR/nCR, 37.5%; very good partial response [VGPR] or better, 57.5%). Patients who underwent stem-cell transplantation (SCT) after VDD (n = 30) experienced increased rates of VGPR or better (53.3% to 76.6% after SCT). Overall, 1-year PFS and OS rates were 92.5% and 97.5%, respectively. Those who achieved VGPR or better after treatment with VDD showed a significantly greater 1-year PFS versus those who achieved less than VGPR (100% v 82%, respectively; P = .03). Similar results were observed in patients who underwent SCT. Grades 3 or 4 hematologic toxicities occurred in < or = 10% of patients; grade 2 painful neuropathy occurred in 7.5%; and grade 3 palmar-plantar erythrodysesthesia occurred in 2.5%. CONCLUSION VDD is highly effective for initial treatment of MM followed by SCT in appropriate patients, and it has a reasonable safety profile. Achievement of VGPR or better with this initial therapy predicted longer PFS, regardless of the consolidation therapy given.

Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial

This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m(2), pegylated liposomal doxorubicin 30 mg/m(2), and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.

A PATHOBIOLOGICAL ROLE OF THE INSULIN RECEPTOR IN CHRONIC LYMPHOCYTIC LEUKEMIA

Purpose: The chromosomal deletion 11q affects biology and clinical outcome in chronic lymphocytic leukemia (CLL) but del11q-deregulated genes remain incompletely characterized. Experimental Design: We have employed integrated genomic profiling approaches on CLL cases with and without del11q to identify 11q-relevant genes. Results: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (∼10-fold higher mean levels than other genomic categories) was confirmed by quantitative PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through flow cytometry, compared with measurements in normal CD19+ B cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo. Higher INSR levels correlated with shorter time to first therapy and shorter overall survival (OS). In bivariate analysis, INSR expression predicted for rapid initial disease progression and shorter OS in ZAP-70–low/negative CLL. Finally, in multivariate analysis (ZAP-70 status, IgVH status, and INSR expression), we detected elevated HRs and trends for short OS for CLL cases with high INSR expression (analyzed inclusive or exclusive of cases with del11q). Conclusions: Our aggregate biochemical and clinical outcome data suggest biologically meaningful elevated INSR expression in a substantial subset of all CLL cases, including many cases with del11q. Clin Cancer Res; 17(9); 2679–92. ©2011 AACR.

Management of multiple myeloma in older adults: Gaining ground with geriatric assessment.

Multiple myeloma increases in incidence with age. With the aging of the population, the number of cases of multiple myeloma diagnosed in older adults each year will nearly double in the next 20years. The novel therapeutic agents have significantly improved survival in older adults, but their outcomes remain poorer than in younger patients. Older adults may be more vulnerable to toxicity of therapy, resulting in decreased dose intensity and contributing to poorer outcomes. Data are beginning to emerge to aid in identifying which individuals are at greater risk for toxicity of therapy; comorbidities, functional limitations, and age over 80years are among the factors associated with greater risk. Geriatric assessment holds promise in the care of older adults with multiple myeloma, both to allow modification of treatment to prevent toxicity, and to identify vulnerabilities that may require intervention. Emerging treatments with low toxicity and attention to individualizing therapy based on geriatric assessment may aid in further improving outcomes in older adults with multiple myeloma.

Neoplastic and non-neoplastic complications of solid organ transplantation in patients with preexisting monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) occurs in 3–7% of the elderly population, with higher prevalence in renal failure patients, and is associated with a 25‐fold increased lifetime risk for plasma cell myeloma (PCM), also known as multiple myeloma. Using the California State Inpatient, Emergency Department, and Ambulatory Surgery Databases components of the Healthcare Cost and Utilization Project (HCUP), we sought to determine whether patients with MGUS who undergo solid organ allograft (n = 22 062) are at increased adjusted relative risk (aRR) for hematologic malignancy and other complications. Among solid organ transplant patients, patients with preexisting MGUS had higher aRR of PCM (aRR 19.46; 95% CI 7.05, 53.73; p < 0.001), venous thromboembolic events (aRR 1.66; 95% CI 1.15, 2.41; p = 0.007), and infection (aRR 1.24; 95% CI 1.06, 1.45; p = 0.007). However, when comparing MGUS patients with and without solid organ transplant, there was decreased aRR for PCM with transplant (aRR 0.34; 95% CI 0.13, 0.88; p = 0.027), and increased venous thromboembolic events (aRR 2.33; 95% CI 1.58, 3.44; p < 0.001) and infectious risks (aRR 1.44; 95% CI 1.23, 1.70; p < 0.001). While MGUS increased the risk of PCM overall following solid organ transplantation, there was lower risk of PCM development compared to MGUS patients who did not receive a transplant. MGUS should not preclude solid organ transplant.

A family-centered intervention for the transition to living with multiple myeloma as a chronic illness: A pilot study

Patients with multiple myeloma and their family caregivers must master self-management tasks related not only to the disease and treatment, but also associated with transitioning to living with chronic illness. The aim of this study was to assess the feasibility, acceptability, safety, and fidelity of an intervention that had a psychoeducational approach and included a low-impact, home-based walking activity. A secondary aim was to obtain preliminary data of the effect of the intervention, as compared to an attention control group, on anxiety, activation for self-management, fatigue, depression and health-related quality of life (HRQOL). A sample of 15 adult patients with multiple myeloma and their family caregivers were randomized into either an intervention or attention-control group. The intervention was delivered to the dyad in one session and booster calls were made at 1 and 3 weeks. The control group received printed educational resources and telephone contacts. Measures were done at baseline, and 6 and 12 weeks. Descriptive statistics were used. The intervention was safe, feasible, and acceptable to patients and caregivers. Fidelity was high for the initial session, but low with booster calls. Improvement in scores for activation, fatigue, depression, anxiety, physical HRQOL, and emotional distress was seen in at least 40% of patients in the intervention group. Fewer caregivers in the intervention group showed improvement on the outcome variables. Leveraging a behavioral strategy such as walking, along with supportive and educational resources, is promising for promoting well-being within the patient/caregiver dyad. Further refinement of the intervention is needed to strengthen its efficacy for the caregiver and exploratory work is essential to understand the interpersonal supportive processes associated with the walking activity.

Use of Bone-Modifying Agents in Myeloma and Bone Metastases: How Recent Dosing Interval Studies Have Affected Our Practice

The management of bone lesions from advanced solid tumors and multiple myeloma typically includes use of a bone-modifying agent to reduce the risk of skeletal-related events. Recent data demonstrate that when using zoledronic acid to reduce the risk of skeletal-related events in metastatic breast cancer, metastatic prostate cancer, and multiple myeloma, the dosing interval of zoledronic acid may be extended from every 4 weeks to every 12 weeks. The ASCO guidelines on the role of bone-modifying agents in metastatic breast cancer and multiple myeloma address zoledronic acid dosing intervals. Herein, we discuss how new data on dosing of bone-modifying agents influence our clinical practice.