Suzanne R. Hayman

Combination Therapy With Thalidomide Plus Dexamethasone for Newly Diagnosed Myeloma

PURPOSE Multiple myeloma is a malignancy of plasma cells and is characterized by increased marrow angiogenesis. Thalidomide, an agent with antiangiogenic properties, is effective in relapsed myeloma. We report the results of a study combining thalidomide and dexamethasone as initial therapy for myeloma. PATIENTS AND METHODS Fifty patients with newly diagnosed myeloma were studied. Thalidomide was given at a dose of 200 mg/d orally. Dexamethasone was given at a dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40 mg/d on days 1 to 4 (even cycles), repeated monthly. RESULTS Of all 50 patients, a confirmed response was seen in 32 patients yielding a response rate of 64% (95% confidence interval, 49% to 77%). Thirty-one patients (62%) proceeded to stem-cell collection after four cycles of therapy including 26 who underwent stem-cell transplantation and five who chose stem-cell cryopreservation. Major grade 3 or 4 toxicities were observed in 16 patients (32%), and the most frequent were deep vein thrombosis (six patients), constipation (four patients), rash (three patients), and dyspnea (two patients). Three deaths occurred during active therapy because of a pancreatitis, pulmonary embolism, and infection. CONCLUSION We conclude that the combination of thalidomide plus dexamethasone is a feasible and active regimen in the treatment of multiple myeloma. It merits further study as an oral alternative to infusional chemotherapy with vincristine, doxorubicin, and dexamethasone and other intravenous regimens currently used as pretransplantation induction therapy for myeloma.

Management of Newly Diagnosed Symptomatic Multiple Myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines

Multiple myeloma is a malignant plasma cell neoplasm that affects more than 20,000 people each year and is the second most common hematologic malignancy. It is part of a spectrum of monoclonal plasma cell disorders, many of which do not require active therapy. During the past decade, considerable progress has been made in our understanding of the disease process and factors that influence outcome, along with development of new drugs that are highly effective in controlling the disease and prolonging survival without compromising quality of life. Identification of well-defined and reproducible prognostic factors and introduction of new therapies with unique modes of action and impact on disease outcome have for the first time opened up the opportunity to develop risk-adapted strategies for managing this disease. Although these risk-adapted strategies have not been prospectively validated, enough evidence can be gathered from existing randomized trials, subgroup analyses, and retrospective studies to develop a working framework. This set of recommendations represents such an effort-the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence.

Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements

PURPOSE Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification. PATIENTS AND METHODS We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials. RESULTS We examined the prognostic value of plasma cell-related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β(2) microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets. CONCLUSION Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.

Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma

PURPOSE Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. PATIENTS AND METHODS Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. RESULTS Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. CONCLUSION The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma.

Bisphosphonates are effective in the prevention and treatment of bone disease in multiple myeloma (MM). Osteonecrosis of the jaw is Increasingly recognized as a serious complication of long-term bisphosphonate therapy. Issues such as the choice of bisphosphonate and duration of therapy have become the subject of intense debate given patient safety concerns. We reviewed available data concerning the use of bisphosphonates in MM. Guidelines for the use of bisphosphonates in MM were developed by a multidisciplinary panel consisting of hematologists, dental specialists, and nurses specializing in the treatment of MM. We conclude that intravenous pamidronate and intravenous zoledronic acid are equally effective and superior to placebo in reducing skeletal complications. Pamidronate is favored over zoledronic acid until more data are available on the risk of complications (osteonecrosis of the jaw). We recommend discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months. These guidelines were developed in the Interest of patient safety and will be reexamined as new data emerge regarding risks and benefits.

Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease

Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.

Treatment of Newly Diagnosed Multiple Myeloma Based on Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART): Consensus Statement

Multiple myeloma is a neoplastic plasma cell dyscrasia that on a yearly basis affects nearly 17,000 individuals and kills more than 11,000. Although no cure exists, many effective treatments are available that prolong survival and improve the quality of life of patients with this disease. The purpose of this consensus is to offer a simplified, evidence-based algorithm of decision making for patients with newly diagnosed myeloma. In cases in which evidence is lacking, our team of 18 Mayo Clinic myeloma experts reached a consensus on what therapy could generally be recommended. The focal point of our strategy revolves around risk stratification. Although a multitude of risk factors have been identified throughout the years, including age, tumor burden, renal function, lactate dehydrogenase, beta2-microglobulin, and serum albumin, our group has now recognized and endorsed a genetic stratification and patient functional status for treatment.

Induction of a Chronic Disease State in Patients With Smoldering or Indolent Multiple Myeloma by Targeting Interleukin 1β-Induced Interleukin 6 Production and the Myeloma Proliferative Component

OBJECTIVE To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma. PATIENTS AND METHODS Stromal cells were cocultured with IL-1beta-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). RESULTS In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years. CONCLUSION In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00635154.

Hypertension in pregnancy: an emerging risk factor for cardiovascular disease

Increasing evidence indicates that hypertension in pregnancy is an under-recognized risk factor for cardiovascular disease (CVD). Compared with women who have had normotensive pregnancies, those who are hypertensive during pregnancy are at greater risk of cardiovascular and cerebrovascular events and have a less favorable overall risk profile for CVD years after the affected pregnancies. One factor that might underlie this relationship is that hypertensive disorders of pregnancy (pre-eclampsia, in particular) and CVD share several common risk factors (e.g. obesity, diabetes mellitus and renal disease). Alternatively, hypertension in pregnancy could induce long-term metabolic and vascular abnormalities that might increase the overall risk of CVD later in life. In both cases, evidence regarding risk-reduction interventions specific to women who have had hypertensive pregnancies is lacking. While awaiting results of large-scale studies, hypertensive disorders of pregnancy should be screened for during assessment of a womans overall risk profile for CVD. Women at high risk must be monitored closely for conventional risk factors that are common to both CVD and hypertensive disorders of pregnancy and treated according to current evidence-based national guidelines.

Long-term Results of Response to Therapy, Time to Progression, and Survival With Lenalidomide Plus Dexamethasone in Newly Diagnosed Myeloma

OBJECTIVE To determine the long-term effects of a combined regimen of lenalidomide and dexamethasone (Rev-Dex) on time to progression, progression-free survival, and overall survival (OS) in patients with multiple myeloma. PATIENTS AND METHODS From March 2004 through October 2004, 34 patients were registered for the study. They were treated with 25 mg/d of lenalidomide on days 1 through 21 of a 28-day cycle and 40 mg/d of dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 of each cycle. After 4 cycles of therapy, patients were allowed to discontinue treatment to pursue autologous stem cell transplant (SCT). Treatment beyond 4 cycles was permitted at the physician s discretion. RESULTS Thirteen patients proceeded to SCT after initial therapy and were censored at that time point for purposes of calculation of response. Thirty-one patients achieved an objective response, defined as a partial response or better (91%; 95% confidence interval, 79%-98%), with a complete response plus very good partial response rate of 56%. The complete response plus very good partial response among the 21 patients who received Rev-Dex without SCT was 67%. The 2-year progression-free survival rates for patients proceeding to SCT and patients remaining on Rev-Dex were 83% and 59%, respectively; the OS rates were 92% and 90% at 2 years and 92% and 85% at 3 years, respectively. The 3-year OS rate for the whole cohort was 88%. CONCLUSION The Rev-Dex regimen is highly active in the treatment of newly diagnosed multiple myeloma. Responses are durable with a low progression rate at 2 years. Randomized trials that incorporate quality-of-life measures are needed to determine if this and other combination regimens are better used early in therapy or should be reserved for later interventions.