Mary Ann Karam

The Role of Aspirin in the Prevention of Thrombotic Complications of Thalidomide and Anthracycline-Based Chemotherapy for Multiple Myeloma

OBJECTIVE To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T). PATIENTS AND METHODS In this phase 2 clinical trial of DVd-T, conducted by the Cleveland Clinic Foundation from August 2001 to October 2003, 105 patients were enrolled. The first 35 patients experienced increased numbers of VTEs. von Willebrand levels and platelet aggregation to ristocetin before and after treatment with DVd-T increased significantly, suggesting a pathophysiology involving platelet-endothelial interaction. Aspirin was added to the regimen, thus generating 3 patient groups: group 1 received aspirin from the start of DVd-T treatment before the study began (58 patients), group 2 received aspirin after the start of DVd-T treatment and after the study began (26 patients), and group 3 did not receive daily low-dose aspirin during the study (19 patients). Two patients being treated with warfarin for other indications were excluded from the study. The primary end point for this study was the incidence of VTE in the form of either deep venous thrombosis or pulmonary embolism. Secondary end points were the time to the first VTE, time to the composite end point of death or first VTE, and incidence of bleeding complications. RESULTS After a median follow-up of 24 months, on an intent-to-treat basis, 26 posttreatment VTEs occurred after a median of 90 days, with 19% occurring in group 1, 15% in group 2, and 58% in group 3. Following multivariate time-to-event analysis, aspirin use continued to be associated with lower relative risk of VTE (hazard ratio, 0.22; confidence interval, 0.10-0.47; P<.001) and of the composite end point (hazard ratio, 0.28; confidence interval, 0.15-0.51; P<.001). CONCLUSION Daily low-dose aspirin (81 mg orally) given to patients with newly diagnosed and relapsed/refractory multiple myeloma who were receiving DVd-T reduced the incidence of VTEs without an increase in bleeding complications.

Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma

OBJECTIVE To evaluate the efficacy and safety of adding thalidomide to the pegylated liposomal doxorubicin, vincristine, and decreased-frequency dexamethasone (DVd) regimen for multiple myeloma. PATIENTS AND METHODS Patients newly diagnosed as having active multiple myeloma and those with relapsed-refractory disease were studied between August 2001 and October 2003. Patients received DVd as previously described. Thalidomide was given at 50 mg/d orally and the dose increased slowly to a maximum of 400 mg/d. At the time of best response, patients received maintenance prednisone, 50 mg orally every other day, and daily thalidomide at the maximum tolerated dose for each patient. The primary end point was the rate of complete responses plus very good partial responses as defined by the European Group for Blood and Marrow Transplantation criteria and the Intergroupe Français du Myélome, respectively. RESULTS Of 102 eligible patients, 53 were newly diagnosed as having multiple myeloma, and 49 had been previously treated for multiple myeloma. The complete response plus very good partial response rate was 49% and 45%, with an overall response rate of 87% and 90% for patients with newly diagnosed and previously treated multiple myeloma, respectively. Furthermore, better responses were associated with improved progression-free and overall survival. The most common grade 3 and 4 adverse events were thromboembolic events (25%), peripheral neuropathy (22%), and neutropenia (14%). CONCLUSIONS The addition of thalidomide to the DVd regimen significantly improves the response rate and quality of responses compared with the DVd regimen alone. This improvement is associated with longer progression-free and overall survival. The rate of observed quality responses is comparable to responses seen with high-dose therapy.

Use of Melphalan, Thalidomide, and Dexamethasone in Treatment of Refractory and Relapsed Multiple Myeloma

Twenty-one patients with relapsed and refractory Durie-Salmon stage III multiple myeloma who had either failed at least three previous regimens or presented with poor performance status, neutropenia, or thrombocytopenia were treated with up to four cycles of combination melphalan (50 mg intravenously), thalidomide (titrated to target of 400 mg orally daily), and dexamethasone (40 mg/day orally on d 1 to 4) every 4–6 wk. Maintenance treatment consisting of daily thalidomide and monthly dexamethasone was continued until disease progression. Although generally tolerated, combination melphalan/thalidomide/dexamethasone produced grade 4 neutropenia and thrombocytopenia in 52% and 38% of patients, respectively. Grade 3 nonhematologic toxicities included fatigue (14% of patients), neuropathy/paresthesia (5%), and nausea (5%). Four patients died while on therapy: two from neutropenic complications and two from progressive disease. Melphalan/thalidomide/dexamethasone was highly active in this poor prognosis population: Serum monoclonal protein reductions ≥25% occurred in 14 (70%) of 20 evaluable patients, including 1 patient with a complete response and 2 (13%) patients with reductions of 96%. Median progression-free-survival was 270 d (range: 73 to >787 d) and median overall survival was 382 d. Median progression-free survival (>420 d) has not been reached among patients responding to melphalan/thalidomide/dexamethasone. These results show that melphalan/thalidomide/dexamethasone therapy is active and generally tolerated in heavily pretreated multiple myeloma patients whose prognosis is otherwise poor.

Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: A phase 2 trial

BackgroundSingle-agent arsenic trioxide has shown promising results in patients with relapsed or refractory multiple myeloma (MM). Because preclinical data suggested greater activity with dexamethasone and ascorbic acid, a phase 2 trial of the combination of arsenic trioxide, dexamethasone, and ascorbic acid in patients with relapsed or refractory MM was conducted.MethodsTwenty patients in whom no more than two previous therapies had failed were enrolled. The mean age was 62 yr, and 55% of the patients had refractory disease. The regimen consisted of 14- or 15-wk cycles, with the first cycle considered induction, followed by one or two consolidation cycles with a reduced steroid schedule and then a maintenance cycle in responding patients.ResultsThe overall response rate was 30%, with at least stable disease in 80% of patients. Median progression-free survival was 316 d in all patients and 584 d in those with a response. The regimen was well tolerated, with most adverse events being mild or moderate.This study showed the clinical efficacy and tolerability of the combination of arsenic trioxide, dexamethasone, and ascorbic acid. Further study is warranted.

Jaw complications associated with bisphosphonate use in patients with plasma cell dyscrasias.

Osteonecrosis of the jaw has been linked with bisphosphonate use in breast cancer and multiple myeloma patients. We report 17 cases of patients with plasma cell dyscrasia being treated with bisphosphonate who developed osteonecrosis/osteomyelitis of the jaw.Seventeen patients evaluated at our institution between 1998 and 2005 are reported. All were being treated with bisphosphonates for a median of 5 mo proor to the onset of jaw symptoms. Sixteen of the 17 patients are 54 yr or older. None of the patients had been irradiated in the jaw nor had obvious osseous manifestation of multiple myeloma in the jaw. Thirteen patients were receiving zoledronic acid and four patients were receiving pamidronate at the onset of jaw symptoms. Six of the 17 did receive both agents at some time and all of these individuals were receiving zoledronic acid at diagnosis. Microorganisms were isolated in 7/17 patients with the most common organism being actinomycosis.We have initiated the following guidelines in an effort to ameliorate the incidence of this complication. Patients should have a full dental examination at the time of diagnosis of the plasma cell dyscrasia especially if bisphosphonates are to be considered as part of the therapy. In addition, bisphosphonates are held for a period of 3 mo prior to invasive dental procedures to allow for the osteoclastic recovery, therefore enhanced debris removal and lessening the chance of creating a fertile bacterial medium. Following the dental procedure we would re-introduce bisphosphonates only after the healing process is complete. Finally, multiple myeloma patients diagnosed with jaw osteonecrosis probably have a concurrent infection and should be aggressively treated with antibiotics.

An association between renal cell carcinoma and multiple myeloma: a case series and clinical implications

To describe an association between renal cell carcinoma (RCC) and multiple myeloma (MM) in patients with both disorders, and suggest possible explanations for the association.

Etanercept therapy in patients with advanced primary amyloidosis.

No effective treatment exists for primary amyloidosis, a plasma cell dyscrasia characterized by deposition of amyloid fibrils consisting of monoclonal light chains in various organs. TNF-α has been implicated in other amyloid disorders; therefore, we used etanercept to treat patients with advanced amyloidosis who had failed other therapies or were ineligible for other treatment regimens. Sixteen patients with amyloidosis that included patients with severe cardiac or multiple organ involvement were treated with etanercept and evaluated every 4–6 wk for evidence of toxicity and clinical response. Patients were treated with etanercept for a median of 42 wk. Eight of 16 patients (50%) experienced objective improvements and 14 patients (88%) experienced subjective improvements in symptoms. Only one patient experienced an adverse effect attributable to etanercept. For the entire group, improvement in performance status was statistically significant (p=0.001), estimated median survival is 24.2 mo, 8 of whom are still alive with a median survival is 26.6 mo. The 12 patients with any cardiac involvement had an estimated median survival of 24.2 mo. Six of those 12 patients are still alive, with a median survival is 26.6 mo. The group of eight patients with severe cardiac involvement showed an estimated median survival of 13.2 mo, three of whom are still alive with a median survival is 25.9 mo.The clinical observations in this group of advanced and relapsed/refractory patients are highly encouraging. For the group as a whole, median survival was 24.2 mo and improvement in performance status was highly significant. Median survival for the patients with severe cardiac involvement was 13.2 mo with 3/8 patients are alive with a median survival of 25+ mo. Moreover, there was a statistically significant improvement in patients’ performance status. These results, even though in a small group of patients, suggest that etanercept may provide a new therapeutic option for the management of amyloidosis that should be studied further.

Combination of rituximab and oral melphalan and prednisone in newly diagnosed multiple myeloma

Clonotypic B lymphocytes may underlie relapse of patients with multiple myeloma. Rituximab, a CD20 monoclonal antibody, may result in eradication of the monoclonal B cells. We conducted a phase II study of rituximab in combination with melphalan and prednisone therapy (MP) followed by rituximab maintenance in newly diagnosed multiple myeloma patients. Sixteen patients (35%) had CD20 positive bone marrow plasma cells, while 9 patients (20%) had unknown CD20 status. No patient had a complete remission, 26 patients (58%) had a partial response, 6 patients (13%) had a minimal response, and 8 patients (18%) had stable disease. The median event-free survival was 14 months, and the 7-year overall survival was 30%. The toxicity of the combination was overall manageable and consistent with what is generally noted with MP chemotherapy. The combination of rituximab to MP therapy did not result in improved response rate or event-free survival.

Skeletal trauma preceding the development of plasma cell dyscrasia: eight case reports and review of the literature.

Plasma cell dyscrasias are clonal proliferations and accumulations of plasma cells. The etiology of monoclonal neoplasms still remains elusive. A direct correlation between a history of trauma and the development of plasma cell dyscrasias has not been established. Two recent case reports have described plasmacytomas that were diagnosed in patients who suffered injury at the site of plasma cell neoplasms. We report a series of eight patients who stated a history of trauma to the site where plasma cell neoplasms were later diagnosed. The duration from the date of injury to diagnosis ranged from 2 mo to 20 yr. The M:F ratio was 6:2. The median age was 52 (28–75). Multiple myeloma was confirmed in six patients and plasmacytoma without systemic disease in the other two patients. All eight patients had a κ monoclonal plasma cell population, and all but one had a detectable peripheral κ light chain. All patients presented with persistent discomfort at the site where they had experienced trauma. Even though this article does not establish a relationship between trauma, and the development of plasma cell dyscrasia, persistent discomfort at a previous trauma site warrants a complete evaluation and consideration for possible plasma cell dyscrasias.

Mature results of MM-011: A phase I/II trial of liposomal doxorubicin, vincristine, dexamethasone, and lenalidomide combination therapy followed by lenalidomide maintenance for relapsed/refractory multiple myeloma

A previous interim report of MM‐011, the first study that combined lenalidomide with anthracycline‐based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long‐term outcomes of all 76 treated patients with follow‐up ≥5 years. This single‐center phase I/II study administered lenalidomide (10 mg on days 1–21 of every 28‐day cycle), intravenous liposomal doxorubicin (40 mg/m2 on day 1), dexamethasone (40 mg on days 1–4), and intravenous vincristine (2 mg on day 1). After 4–6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1–7); 49 (64.5%) patients had refractory disease. Forty‐three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment‐related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression‐free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline‐based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM (ClinicalTrials.gov number, NCT00091624). Am. J. Hematol. 89:349–354, 2014.