Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study.

BACKGROUND: Waldenstrom macroglobulinemia (WM) is a non-Hodgkin lymphoma (NHL) subtype. Little is known about the incidence and trends for this disease in the United States. METHODS: Twenty-year data from the Surveillance, Epidemiology, and End Results (SEER) program were used for this study. SEER*Stat was used for data analysis. RESULTS: Of the 95,797 cases of NHL diagnosed between 1988 and 2007 in 9 SEER registries, 1835 (1.9%) were new cases of WM. Median age at diagnosis of WM was 73 years. The overall annual age-adjusted incidence was 0.38 per 100,000 persons per year, which increased with age, ranging from 0.03 in patients aged <50 years to 2.85 in patients aged ≥80 years. The incidence of WM was higher in men (0.54) than in women (0.27; P < .001) and was higher in whites (0.41) than in African Americans (0.18) or other races (0.21; P < .05). The annual percentage change for the whole population was 1.01% (P > .05). The annual percentage change was 1.21% for whites (P < .05) and 0.80% (P > .05) for nonwhites. Significant annual percentage change increases were seen in the group aged 70 to 79 years (1.24%; P < .05) and in 3 geographic registries (P < .001). CONCLUSIONS: Although the overall incidence of WM remained steady over time, significant increases in incidence were seen over the past 20 years in whites, in those aged 70 to 79 years, and in 3 geographic registry areas.

Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.

PURPOSE: To evaluate the activity of thalidomide in patients with asymptomatic multiple myeloma and of thalidomide-dexamethasone in patients with previously untreated symptomatic myeloma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated asymptomatic myeloma were treated with thalidomide 100 to 200 mg orally (PO) at bedtime (qhs) with serial increments of 50 to 100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. Forty consecutive previously untreated patients with symptomatic myeloma were also treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m(2) for 4 days beginning on days 1, 9, and 17; the second and third cycles of repeated dexamethasone were begun on day 30. Both groups of patients were treated for at least 3 months. RESULTS: The response rate was 36% for patients treated with thalidomide alone and 72% for patients treated with thalidomide-dexamethasone, the latter including complete remission in 16% of patients. The median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone. Grade 3 toxicity included infections (nine patients) and thrombotic/embolic events (seven patients). Five deaths have occurred as a result of multiple myeloma (two patients), infection (one patient), unknown cause (one patient), and a possible thromboembolic event (one patient). CONCLUSION: Thalidomide alone was effective in patients with newly diagnosed myeloma. The combination with dexamethasone induced a high frequency of response, rapid onset of remission, and low incidence of serious irreversible toxicity. These observations support further studies of this promising combination for patients with newly diagnosed multiple myeloma.

Thalidomide with or without dexamethasone for refractory or relapsing multiple myeloma.

Both thalidomide and intermittent high-dose dexamethasone are agents with established activity against multiple myeloma. We summarized our experience with thalidomide alone, and then in combination with dexamethasone, for groups of patients with myeloma resistant or relapsing despite standard treatments. Criteria of response were based on greater than 50% reduction of serum myeloma protein and/or greater than 75% reduction of Bence Jones protein for patients treated with thalidomide alone and greater than 75% reduction of serum myeloma protein and/or greater than 90% reduction of Bence Jones protein for those who received thalidomide with dexamethasone. Among patients with resistant or relapsing disease treated with a combination of thalidomide and dexamethasone, 47% of patients achieved remission with significant prolongation of survival for responsive patients. Among patients in stable partial remission after intensive therapy who received the same program, myeloma protein was reduced further by greater than 90% in 52% of patients who had not received prior thalidomide/dexamethasone. Side effects were frequent, mild and reversible, and often preventable. Our program of thalidomide/dexamethasone was a safe and effective combination for patients with resistant or relapsing disease, or as consolidation of partial remission after intensive therapy.

2-Chlorodeoxyadenosine alone and in combination for previously untreated Waldenstrom's macroglobulinemia.

Treatment for Waldenstrom's macroglobulinemia (WM) has usually been reserved for symptomatic patients and has included alkylating agent-steroid combinations and, more recently, nucleoside analogues. We now describe our experience with 2-chlorodeoxyadenosine (2-CdA) alone and in combination at our center. We treated 90 consecutive, previously untreated patients with symptomatic WM using either 2-CdA alone or in combination with other agents including prednisone (pred), cyclophosphamide (Cy), and rituximab (Rit) as follows: January 1991 to December 1992- 2-CdA 0.1 mg/kg by continuous infusion (CI) over 24 hours for days (16 patients); December 1992 to December 1995-2-CdA 0.1 mg/kg CI over 24 hours for 7 days plus pred 60 mg/m(2) orally daily for 7 days (20 patients); July 1996 to March 1998-2-CdA 1.5 mg/m(2) by subcutaneous injection (SC) every 8 hours for 7 days plus Cy 40 mg/m(2) orally twice daily for 7 days (37 patients); August 1999 to December 2001-2-CdA 1.5 mg/m(2) SC every 8 hours for 7 days plus Cy 40 mg/m(2) orally twice daily for 7 days plus Rit 375 mg/m(2) by intravenous infusion (IV) weekly for 4 weeks (17 patients). For nearly all patients, a second course was repeated after at least 6 weeks. Responding patients were monitored without further treatment until relapse. Overall response (complete [CR] + partial response [PR]) was 94% for 2-CdA alone, 60% for 2-CdA/pred, 84% for 2-CdA/Cy, and 94% for 2-CdA/Cy/Rit. Median overall survival is 73 months for 2-CdA, 41 months for 2-CdA/pred, and has not been reached for 2-CdA/Cy or 2-CdA/Cy/Rit. Cause-specific survival for 2-CdA/pred is 78 months and has not been reached for all other programs. The only poor prognostic factor for cause-specific survival was hemoglobin < 9 g/dL. 2-CdA regimens provide excellent response rates and improve cause-specific survival, with minimal treatment and little toxicity. These observations support the potential role of 2-CdA regimens as the treatment of choice for previously untreated WM.

Electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy in multiple myeloma: a feasibility study.

BACKGROUND: This single-arm study evaluated feasibility, safety, and initial efficacy of electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy (PN) in cancer patients with multiple myeloma. METHODS: Patients with neuropathy ≥ grade 2 received 20 acupuncture treatments over 9 weeks. RESULTS: For the 19 evaluable patients, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity (FACT/GOG/NTX) mean (SD) scores improved significantly between baseline and week 13 (20.8 [9.6] vs 13.2 [8.5], p = 0.0002). Moderate effect size differences began on week 4, with the largest effect size differences found at week 9 for FACT/GOG/NTX scores, worst pain in the last 24 hours, and pain severity (Cohen's d = 1.43, 1.19, and 1.08, respectively) and continuing through week 13 (Cohen's d = 0.86, 0.88, and 0.90, respectively). From baseline to week 13, additional significant improvements were seen as follows: postural stability (1.0 [0.6] vs 0.8 [0.4], p = 0.02); coin test (10.0 [7.4] vs 5.6 [1.9], p < 0.0001); button test (96.1 [144.4] vs 54.9 [47.3], p < 0.0001); and walking test (21.6 [10.0] vs 17.2 [7.7], p = 0.0003). No significant changes were seen with NCS. CONCLUSIONS: Acupuncture may help patients experiencing thalidomide- or bortezomib-induced PN. Larger, randomized, clinical trials are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00891618.

High frequencies of response after limited primary therapy for multiple myeloma.

UNLABELLED: In an effort to maintain high primary response rates against multiple myeloma and without serious toxicity, we assessed 3 different bortezomib combinations in small numbers of patients, with combinations that included cyclophosphamide and lenalidomide in modest doses and for short courses. Remissions occurred in approximately 90% of patients, with rare episodes of serious drug-related adverse effects. BACKGROUND: Recent bortezomib combinations have induced remission in approximately 90% of patients newly diagnosed, with moderate frequency of adverse effects. PATIENTS: In an attempt to reduce adverse effects, and to prepare qualified patients for early intensification, we assessed the antimyeloma effect and toxicity of 3 different bortezomib combinations in small numbers of patients. METHODS: With reduced doses and short durations of exposure, we combined bortezomib with (a) cyclophosphamide/dexamethasone, (b) lenalidomide/dexamethasone/liposomal doxorubicin, and (c) cyclophosphamide/dexamethasone/lenalidomide. RESULTS: Response rates were high, with rare episodes of severe drug-related toxicity. CONCLUSIONS: Further study of similar combinations of effective drugs given in limited doses and for short durations would be useful.

Curability of multiple myeloma.

Among 792 patients with multiple myeloma treated from 1987 to 2010 and assessed after 18 months, there were 167 patients with complete remission. For those 60 patients treated between 1987-1998 and with long followup, the latest relapse occurred after 11.8 years, so that 13 patients have remained in sustained complete remission for longer than 12 years (range 12-22 years). These results suggest that 3% of all patients treated during that period may be cured of multiple myeloma. In addition to immunofixation, more sensitive techniques for the detection of residual disease should be applied more consistently in patients with apparent complete remission in order to identify those with potential cure.

Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma.

OBJECTIVES: In vitro studies have shown synergistic antimyeloma effects with the combination of bortezomib and alkylating agents. Combinations of bortezomib, cyclophosphamide, and dexamethasone are rational with the prospect of superior antitumor activity with independent toxicity. METHODS: Between December 2004 and April 2007, we treated 44 patients with relapsing multiple myeloma with the combination of bortezomib 1.3 mg/m intravenously on days 1, 4, 8, 11; dexamethasone 20 mg/m orally daily for 4 days beginning on days 1, 9 and 17; and cyclophosphamide 70 mg/m orally twice daily for 4 days. A second course was given 1 month later. RESULTS: Clinical response was observed in 32 patients (73%) including 26 with disease in partial remission (59%), and 6 with disease in complete remission (14%). Side effects were uncommon and mild, except for grade 3 thrombocytopenia in 15%, infection in 5% and constipation in 2% of patients. The median remission time of responding patients was 10 months that contributed to significantly longer median survival for patients with responsive disease (33 mo) than for those with unresponsive disease (12 mo) (P < 0.01). CONCLUSION: Bortezomib-cyclophosphamide-dexamethasone was an effective, well-tolerated combination for the treatment of relapsing multiple myeloma.

Multiple myeloma, painful neuropathy, acupuncture?

Thalidomide and bortezomib are remarkably efficacious in the treatment of multiple myeloma. Unfortunately, their use can cause sensory neuropathy, a common and serious adverse event that frequently limits dose and duration of treatment. Although the relationship between peripheral neuropathy and therapeutic dose is controversial, many authors have demonstrated a positive correlation between neuropathy and cumulative dose, dose intensity, and length of therapy. Peripheral neuropathic pain is the most troublesome symptom of neuropathy. Spontaneous pain, allodynia, hyperalgesia, and hyperpathia are often associated with decreased physical activity, increased fatigue, mood, and sleep problems. Symptoms are often difficult to manage, and available treatment options rarely provide total relief. Moreover, the adverse effects of these treatments often limit their use. Several studies have demonstrated the efficacy of acupuncture, with fewer adverse effects than analgesic drugs, in the treatment of painful diabetic and human immunodeficiency virus-related neuropathy. However, the effectiveness of acupuncture in treating toxic neuropathy has not been assessed. Although its putative mechanisms remain elusive, acupuncture has strong potential as an adjunctive therapy in thalidomide- or bortezomib-induced painful neuropathy, and a better understanding might guide its use in the management of chemotherapy-induced neuropathic pain. Well-designed clinical trials with adequate sample size and power are warranted.

Immunotherapy in mantle cell lymphoma: anti-CD20-based therapy and beyond.

Mantle cell lymphoma (MCL), an aggressive non-Hodgkin's lymphoma characterized by t(11; 14)(q13; q32) chromosomal translocation and overexpression of cyclin D1, has the worst prognosis among all lymphomas. Recent advances in biology, genetics, and immunology have supported the development of immunotherapy in MCL. Rituximab monotherapy in MCL has limited activity. It is more effective when used in combination with chemotherapy such as R-CHOP, R-hyperCVAD/MTX-Ara-C, or R-FCM as front-line or salvage therapy for mantle cell lymphoma. Maintenance with Rituximab was shown to prolong response duration. Although most results have suggested that combining autologous stem cell transplantation with Rituximab may lead to durable remission, the sample size was not sufficient to declare survival benefit. Anti-CD20 radioimmunoconjugates (RICs) (90)Yttrium-ibritumomab tiuxetan and (131)Iodine-tositumomab have been used in mantle cell lymphoma even when patients are relatively resistant to Rituximab-based therapy. Allogeneic stem cell transplantation is a treatment modality in advanced or relapsed MCL, particularly using reduced-intensity conditioning. MCL may have high response rates and sustained remissions after donor lymphocyte infusion. Dendritic cells (DCs) fused with MCL cells for immunostimulation have preliminarily shown anti-lymphoma effects as well. Idiotype vaccination in MCL patients following Rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells. Other immunotherapy, such as the combination of thalidomide with Rituximab, has shown substantial antitumor activity. A Phase I/II study is ongoing to determine the maximum tolerated dose (MTD) and the efficacy of lenalidomide in combination with Rituximab for relapsed/refractory MCL. This review summarizes the latest and exciting advances in MCL.

Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004.

BACKGROUND: Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin's lymphoma. To the authors' knowledge, little is known regarding its incidence patterns and associated factors. The purpose of the current study was to examine the incidence of MCL over a period of 13 years and to identify the factors associated with the incidence patterns. METHODS: Patients diagnosed with MCL between 1992 and 2004 were identified from the Surveillance, Epidemiology, and End Results (SEER) Tumor registries. SEER*Stat statistical software was used for analysis. RESULTS: Of the 87,166 patients diagnosed with non-Hodgkin's lymphoma during the 13-year period between 1992 and 2004, 2459 (2.8%) had confirmed MCL. The overall incidence of MCL (per 100,000) was 0.55, which increased with age: 0.07 in patients aged <50 years, 2.97 in patients aged 70 to 79 years, and 2.78 in those aged > or =80 years. The age-adjusted incidence rate increased from 0.27 of 100,000 in 1992 to 0.69 of 100,000 in 2004, and the annual percent change was 5.87% (P < .05). The median age at diagnosis was 68 years. The incidence of MCL was higher in men (0.84 of 100,000) than in women (0.34 of 100,000) (P < .05), and was higher in Caucasians (0.61 of 100,000) than in African Americans (0.32 of 100,000). Late-stage (III-IV) MCL was diagnosed in 74.6% of patients. There were significant geographic variations noted (P < .05). CONCLUSIONS: The incidence of MCL increased from 1992 to 2004, and was significantly higher in men, in Caucasians, and patients aged > or =50 years. Most patients were diagnosed with late-stage MCL, and there also were considerable geographic variations observed in incidence rate.

Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma.

The value of thalidomide-dexamethasone was assessed in 26 consecutive, previously untreated patients with multiple myeloma of high tumor mass. All showed Hgb < 8.5 g/dL, serum calcium > 11.5 mg/dL, or both. The response rate was 73%, frequency of early death < 3 months was 5%, projected median survival was 30 months, and projected median remission time was 25 months. There were no occurrences of grade 3 or 4 neutropenia or thrombocytopenia, so that serious infection occurred in only 12% of patients. Thalidomide-dexamethasone was useful for these patients with advanced disease because of the high response rate and acceptable survival, with a low frequency of serious complications.

Thalidomide and dexamethasone for resistant multiple myeloma.

Between November 1998 and April 2000, the combination of thalidomide and dexamethasone was evaluated in 47 consecutive patients with multiple myeloma that was resistant to prior high-dose dexamethasone-based therapies. Remission was observed in 22 patients (47%), including six patients with complete remission. Side-effects were frequent, mild and usually reversible, but deep vein thrombosis occurred in 8% of patients. Survival and remission times were longer among patients treated for previous resistant disease rather than for resistant relapse. This experience supports the use of thalidomide-dexamethasone in myeloma patients with resistant disease and justifies further trials in newly diagnosed patients.

Persistence of myeloma protein for more than one year after radiotherapy is an adverse prognostic factor in solitary plasmacytoma of bone.

BACKGROUND: Prognostic factors for solitary plasmacytoma of bone (SPB), whether measured before or after radiotherapy (RT), have not been established. The authors analyzed multiple factors for myeloma-free survival (MFS) and cause-specific survival (CSS) in SPB patients treated with RT alone. METHODS: Between 1965 and 2000, 60 patients with carefully staged SPB were treated with RT alone at the M. D. Anderson Cancer Center. Patient ages ranged from 29-77 years (median, 54 years), and 75% of patients had a myeloma (M) protein in the blood and/or urine. No patients showed other lesions on skeletal survey or, in recent years, magnetic resonance imaging (MRI) of the spine; marrow aspirate was normal in all patients. Radiotherapy to the solitary lesion was given to a total dose of 30-70 Gy (median, 46 Gy). The authors analyzed the impact of multiple factors on MFS and CSS, including resolution v. persistence of M protein after RT, secretory v. nonsecretory disease at diagnosis, presence v. absence of an associated soft tissue mass on computed tomography or MRI scan, magnitude of serum M protein elevation at diagnosis, age, spinal v. nonspinal location, Karnofsky performance status, total RT dose, and tumor size. RESULTS: Median follow-up was 7.8 years (range, 1.0-25.5 years). On multivariate analysis, persistence of M protein more than one year after RT was the only independent adverse prognostic factor for MFS (P = 0.005) and CSS (P = 0.04). Most patients with M protein that persisted for more than one year after RT were diagnosed with multiple myeloma within 2.2 years of treatment. CONCLUSIONS: Patients with M protein that persists for more than one year after RT should be monitored frequently and considered for standard chemotherapy followed by intensive consolidation therapy when they either develop symptoms or show an increasing M protein level.