Multiple Myeloma (MM) is a malignancy of terminally differentiatedplasma cells and is the second most common hematologicalneoplasm to Non-Hodgkin’s Lymphoma. Generally,it is disease of older patients. Our knowledge about theunderlying biological and cytogenetic abnormalities leadingto MM is rapidly increasing. Similarly our ability is improvingto treat this complex disease. A number of new treatmentshave been introduced into our armamentarium in the past10-15 years. Until recently, high rates of complete responses(CR) and other major responses were seen only in patientsundergoing treatment with high dose chemotherapy with autologousstem cell support (HD+ASCT). However new regimens,incorporating new agents (thalidomide, lenalidomide,bortezomib) are now offering similar response rates and lowertoxicity than HD+ASCT. The new agents seem to combinewell with classical chemotherapy agents (melphalan, cyclophosphamide),modern chemotherapy (pegylated liposomaldoxorubicin) and steroids (dexamethasone, prednisone).In addition, the novel agents show significant activity whencombined with each other in patients with newly diagnosedas well as relapsed/refractory MM patients. Although this isstill considered an incurable disease, the life expectancy andquality of life of MM patients is continuously improving. Ourhope is that progress in this area of research will continuewith the advent of new treatment options and will lead to theultimate goal: a cure.

The design of innovative, more effective, less toxic therapy of multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm of patients with MM. Its efficacy, however, has been compromised by significant side effects. IMiDs (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifically designed to create new agents with enhanced immunomodulatory and anticancer properties and better tolerability profiles. In this article, we review the clinical trial development of the second-generation IMiDs, lenalidomide and pomalidomide. Both agents demonstrate potent activity and are highly effective and well tolerated treatment options for patients with MM.

This report describes an unusual case of cyclin D1 expression by an otherwise typical follicular lymphoma, of low histological grade. BCL2–IGH and CCND1–IGH fusions were identified by interphase fluorescence in situ hybridisation.

e19517 Background: The multikinase inhibitor sorafenib targets several serine/threonine and receptor tyrosine kinases by blocking RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway regulated by the Ras oncogene, which is mutated both in primary patient samples and in human MM lines (35-50%). As the frequency of these mutations increases with advancing disease and increasing drug resistance, inhibition of the RAF/MEK/ERK signaling pathway, as well the angiogenic VEGFR-2/PDGFR beta cascade by sorafenib may be a useful new approach for the treatment of MM. METHODS SWOG evaluated the effect of sorafenib as a single agent in relapsed/refractory MM patients. In this phase II study we assessed response rate, overall (OS) and progression-free survival (PFS) as well as toxicities associated with this treatment. Twenty-three heavily pretreated MM patients were enrolled in the study. Sorafenib was started at oral dose of 400 mg daily until progression or toxicity. This dose was based on the label for metastatic renal cell carcinoma. RESULTS The study was closed as planned due to lack of efficacy in first 18 patients who were assessable for toxicity and response. Three patients experienced Grade 4 toxicity consisting of thrombocytopenia, anemia and renal failure. 8 cases suffered Grade 3 toxicities including thrombocytopenia, neutropenia, anemia, hand-foot syndrome, diarrhea and dyspnea. No responses were observed. 3 patients had stable disease (2.4-15.9 months) and the remainder progressed. Median PFS is one month, and OS at 12 months is 50%. CONCLUSIONS Thus, single agent sorafenib did not show activity in this group of heavily pretreated MM patients previously exposed to bortezomib. As the frequency of RAS oncogene mutations increases resulting in resistance to traditional chemotherapeutic agents as well as possibly supporting cytokine resistance to immune modulators, sorafenib might have a supportive role in combination therapy with bortezomib, lenalidomide or everolimus in relapsed/refractory MM which is currently being evaluated in ongoing studies. No significant financial relationships to disclose.

The objective of this study was to examine the in vivo and in vitro gonadotropin-inhibiting potencies, edematogenic activities and the receptor binding affinities of the D-Cit6, D,L-Cit6 and L-Cit6 forms of the LH-RH antagonist Cetrorelix (SB-75) [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH- RH. In order to demonstrate the suppressive effects of two different diastereomers of SB-75 and their racemic mixture on LH and FSH release, [D-Cit6] SB-75 was injected subcutaneously in doses of 2.5 and 10 micrograms/rat, [D,L-Cit6]-SB-75 in doses of 5 and 20 micrograms/rat and [L-Cit6] SB-75 in doses of 12.5 and 50 micrograms/rat to castrated male rats. Two hours after administration, there was no difference in LH levels between rats injected with the L-form and control animals, indicating a low activity and/or a rapid enzymatic degradation of this peptide. The (1:1) diastereomeric mixture was only about half as potent in suppression of LH release compared to [D-Cit6] SB-75. Serum FSH levels were suppressed significantly (p < 0.01) for more than 48 h after the administration of 10 micrograms [D-Cit6] SB-75 and 20 micrograms of [D,L-Cit6] SB-75, respectively. [D-Cit6] SB-75 administered at a dose of 2 micrograms/rat induced 100% inhibition of ovulation, while 4 micrograms/rat of the D,L-Cit6 peptide were necessary to produce the same effect.(ABSTRACT TRUNCATED AT 250 WORDS)

15089 Background: Although it is agreed that patients with stage III disease benefit from adjuvant treatment, whether all patients with stage II disease should receive such treatment remains debata...

Alemtuzumab is a humanized anti‐CD52 monoclonal antibody indicated for treatment of fludarabine‐refractory B‐cell chronic lymphocytic leukemia (B‐CLL). Severe lymphopenia is one of the most profound hematologic effects of alemtuzumab, often predisposing patients to infectious complications such as herpes simplex virus, cytomegalovirus, and Pneumocystis jiroveci pneumonia. Opportunistic infections secondary to mycobacterial sources have been documented less frequently. We describe the case of a 46‐year‐old man who developed a 40‐mm lymph node mass 4 months after completing alemtuzumab therapy. After a thorough evaluation, he began treatment for tuberculosis with a four‐drug combination regimen. The patient's final biopsy report indicated the presence of Mycobacterium avium complex. All clinical signs of the infection resolved with no recurrence. To our knowledge, this is the first published report of a patient who developed M. avium complex after alemtuzumab therapy. Consideration of primary prophylaxis against M. avium complex infections in aggressively treated patients with advanced B‐CLL or other clinical indications may be warranted if future reports of such atypical infections emerge.

Waldenstrom’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic disorder associated with an IgM monoclonal protein that may present with anemia, lymphadenopathy, and hepatosplenomegaly. Since combination chemotherapy and Rituximab are both active in this disease, it is possible the response rate can be enhanced by using a combined modality of Rituximab and CHOP. This approach has been used in indolent lymphoma with remarkable results and limited toxicity. Objective: To determine the response rate in previously untreated patients with Waldenstrom’s Macroglobulinemia receiving rituximab and CHOP. Methods: This was a phase II study of standard R-CHOP in symptomatic WM patients. The study was activated on June 15, 2004 and closed on April 26, 2007 due to poor accrual. The median age of the sixteen patients enrolled was 60 (44–79 years), β 2 M 3 ug/ml (2.1–7.6), median hemoglobulin was 9 g/dl (7.7–10.9), Viscosity 3.4(1.6–10), and IgM 6389 (3229–13300 mg/dl). The most common symptoms were Fatigue (13/16), visual disturbance (7/16) and parasthesias or painful/numb feet (6/16). Only one patient had bulky adenopathy (6.3%). Results: Of 16 patients treated, 5 patients have no response data available (it will be presented at the meeting). Objective response was 91% (90% CI: 63.5% ∼ 99.5%) and 1 patient had a minor response with an overall response rate of 100%. Median time to response was 1.6 months from registration and median time to maximum response was 2.1 months. Median duration of response has not been reached. The median follow up time of the 16 patients was 18.3 months with a range of 3.6–24.8 months. Among the 16 treated patients, there were 8 (50%, 90% exact binomial CI: 27.9%∼72.1%) grade 4 neutropenia. 8 patients experienced grade 3 lymphopenia (50%, 90% exact binomial CI: 27.9%∼72.1%). Only 2 grade 3 febrile neutropenia were noted. As of August 4, 2007, none of the 16 patients has died. R-CHOP is a promising regimen in the treatment of patients with Waldenstrom’s Macroglobulinemia. To succeed in completing clinical trials in this rare disease better international collaboration and involvement in advocacy groups are required.

BACKGROUND Lenalidomide is active and well tolerated in relapsed and refractory multiple myeloma. We conducted a phase I/II trial of the combination of lenalidomide and chemotherapy to evaluate the safety and efficacy of the combination. METHODS The 62 patients enrolled received liposomal doxorubicin 40 mg/m(2) i.v. and vincristine 2 mg i.v. on day 1, dexamethasone 40 mg p.o. on days 1-4 (DVd), and lenalidomide on days 1-21 in 28-day cycles. Primary end points were maximum tolerated dose (MTD) of lenalidomide with DVd chemotherapy and overall response rate (ORR) by Southwest Oncology Group criteria of the combination. FINDINGS The median age was 62 years, 70% of patients were males and 65% had refractory multiple myeloma. The MTD of lenalidomide with DVd chemotherapy was 10 mg and the dose-limiting toxicity was non-neutropenic sepsis. After 7.5 months of median follow-up, the ORR of the combination was 75%, with 29% of patients achieving a complete or near complete remission. The median progression-free survival was 12 months, while the median overall survival has not yet been reached. INTERPRETATION The combination of lenalidomide and DVd chemotherapy was well tolerated and resulted in high response rates in this mostly refractory patient population. Evaluation of this combination in newly diagnosed patients is warranted.

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.

PURPOSE To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Bortezomib, a first‐in‐class proteasome inhibitor, has shown clinical activity in relapsed, refractory multiple myeloma in a pivotal Phase II trial, SUMMIT.

BACKGROUND AND OBJECTIVES The efficacy and safety of added dexamethasone were assessed in patients with relapsed and/or refractory multiple myeloma who had a suboptimal response to bortezomib alone. DESIGN AND METHODS In two previously reported, open-label, multicenter phase 2 studies, bortezomib 1.0 or 1.3 mg/m2 was administered intravenously twice weekly for 2 weeks of a 3-week cycle for up to 8 cycles to patients who had failed either > or = 2 lines of therapy (SUMMIT, n=202) or first-line therapy (CREST, n=54). Patients with progressive disease after the first two cycles or stable disease after four cycles of bortezomib were eligible for addition of oral dexamethasone 20 mg on the day of and after each bortezomib dose. Responses were assessed by an Independent Review Committee using European Group for Blood and Marrow Transplantation criteria. RESULTS Addition of dexamethasone to bortezomib was associated with improved responses in 13 of 74 evaluable patients (18%) in SUMMIT and 9 of 27 (33%) in CREST; eight of these 22 patients had been previously refractory to dexamethasone. There were 2 complete, 8 partial, and 12 minimal responses. Dexamethasone did not appear to alter the type or number of adverse events. Treatment-emergent adverse events reported in > or = 20% of patients receiving combination therapy were fatigue (25%), thrombocytopenia (24%), insomnia (21%), and nausea (20%). INTERPRETATION AND CONCLUSIONS Addition of dexamethasone to bortezomib in patients with relapsed and/or refractory myeloma who had suboptimal responses to bortezomib alone was associated with improvement in responses without prohibitive toxicity.