Rafael Fonseca

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

Summary. The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B‐cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M‐protein is ≥ 30 g/l and/or bone marrow clonal cells ≥ 10% but no related organ or tissue impairment (ROTI)(end‐organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non‐secretory myeloma is characterized by the absence of an M‐protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (± recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Review of 1027 Patients With Newly Diagnosed Multiple Myeloma

OBJECTIVE To determine the clinical and laboratory features of newly diagnosed multiple myeloma. PATIENTS AND METHODS Records of all patients in whom multiple myeloma was initially diagnosed at the Mayo Clinic in Rochester, Minn, from January 1, 1985, to December 31, 1998, were reviewed. RESULTS Of the 1027 study patients, 2% were younger than 40 years, and 38% were 70 years or older. The median age was 66 years. Anemia was present initially in 73% of patients, hypercalcemia (calcium level > or = 11 mg/dL) in 13%, and a serum creatinine level of 2 mg/dL or more in 19%. The beta2-microglobulin level was increased in 75%. Serum protein electrophoresis revealed a localized band in 82% of patients, and immunoelectrophoresis or immunofixation showed a monoclonal protein in 93%. A monoclonal light chain was found in the urine in 78%. Nonsecretory myeloma was recognized in 3% of patients, whereas light-chain myeloma was present in 20%. Conventional radiographs showed an abnormality in 79%. The plasma cell labeling index was 1% or more in 34% of patients. Multivariate analysis revealed that age, plasma cell labeling index, low platelet count, serum albumin value, and the log of the creatinine value were the most important prognostic factors. CONCLUSION The median duration of survival was 33 months and did not improve from 1985 through 1998.

Initial genome sequencing and analysis of multiple myeloma

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.

Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group

PURPOSE To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma. PATIENTS AND METHODS Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A. RESULTS Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively). CONCLUSION Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial

BACKGROUND High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide. METHODS Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475. FINDINGS 445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1.75, 80% CI 1.30-2.32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94-99) in the low-dose dexamethasone group compared with 87% (82-92) in the high-dose group (p=0.0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0.0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0.003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0.0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0.04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0.08), respectively. INTERPRETATION Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma. FUNDING National Cancer Institute, Rockville, MD, USA.

Genetics and Cytogenetics of Multiple Myeloma A Workshop Report

Much has been learned regarding the biology and clinical implications of genetic abnormalities in multiple myeloma. Because of recent advances in the field, an International Workshop was held in Paris in February of 2003. This summary describes the consensus recommendations arising from that meeting with special emphasis on novel genetic observations. For instance, it is increasingly clear that translocations involving the immunoglobulin heavy-chain locus are important for the pathogenesis of one-half of patients. As a corollary, it also clear that the remaining patients, lacking IgH translocations, have hyperdiploidy as the hallmark of their disease. Several important genetic markers are associated with a shortened survival such as chromosome 13 monosomy, hypodiploidy, and others. The events leading the transformation of the monoclonal gammopathy of undetermined significance (MGUS) to myeloma are still unclear. One of the few differential genetic lesions between myeloma and MGUS is the presence of ras mutations in the latter. Gene expression platforms are capable of detecting many of the genetic aberrations found in the clonal cells of myeloma. Areas in need of further study were identified. The study of the genetic aberrations will likely form the platform for targeted therapy for the disease.

International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.

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.

Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma

PURPOSE Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL. PATIENTS AND METHODS Patients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance. RESULTS Thirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week. CONCLUSIONS Single-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.

Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis

PURPOSE Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL. PATIENTS AND METHODS Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 microg/L, and cTnI < 0.1 microg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively. RESULTS Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively. CONCLUSION Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.