Evangelos Terpos

International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid

BACKGROUND Osteonecrosis of the jaw (ONJ) is a well-described complication of bisphosphonates use in patients with multiple myeloma (MM). We investigated whether the occurrence of ONJ decreased after the implementation of preventive measures in 128 patients with MM who received zoledronic acid. PATIENTS AND METHODS Patients with MM who received zoledronic acid were included in this analysis. Patients with a previous use of other bisphosphonates were excluded; patients were stratified into group A (n=38) and group B (n=90) if treatment was started before or after the implementation of preventive measures. RESULTS One hundred and twenty-eight patients were included in this analysis. Sixteen patients (12.5%) developed ONJ--group A: 8 (26.3%), group B: 2 (6.7%) (P=0.002). The incidence rate (IR) was 0.671/100 person-months for group A and 0.230/100 person-months for group B [IR ratio 2.92, P=0.029, 95% confidence interval 1.06-8.03]. No patient in group B developed stage III ONJ. CONCLUSION In conclusion, the risk of developing ONJ after treatment of zoledronic acid is reduced (but not deleted) by the implementation of preventive measures.

Renal Impairment in Patients With Multiple Myeloma: A Consensus Statement on Behalf of the International Myeloma Working Group

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.

International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma

Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/beta(0)-thal, and 165 with HbS/beta(+)-thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P = .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/HbS, HbS/beta (0)-thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients.

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid

For patients with bone metastases, high N‐telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal‐related events and death. However, the relation between NTX decreases and clinical benefits is unclear.

Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN)

Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients with MM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.

Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506).

International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

PURPOSE The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. METHODOLOGY An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. RECOMMENDATIONS Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone

Background and Objectives High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis. Design and Methods Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD. Results Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients. Interpretation and Conclusions The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment.