Martina Kleber

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

European myeloma network guidelines for the management of multiple myeloma-related complications

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6–8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).

Chemotherapy safety and severe adverse events in cancer patients: strategies to efficiently avoid chemotherapy errors in in- and outpatient treatment.

To enhance the quality and safety in cancer treatment, and in acknowledgement that medical errors occur, we have established 2 error management systems: one monitors chemotherapy errors, the other records all severe adverse events occurring in chemotherapy‐treated cancer patients (SAECTx) in in‐ and outpatient treatment. These error systems have been implemented by our departmental “Clinical Service Center,” a multidisciplinary team which controls all chemotherapy protocols and orders prior to the medication reaching the patient. We performed a prospective cohort study in consecutive cancer patients who received chemotherapies in our department between January 2005 and December 2006. Over this 2‐year period, 2,337 patients were treated, with an equal distribution as in‐ and outpatients: 22,216 consecutive chemotherapy orders were analyzed, of which 83.5% were completely flawless, whereas we detected and corrected medical and administrative errors in 17.1%: in 3.8%, these errors involved the chemotherapy itself, in 4.5% the patient data and in 8.7% missing written informed consent forms. Chemotherapy errors were less frequent in outpatients than inpatients (3.3 vs. 4.5%, respectively). In outpatients, the rate of chemotherapy errors decreased from 4% in 2005 to 2.8% in 2006, but remained stable for inpatients (4.4% 2005 vs. 4.7% 2006). Among a total of 3,792 detected errors, only 3 reached the patient, resulting in an error rate in patients of 0.079%. Therefore, since we detected a substantial number of chemotherapy‐related errors and intercepted 99.9%, we recommend our efficient surveillance system as an important safety check, thereby ensuring that chemotherapies are delivered error‐free to cancer patients.

Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM-comorbidity score.

Comorbidities have been demonstrated to affect progression-free survival (PFS) and overall survival (OS), although their impact in multiple myeloma (MM) patients is as yet unsettled. We (1) assessed various comorbidities, (2) compared established comorbidity indices (CIs; Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), Kaplan Feinstein (KF) and Satariano index (SI) and (3) developed a MM-CI (Freiburger comorbidity index, FCI) in 127 MM patients. Univariate analysis determined moderate or severe pulmonary disease (hazard ratio (HR): 3.5, P<0.0001), renal impairment (via estimated glomerular filtration rate (eGFR); HR: 3.4, P=0.0018), decreased Karnofsky Performance Status (KPS, HR: 2.7, P=0.0004) and age (HR: 2, P=0.0114) as most important variables for diminished OS. Through multivariate analysis, the eGFR ⩽30 ml/min/1.73m2, impaired lung function and KPS ⩽70% were significant for decreased OS, with HRs of 2.9, 2.8 and 2.2, respectively. Combination of these risk factors within the FCI identified significantly different median OS rates of 118, 53 and 25 months with 0, 1 and 2 or 3 risk factors, respectively, (P<0.005). In light of our study, comorbidities are critical prognostic determinants for diminished PFS and OS. Moreover, comorbidity scores are important treatment decision tools and will be valuable to implement into future analyses and clinical trials in MM.

Detection of renal impairment as one specific comorbidity factor in multiple myeloma: multicenter study in 198 consecutive patients

Objectives:  Comorbidity factors have been reported in cancer patients to predict progression free survival (PFS) and overall survival (OS). Renal impairment (RI) is postulated as one negative prognostic factor in multiple myeloma (MM). The study aim was to detect the best way to define RI and the impact of different RI stages on MM outcome.

The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network

Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström’s macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance.

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches

Treatment for multiple myeloma (MM) has changed beyond recognition over the past two decades. During the early 1980s, MM inevitably resulted in a slow progressive decline in quality of life until death after about 2 years, while today patients can expect a 50% chance of achieving a complete remission, median survival of 5 years, and a 20% chance of surviving longer than 10 years. An international expert opinion meeting (including members of the GIMEMA and DSMM study groups) was held in 2009. One of the outcomes of the meeting was the development of a consensus statement outlining contemporary optimal clinical practice for the treatment of MM. The international panel recommended that the state of the art therapy for MM should comprise: (a) evidence-based supportive care, (b) effective and well-tolerated chemotherapeutic regimens, (c) autologous hematopoietic stem cell transplant (ASCT) for patients suitable for intensive conditioning therapy, and (d) evidence-based incorporation of novel anti-MM agents. Maintenance strategies have also become increasingly important for the prolongation of remission after front-line therapies. In addition, improved understanding of the biology of MM has led to the development of novel biological therapeutic agents such as thalidomide, lenalidomide, bortezomib, and others. These agents specifically target intracellular mechanisms and interactions, such as those within the bone marrow microenvironment, and have been integrated into MM treatment. This report reviews recent clinical advances in the treatment strategies available for MM and provides an overview of the state of the art management of patients with MM.

Conditional Survival: A Useful Concept to Provide Information on How Prognosis Evolves over Time

Conditional survival (CS) is defined as the probability of surviving further t years, given that a patient has already survived s years after the diagnosis of a chronic disease. It is the simplest form of a dynamic prediction in which other events in the course of the disease or biomarker values measured up to time s can be incorporated. CS has attracted attention in recent years either in an absolute or relative form where the latter is based on a comparison with an age-adjusted normal population being highly relevant from a public health perspective. In its absolute form, CS constitutes the quantity of major interest in a clinical context. Given a clinical cohort of patients with a particular type of cancer, absolute CS can be estimated by conditional Kaplan–Meier estimates in strata defined, for example, by age and disease stage or by a conditional version of the Cox and other regression models for time-to-event data. CS can be displayed as a function of the prediction time s in parametric as well as nonparametric fashion. We illustrate the use of absolute CS in a large clinical cohort of patients with multiple myeloma. For investigating CS, it is necessary to ensure almost complete long-term follow-up of the patients enrolled in the clinical cohort and to consider potential age–stage migration as well as changing treatment modalities over time. CS provides valuable and relevant information on how prognosis develops over time. It also serves as a starting point for identifying factors related to long-term survival. Clin Cancer Res; 21(7); 1530–6. ©2015 AACR.

Prognostic Risk Factor Evaluation in Patients With Relapsed or Refractory Multiple Myeloma Receiving Lenalidomide Treatment: Analysis of Renal Function by eGFR and of Additional Comorbidities by Comorbidity Appraisal

INTRODUCTION Renal impairment (RI) is a dreaded complication in multiple myeloma (MM) and has been associated with decreased progression-free survival (PFS) and overall survival (OS). METHODS Forty-five consecutive patients with MM received lenalidomide therapy combined with either dexamethasone or standard chemotherapy, with dose modification according to current guidelines. Comorbidity indices (hematopoietic cell transplantation-specific comorbidity index [HCT-CI], Kaplan Feinstein [KF], and the Freiburg comorbidity index [FCI]) were analyzed and renal function was determined by estimated glomerular filtration rate (eGFR) before lenalidomide treatment and 1, 3, and 6 months after treatment. RESULTS The median patient age was 66 years. Pretreatment was substantial with ≥ 2 treatment lines in 71% of patients. Lenalidomide induced median PFS and OS of 13 and 25 months, respectively. The analysis of comorbidity scores identified only the FCI as significant, with different PFS for low-risk vs. high-risk patients of 20 vs. 9 months (p = .0036) and OS of not reached vs. 12.8 months (p < .0001), respectively. Although baseline renal function by serum creatinine evaluation appeared normal (median 1.0 mg/dL), mild RI was readily detectable by eGFR (median 83 mL/min/1.73 m(2)). When patients without RI were compared with those with mild, moderate, and severe RI, 1- and 2-year PFS rates were similar (hazard ratio [HR] with decreasing eGFR, 1.028; p = .6927). For OS, the HR of 1.192 indicated decreased survival probabilities with deteriorating eGFR (p = .0411), which was perceived by eGFR but not serum creatinine assessment (p = .2253). CONCLUSIONS Lenalidomide was well tolerated in intensively pretreated and elderly MM patients, including those with RI. PFS was not significantly different in patients with decreasing eGFRs, albeit RI and other comorbidities remained significant for OS.

Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years

Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P<0.05). Cumulative incidence rates for myeloma death were increased with higher stage and age, but decreased in IgG-subtypes and due to anti-myeloma treatment (P<0.05). Cytogenetics in patients acquiring second primary malignancies were predominantly favorable, suggesting that indolent myeloma and long disease latency may allow the manifestation of additional malignancies. An assessment of the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute and our data with long-term follow up of 25 years confirmed a prevalence of second malignancy of 10% at 25 years, whereas death from myeloma decreased from 90% to 83%, respectively. Our important findings widen our knowledge of second malignancies and show that they are of increasing relevance as the prognosis in myeloma improves and mortality rates decrease.