Multiple myeloma in elderly patients: prognostic factors and outcome

Abstract:  Objectives : Purpose of this study was to compare prognostic factors and outcome of patients with multiple myeloma (MM) aged >70 yr at diagnosis with those of younger patients. We also applied the recently proposed International Staging System (ISS) for MM in these patients. Patients and methods : Among 1,162 newly diagnosed, symptomatic MM patients included in our database, 357 (31%) were >70 yr of age. Clinical and laboratory variables were evaluated in patients >70 yr and in younger patients and were assessed for possible correlation with survival in patients >70 yr of age. Results : Most clinical and laboratory features were similar in the two groups of patients but older patients presented more frequently with advanced ISS ( P  = 0.02). Despite similar response rates to primary treatment, younger patients survived longer than patients >70 yr of age (40 vs. 28 months, P  = 0.001). There was a longer survival of younger patients than that of older patients diagnosed with ISS stage 1 (median 71 vs. 54 months, P  = 0.007) and ISS stage-2 patients (median: 38 vs. 26 months, P  = 0.0008) but for patients with ISS stage 3 median survival was similarly poor in the younger and older age group (21 and 20 months, P  = 0.283). Other variables associated with impaired prognosis were severe anemia, extensive bone marrow plasmacytosis and elevated serum LDH. Conclusions : Older patients with MM present more often with advanced ISS and have significantly shorter survival than younger patients. The ISS retained its prognostic significance within the group of elderly patients.     

Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases

Summary. From January 1982 to December 1993, 30 patients with multiple myeloma (MM) required haemodialysis (HD) at our institution. The subgroup of 20 patients who survived more than 2 months on HD is the subject of this study. Four patients were already on HD, due to previous nephropathy, when MM was diagnosed. 13 patients presented with acute renal failure and were on dialysis from the time of diagnosis. The remaining three cases developed renal failure later in the course of the disease. The objective response rate was 40% (8/20). Only two patients could discontinue HD (one had a late partial recovery and one received a kidney graft). Mean hospitalization per year was 19.3 d. The subgroup of patients who survived < 1 year spent a mean of 38.3 d in hospital. Whereas in the subgroup with a survival > 1 year mean hospitalization days was 9.6 (P < 0.001). The median survival was 20 months and six patients survived for > 3 years. In summary, patients with MM and severe renal failure who survive the first 2 months on dialysis have an objective response rate to chemotherapy of 40% and a median survival of almost 2 years, with 30% long-term survivors.     

Multiple myeloma: clinical features and indications for therapy

Multiple myeloma is a malignant plasma-cell proliferative disease with an expected 15,270 new cases and 11,070 deaths in the USA in 2004 alone. This accounts for 1% of all malignancies and slightly more than 10% of all hematologic malignancies in Caucasians and 20% in African Americans. The diagnosis is based on the presence of bone pain, anemia, and plasma-cell infiltrate in the bone marrow or within bone lesions. It is essential that the spectrum of plasma-cell proliferative disorders be recognized: monoclonal gammopathy of undetermined significance (MGUS), smoldering (asymptomatic) multiple myeloma (SMM), and active (symptomatic) MM. These distinctions affect important management decisions. Other related disorders include primary systemic amyloidosis, POEMS syndrome, and acquired Fanconi syndrome.     

Impact of response to treatment on survival in multiple myeloma: results in a series of 243 patients

Summary. Two hundred and forty-three patients diagnosed with multiple myeloma (MM) in a single institution over a 22-year period and treated with standard chemotherapy were analysed in an attempt to determine the impact of response to therapy on survival. The overall response rate in 229 evaluable patients was 50.1% (34.9% objective response plus 15.2% partial response). Median survivals of patients with objective and partial response were 43.4 and 42.8 months, respectively, versus 19 months for nonresponders. Median survival of 14 patients who achieved a complete remission was 42 months, whereas in 21 rapid responders (≤ 2 months) median survival was 43.3 months. A significant correlation between response and survival was observed with the landmark (P = 0.0169), the Mantel & Byar (P = 0.0001) and the Cox regression model (P < 0.0001) methods. These results indicate that, in responding patients, neither the degree of response nor the response kinetics has a significant influence on survival. However, the response to therapy is associated with a significantly longer survival in MM patients.     

多发性骨髓瘤并发髓外浸润的临床分析

目的:了解多发性骨髓瘤(MM)髓外浸润的发生率及临床特点.方法:回顾分析357例MM患者中并发髓外浸润患者的临床表现、实验室检查、疗效及预后.结果:共有43例患者在初诊或治疗过程中出现髓外浸润,发生率为12.04%.Logistic回归分析,发现仅M蛋白类型与是否浸润相关(P<0.05).最常见的发病部位为软组织(19...     

Presenting Features and Prognosis in 72 Patients With Multiple Myeloma Who Were Younger Than 40 Years

The purpose of this study was to analyse the presenting clinical and laboratory features and the outcome of 72 patients with multiple myeloma (MM) who were younger than 40 years. The records of all Mayo Clinic patients with MM younger than 40 years who were seen between 1 January 1956 and 31 December 1992 were reviewed. Survival was measured from the date when treatment was required to the date of last follow-up or death. The frequency of MM in patients younger than 40 and 30 years in 3278 Mayo Clinic patients was 2.2% and 0.3%, respectively. The main presenting clinical features were bone pain (66%), fatigue (26%), extramedullary plasmacytomas (19%) and bacterial infection (11%). Renal function impairment (creatinine level ≥ 177 μmol/l) and hypercalcaemia (serum calcium value ≥2.75 mmol/l) occurred in 29% and 30% of patients, respectively. Among the 57 patients evaluable for response the objective response rate was 54%. 14/35 patients treated with a single alkylating agent achieved an objective response, whereas 17/22 patients given combination chemotherapy had an objective response ( P  = 0.013). However, this higher response rate did not result in a significantly longer survival. The median survival for the 72 patients was 54 months. Patients with good prognostic features (normal renal function or low β₂-microglobulin level) had a median survival of 8 years. The actuarial survival at 5 and 10 years after initiation of therapy was 43% and 13%, respectively. In summary, survival in very young patients with myeloma is longer than that observed in series of patients of all ages, especially in those with good prognostic factors.     

Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma

High‐dose chemotherapy with melphalan followed by autologous haematopoietic cell transplantation (AHCT) is a standard of care in young patients (<65 years) with multiple myeloma. Most myeloma patients, however, are older than 65 years at the time of diagnosis, and the findings of numerous single‐centre and registry studies provide evidence that AHCT can be a feasible and effective treatment option in these patients. Nevertheless, AHCT is not generally recommended as standard treatment in the elderly, due to the fact that a benefit of AHCT over conventional‐dose therapy has not been demonstrated by prospective randomized trials. Yet, the use of AHCT has increased substantially in older patients in recent years, and an increasing number of reports suggest comparable outcomes for older and younger patients after AHCT. In this review we summarize the results of AHCT for elderly patients with multiple myeloma.     

Treatment of patients with multiple myeloma who are not eligible for stem cell transplantation: position statement of the myeloma foundation of Australia Medical and Scientific Advisory Group

Options for treatment of elderly patients with multiple myeloma have expanded substantially following the development of immunomodulatory drugs (IMiD), proteasome inhibitors and with enhancement in safety of high‐dose therapy and autologous stem cell transplant (HDT + ASCT). The recognition of biological heterogeneity among elderly patients has made delivery of therapy more challenging. An individualised approach to treatment selection is recommended in an era in which highly efficacious treatment options are available for transplant‐ineligible patients. Here, we summarise recommendations for patients who are considered unsuitable for HDT + ASCT, including pretreatment considerations, and induction, maintenance and supportive care therapies.     

Multiple myeloma presenting with musculoskeletal manifestations: a case report

Multiple myeloma (MM) is a malignant plasma cell disorder. Musculoskeletal and skin manifestations of this disorder are rare. Here we report a case of a young male patient presenting with polyarthritis and skin rash resembling vasculitis. Detailed investigations revealed that he was suffering from multiple myeloma in which arthritis was a musculoskeletal complication of the disease.     

Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma

Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age > or =65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated substantial clinical activity in these patients. Response rate (34-40% vs. 13-19%), including complete response rate (5-8% vs. 0-1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-treated patients aged > or =65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed multiple myeloma.     

Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1

In comparison to total therapy 1 (TT1), the phase 3 trial total therapy 2 (TT2) evaluated the benefit of up-front administration of thalidomide (THAL); TT2 also introduced post-transplant consolidation chemotherapy. With median follow-up times of 5 and 12 years, respectively, outcome comparisons were made of 668 patient's enrolled on TT2 and 231 patients treated on TT1. Complete response (CR) rates were similar at 40% for TT1 and TT2 without THAL versus 60% on the THAL arm of TT2. CR durations were similar with either TT2 arm and both were superior to results of TT1. Event-free and overall survivals were extended from 2.6 to 5.7 years, respectively, with TT1 to 4.8 and 8.0 years with TT2. TT2's major advance vis-à-vis TT1 pertained to the subgroup without cytogenetic abnormalities (CA), supporting the role of post-transplant consolidation therapy, whereas the improved survival of the CA subgroup on the experimental versus control arm of TT2 attests to the role of THAL in this setting. Adjusting for prognostic variables in multivariate and pair-mate analyses, TT2 was superior to TT1 in terms of CR duration, event-free and overall survival. These results provide a basis for the prospective evaluation of the consolidation strategy in a randomized clinical trial design.     

Clinicopathological features of extramedullary recurrence/relapse of multiple myeloma

Extramedullary relapses of multiple myeloma (MM) during the course of disease are rare. We report a series of six patients with primary intramedullary MM that were treated with immunomodulatory therapy and/or stem cell transplant, and that later developed extramedullary relapses at various body sites. These six cases represent 3.9% of the 156 patients treated for MM at our institution over a 9-yr period (1999-2007). Five (83.3%) of the six cases showed immature/high-grade histology in the extramedullary relapses as compared with their antecedent MM. The neural cell adhesion molecule, CD56, was immunohistochemically demonstrable in 75% (three of four) of the original myelomas tested, but was absent in 83.3% (five of six) of their extramedullary relapses. The disease typically behaved aggressively and was rapidly fatal in all six patients even when therapy was administered. The median time of progression to extramedullary relapse was 29 months (range 9-64 months), and the median survival after diagnosis of the relapses was only 38 d (range 1-106 d). Our case series shows that extramedullary relapse of MM is characterized by high-grade histology, loss of CD56 expression, frequent resistance to current therapeutic regimens, aggressive biological behavior, and very short survival.     

Continuous prednisolone versus conventional prednisolone with VMCP-interferon-alpha2b as first-line chemotherapy in elderly patients with multiple myeloma

We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-alpha 2b (IFN-alpha 2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-alpha 2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P=0.81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.74-1.33, P=0.97] and overall survival (median: 34 months vs. 37 months; HR: 1.16, 95% CI: 0.85-1.59, P=0.35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high beta2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-alpha 2b did not improve outcome.     

Autologous stem cell transplantation in multiple myeloma: outcome in patients with renal failure

The impact of renal failure on prognosis of multiple myeloma patients treated with high-dose chemotherapy and stem cell support is incompletely studied. A total of 137 patients received high-dose chemotherapy with autologous transplantation at our centre. The patient population was divided into three groups based on their estimated creatinine clearance (Ccr); renal failure defined as Ccr < 60 mL/min: Group A: normal renal function both at diagnosis and at transplant (n = 78), Group B: renal failure at diagnosis but normal renal function at transplant (n = 30), Group C: renal failure both at diagnosis and at transplant (n = 29). There were no differences in the number of stem cells harvested, time to engraftment or response to transplantation between the groups. Ten of the patients in Group C had a normalisation of renal function post-transplant. Significantly longer hospitalisation, increased use of blood products and increased number of infections were seen in Group C compared to Groups A and B. The transplant-related mortality was 17% in Group C compared to 0% and 1% in Groups B and A respectively. Eight patients were on dialysis during transplant and four of these died within the first 100 d post-transplant. Disease response was similar in the three groups. Overall survival was significantly longer in Group A than in Groups B and C. High-dose chemotherapy with autologous transplantation is feasible in MM with renal failure. Whereas patients with moderate renal insufficiency seem to benefit from this treatment, patients in need for dialysis at the time of transplant must be carefully evaluated before proceeding to high-dose chemotherapy.     

Prognostic features of multiple myeloma

The outcome of myeloma patients is highly heterogeneous, with survival ranging from a few months to more than 10 years. Accordingly, investigation of prognostic factors may contribute to identification of risk categories and to provision of more accurate information about individual disease outcome. For many years prognostic factors have relied on clinical parameters such as age, hemoglobin level and renal function. Subsequently, biological parameters such as the proliferative activity of plasma cells and beta2-microglobulin have been added to the prognostic arsenal. More recently, cytogenetic and molecular markers with significant influence on disease outcome have been identified. Here we will review the most relevant prognostic factors reported in the literature in patients treated with both conventional chemotherapy and high-dose therapy followed by autologous stem-cell support, as well as in asymptomatic MM and MGUS patients.