Comparison Among Immunologically Different Subtypes of 595 Untreated Multiple Myeloma Patients in Northern China

BackgroundGenerally, characteristics of heterogeneous multiple myeloma (MM) have been described as a whole. Actually, isolated immunologic subtypes of MM may be associated with prognostic significance.Patients and MethodsThe aim of this retrospective single-center study was to determine the characteristics of immunologically different subtypes among 595 evaluable cases with previously untreated MM in northern China.ResultsThe major distribution of MM subtypes were immunoglobulin (Ig)G, 47.9%; IgA, 23.3%; and light-chain, 21.0%. Nonsecretory, IgD, and biclonal subtypes were rarely seen, comprising only 7.7%. The male-to-female ratio was 1:7, and the median age was 59 years. In the IgG subtype, more patients presented with elevated M protein, fulfilling the major diagnostic criteria determined by Durie, and infection occurred more frequently; however, the prognosis was favorable. In the IgA subtype, in which survival was significantly poorer, the extent of anemia was more severe, and nonhyperdiploid abnormality may be its adverse indicator. In the light-chain subtype, the mean level of serum IL-6 was the highest, and more patients presented with advanced renal dysfunction, bone destruction, and thrombocytopenia. However, more light-chain patients were staged at International Staging System I, partially resulting in the favorable median survival of 51 months (almost equivalent to 50 months with the IgG subtype). Another rare subtype with unfavorable outcome was IgD myeloma, in which the median age was 50 years, and the serum calcium level was significantly decreased. Intriguingly, we also noted that more patients presented hypocalcemia than hypercalcemia (37.7% vs. 15.7%) in the current series. Multivariate analysis revealed that independent adverse indicators included age > 50 years, Durie-Salmon stage III, and increased values of C-reactive protein and β²-microglobulin.ConclusionThe median duration of survival in MM reached 36.0 months. Distinctions among immunologically different subtypes can predict prognostic significance, namely, favorable in IgG and light-chain subtypes but significantly poorer in IgA and IgD subtypes.     

Incorporating Novel Agents in the Management of Elderly Myeloma Patients

In recent years, the treatment of multiple myeloma has undergone significant changes. The availability of novel agents bortezomib, thalidomide and lenalidomide considerably improved the outcome of patients. The advantages related to the use of novel agents have been shown in various studies in patients eligible and ineligible for transplant. In elderly patients, novel agents have also revolutionized the treatment paradigm and have replaced the traditional melphalan-prednisone regimen. A sequential approach consisting of an induction regimen associated with a high rate of complete response, followed by consolidation/maintenance therapy, induces a profound cytoreduction and delays relapse, thus improving survival. Patients older than 75 years or who are otherwise vulnerable are more susceptible to adverse events. In this setting, less toxic regimens and appropriate dose-reductions should be adopted. This article provides an overview of the main trials for transplant-ineligible multiple myeloma patients. Recommendations on how to manage unfit patients and treatment-related toxicities are also provided.     

Representation of Minorities and Elderly Patients in Multiple Myeloma Clinical Trials

Multiple myeloma (MM) occurs in all races, but the incidence in non‐Hispanic black patients (NHBs) is two to three times higher than in non‐Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p < .0001) and Hispanic patients (EF 0.04%, p < .0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients.     

Lenalidomide Plus Melphalan Without Prednisone for Previously Untreated Older Patients With Multiple Myeloma: A Phase II Trial

BackgroundWe conducted a phase II trial that evaluated the tolerability and efficacy of combining lenalidomide with melphalan in previously untreated patients with multiple myeloma who were not candidates for autologous stem cell transplantation.MethodsAfter a run-in phase of 6 patients, we planned to conduct a randomized phase II selection-design trial that assessed 2 dose levels of lenalidomide, given days 1 to 21, combined with melphalan, given days 1 to 4, and every 28 days. Planned doses of melphalan were 9 mg/m²/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). Coprimary endpoints were the frequency of dose-limiting Planned doses of melphalan were 9 mg/m²/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). toxicities (DLT) and complete response (CR).ResultsFour patients received M9L10; all experienced DLTs, which resulted in closure of this cohort. When using the same schedule, we then sequentially tested M6L10 (melphalan 6 mg/m² on days 1 to 4 and lenalidomide 10 mg/d on days 1 to 21 every 28 days) (6 patients), M4L15 (melphalan 4 mg/m² on days 1 to 4 and lenalidomide 15 mg/d on days 1 to 21 every 28 days) (6 patients), and M5L10 (melphalan 5 mg/m² days 1 to 4 and lenalidomide 10 mg/d days 1 to 21 every 28 days) (34 patients). In each cohort, the DLT endpoint was reached because of severe and prolonged hematologic toxicity. At the final dose level, M5L10, 20 of 27 patients experienced DLTs within their first 3 cycles; among 10 patients who received at least 6 cycles, none achieved a CR.ConclusionsCombining lenalidomide plus melphalan without prednisone is associated with substantial hematologic toxicity that precludes cyclical administration of adequate drug doses.     

Clinical Outcomes Associated With Chronic Kidney Disease in Elderly Medicare Patients With Multiple Myeloma

BackgroundChronic kidney disease (CKD) is common in patients with multiple myeloma (MM) and is associated with a poor prognosis. We assessed CKD-associated clinical outcomes among elderly patients with MM initiating chemotherapy in the United States.Materials and MethodsWe identified elderly Medicare beneficiaries (≥66 years) diagnosed with MM who initiated first-line therapy from 2008 to 2014. We identified CKD using diagnosis codes. We followed patients for death, time to next treatment (TTNT), and myeloma-defining events (anemia, hypercalcemia, skeletal-related events, progression to/of CKD) until September 30, 2015. We estimated overall survival, TTNT, and cumulative incidence of myeloma-defining events using the Kaplan-Meier method and risk of CKD-associated outcomes using Cox proportional hazards models, adjusting for demographics and comorbid conditions.ResultsOf 22,484 included patients, 8704 (39%) had CKD at first-line therapy initiation. Compared with patients without CKD, patients with CKD had shorter median overall survival (2.1 vs. 3.6 years) and median TTNT (10.0 vs. 12.4, 9.7 vs. 11.2, 8.3 vs. 9.2, and 6.9 vs. 8.3 months at first- to fourth-line therapy). Probability of CKD progression for patients at stages 1 to 5 was higher than the probability of developing CKD for patients without CKD (3-year cumulative incidence [95% confidence interval, CI], 47% [45-48%] vs. 27% [24-26%]). Adjusted hazard ratios for CKD versus non-CKD were: all-cause death, 1.23 (95% CI, 1.18-1.28); anemia, 1.34 (95% CI, 1.24-1.45); hypercalcemia, 1.23 (95% CI, 1.09-1.38); skeletal-related events, 0.85 (95% CI, 0.90-0.91); and TTNT, from 1.03 (95% CI, 0.96-1.10) at third-line therapy to 1.15 (95% CI, 1.04-1.27) at fourth-line therapy.ConclusionData from the study suggest that CKD-associated clinical burden is substantial in elderly patients with MM.     

Special Considerations for Supportive Care and Management of Complications in Elderly Patients With Multiple Myeloma

Multiple myeloma is a progressive and incurable hematologic malignancy. It is predominantly a disease of older individuals, with a third of these patients considered to be elderly. In recent years, there has been a focus and emphasis on identifying and stratifying patients based on their functional status and frailty. There are several hallmark complications of the disease—hypercalcemia, renal insufficiency, anemia, bone pain—along with thromboembolism and compromised immunity that are common in patients with multiple myeloma. Due to the wide range of patient ages and functional status, there are, accordingly, different considerations for management of the above complications based on numerous factors, including frailty status. This review focuses on considerations and management of common complications of multiple myeloma in elderly patients. These include renal failure, skeletal complications, anemia, thromboembolism, and infectious complications.     

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia

BackgroundMidostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.Patients and MethodsPrimary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m² on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle.ResultsTwenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3.ConclusionMultiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.     

Hemostatic Abnormalities in Multiple Myeloma Patients

Background: Multiple myeloma (MM) is a neoplastic plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow. Diverse hemostatic abnormalities have been reported in patients with myeloma which predispose to bleeding and also thrombosis. Methods: Complete blood count, biochemical parameters and parameters of hemostasis i.e. platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), factor VIII assay results, plasma fibrinogen, D-dimer and lupus anticoagulant, were assessed in 29 MM patients and 30 age matched controls. Results: The most frequent abnormal screening parameter was APTT. Of the six indicative of a bleeding tendency i.e. thrombocytopenia, prolonged PT, APTT, TT, reduced plasma fibrinogen and factor VIII, at least one was abnormal in 8 (27.6%) patients. Of the four prothrombotic markers, lupus anticoagulant, D-dimer, elevated factor VIII and plasma fibrinogen, one or more marker was present in 24 (82.7%). D-dimer was the most common prothrombotic marker, being elevated in 22 (75.9%) patients. One or more laboratory parameter of hemostasis was abnormal in all 29 (100%) patients. Though thrombotic complications are reported to be less frequent as compared to hemorrhagic manifestations, one or more marker of thrombosis was present in 24 (82.7%) patients. Conclusion: This study provided laboratory evidence of hemostatic dysfunction which may be associated with thrombotic or bleeding complications at diagnosis in all MM patients. Hence, screening for these abnormalities at the time of diagnosis should help improved prognosis in such cases.     

沙立度胺联合地塞米松治疗初发多发性骨髓瘤25例

目的观察沙立度胺联合地塞米松方案治疗多发性骨髓瘤的疗效及其不良反应。方法沙立度胺,口服,起始剂量每天50mg,50mg每晚顿服,根据患者耐受情况每周增加剂量50mg/d,直到最大剂量达到400mg/d。地塞米松40mg/d,第1～4日,第9～12日,第17～20日分别静脉或口服给药,每28日为1个疗程。该方案治疗至少3个月。结果完全缓解4例(16%),部分缓解6例(24%),进展10例(40%),无效5例(20%),总有效率80%。常见的不良反应为便秘、嗜睡、疲乏、水肿、指端麻木等。结论沙立度胺联合地塞米松是初治多发性骨髓瘤有效的治疗方案,不良反应少。     

Deep Sequencing Reveals Myeloma Cells in Peripheral Blood in Majority of Multiple Myeloma Patients

IntroductionThe evaluation of myeloma cells in multiple myeloma (MM) patients has generally been limited to the assessment of bone marrow involvement because of the sensitivity limitations of traditional minimal-residual-disease–detection methods.Materials and MethodsWe developed a sequencing-based method to identify myeloma cells in bone marrow (BM) and peripheral blood (PB) samples, based on their unique immunoglobulin gene rearrangements, that can detect cancer clones at levels well below 1 in 1 million leukocytes (0.0001%). In this multisite study, we used this sequencing method to determine the fraction of patients with myeloma cells in their PB at diagnosis and posttreatment time points.ResultsUsing this sequencing approach, we detected myeloma cells in the PB in the vast majority of MM patients (44/46, 96%). We demonstrated a clear correlation (R² = 0.57) between myeloma clone levels in paired BM and PB samples, and noted that PB clone levels were approximately 100-fold lower than levels in BM samples. The sequencing assay demonstrated a clear sensitivity advantage in the BM compartment and at least equivalent sensitivity in the PB compared with that of monoclonal-protein results.ConclusionThis study highlights the promise of a blood-based, sequencing minimal-residual-disease assay that can be used to measure MM disease burden at different time points and various disease stages.     

Clinical Study of Thalidomide Combined with Dexamethasone for the Treatment of Elderly Patients with Newly Diagnosed Multiple Myeloma

Objective: To investigate the relationship between the efficacy and safety of different doses of thalidomide(Thal) plus dexamethasone (Dex) as the initial therapy in elderly patients with newly diagnosed multiplemyeloma (MM). Methods: Clinical data of 28 elderly patients with newly diagnosed MM who underwent theTD regimen as the initial therapy were analyzed retrospectively. The patients were divided into two groupsaccording to the maximal sustained dose of Thal: lower dose (group A) and higher dose (group B). The overallresponse rate (ORR), progression free survival (PFS), overall survival (OS), and adverse events (AES) werecompared between the two groups. Results: A total of 28 patients were followed up with a median of 18 months.The ORR was 60.1%. The median response time and PFS were 2.0 and 17.0 months, respectively. The meansustained dose of Thal in group B was significantly higher than group A (292.9 mg v 180.4 mg, P=0.01). Therewas no significantly difference in ORR (57.1% v 64.3%, P=1.00) and PFS (9.63months v 17.66 months, P=0.73)between groups A and B. During the follow up, only five patients died (<40%) and, therefore, median OS valueswere not available. It is estimated, however, that the mean survival time in the two groups was 35.6 and 33.4months (P>0.05), respectively. All of the patients tolerated the treatment well. The incidence of AES in patientswith a grading above 3 in group B was significantly higher than in group A (P=0.033). Conclusions: The TDregimen results in a high response rate and manageable AES as the initial therapy in elderly patients with MM.TD should be considered as the front line regimen for the treatment of elderly patients with MM in areas withfinancial constraints. The clinical response can be achieved at a low dose Thal with minimal toxicity.