Treatment and disease-related complications in multiple myeloma: Implications for survivorship

New treatments have transformed multiple myeloma into a chronic disease. Hence, optimal management of treatment and disease-related complications remains a critical component of survivorship care. Survivorship care model in cancers requiring a fixed-duration therapy may not be applicable to myeloma, since patients are exposed to multiple lines of continuous therapy along the disease trajectory. The two most common therapy-related causes of death, which require special consideration, are infection and second cancers. Identifying patients at a high risk of toxicities will facilitate individualized treatment selection and designing clinical trials for protective strategies targeting those patients. For example, prophylactic antibiotic or immunoglobulin replacement can be tested for primary prevention of infections in high-risk patients. Long-term follow up of ongoing trials and epidemiologic data will help identify the nature and trajectory of rare toxicities with a long latency, such as secondary cancers. Patients who are frail, have persistent renal insufficiency, and refractory to multiple lines of therapy need special attention regarding treatment toxicity and quality of life. In this review, we discuss the incidence, risk-factors, and management of treatment and disease-related complications in myeloma, discuss knowledge gaps and research priorities in this area, and propose a survivorship care model to improve health-care delivery to a growing pool of myeloma survivors.     

Therapy-related myeloid neoplasms after treatment for plasma-cell disorders

Therapy-related myeloid neoplasms (t-MN), including therapy-related acute myeloid leukaemia and myelodysplastic syndrome, are second primary malignancies (SPM) that are of growing importance as patients with plasma cell disorders (PCD) such as multiple myeloma (MM) are living longer with more effective therapies. Both patient-specific and treatment-specific factors likely impact the risk of t-MN development after diagnosis and treatment of PCD. Alkylating chemotherapy, especially melphalan, has been strongly tied to the risk of t-MN. More recently, there has been a shift away from long-term alkylating therapies to immunomodulatory agents and high-dose therapy with autologous stem cell transplant (HD-ASCT). This shift has led to improved survival and long-term outcomes for most MM patients. However, the risks of t-MN remain despite the improved efficacy of these treatments, and patients who develop t-MN have a poor prognosis. Understanding the risk factors predisposing MM patients to t-MN can thus help to tailor individualized therapy to maximize anti-myeloma efficacy and minimize the risks of t-MN.     

Cure of multiple myeloma -- more hype, less reality

Randomized studies have firmly established the role of autologous transplant as initial therapy in multiple myeloma (MM). Indeed, MM has emerged as the commonest indication for autologous SCT in North America. The conceptual basis for high-dose therapy is the goal of complete remission (CR) through steep reduction in tumor burden affected by single and tandem transplants. Careful analysis of the data challenges the notion of CR as a surrogate to success. Intrinsically aggressive MM, defined by known unfavorable biologic risk factors, overrides the benefit of CR. In contrast, subgroups of patients with favorable biological risk factors may achieve prolonged survival, often without ever achieving CR. Unfortunately, even with tandem transplants, there is no plateau in survival curves. To this end, sequential autologous followed by nonmyeloablative allotransplants are a novel attempt at 'curing' myeloma, but the results thus far have failed to show a definite plateau in survival. Given the improvements in supportive care and concomitant reduction in transplant-related mortality, conventional myeloablative allogeneic transplants need to be re-examined as an option in high-risk aggressive myeloma. At the same time, novel antimyeloma therapies, newer risk stratification and staging tools are transforming the treatment algorithm. We examine the changing role of transplantation in myeloma in the context of novel drug therapy, biologic risk stratification and improving supportive care while arguing that the current 'one size fits all' transplant approaches are far from a cure.     

Severe autologous GVHD after hematopoietic progenitor cell transplantation for multiple myeloma

GVHD is a recognized complication of autologous hematopoietic progenitor cell transplantation (HPCT), but has typically been reported to respond well to primary therapy with corticosteroids. In this study, we report the development of severe autologous GVHD in five patients who underwent HPCT for multiple myeloma. In all cases, response to corticosteroids was unsatisfactory and three of these patients ultimately died from complications that ensued from prolonged immunosuppressive therapy. Severe autologous GVHD occurred only in patients transplanted for multiple myeloma and was observed at a much higher frequency in patients undergoing their second HPCT. The severity of this syndrome primarily in patients undergoing second HPCTs suggests that repetitive exposure to high-dose therapy may compromise endogenous peripheral regulatory mechanisms and predispose these patients to autoimmunity. Given the evolving role of second autologous transplantations in the therapeutic armamentarium for multiple myeloma, consideration of this potential toxicity may be appropriate when considering treatment options for these patients.     

Second malignancies after multiple myeloma: from 1960s to 2010s

Based on small numbers, recent reports from 3 randomized trials have consistently demonstrated more hematologic malignancies in patients treated with lenalidomide as maintenance (vs placebo). This fact has prompted concern and highlighted the association between multiple myeloma and second malignancies. Furthermore, an excess of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after multiple myeloma has been known for over 4 decades. Most prior studies have been restricted because of small numbers of patients, inadequate follow-up, and limitations of ascertainment of second malignancies. Although the underlying biologic mechanisms of AML/MDS after multiple myeloma are unknown, treatment-related factors are presumed to be responsible. Recently, an excess risk of AML/MDS was found among 5652 patients with IgG/IgA (but not IgM) monoclonal gammopathy of undetermined significance, supporting a role for disease-related factors. Furthermore, there is evidence to suggest that polymorphisms in germline genes may contribute to a person's susceptibility to subsequent cancers, whereas the potential influence of environmental and behavioral factors remains poorly understood. This review discusses current knowledge regarding second malignancies after multiple myeloma and gives future directions for efforts designed to characterize underlying biologic mechanisms, with the goal to maximize survival and minimize the risk for second malignancies for individual patients.     

Advances in understanding prognosis in myeloma

In the last two decades outcomes in multiple myeloma (myeloma) have greatly improved, due to the introduction of newer, more effective therapies. This improvement is not uniform. Response to treatment and survival remains heterogeneous, with some patients living for 1–2 years whilst others are alive and progression‐free at 10 years. This variation in outcome is due to patient characteristics plus features intrinsic to the myeloma tumour. Alongside the introduction of novel therapies there has been a greater understanding of disease biology and mechanisms of resistance. This has led to an increase in the number of prognostic markers that can be used in myeloma. This is important not only for more accurate counselling of patients in terms of disease outcome, but also in paving the way for risk‐adapted therapy. Both newer and traditional prognostic markers need to be used in the context of planned therapy. Indeed, the prognostic value of certain markers varies according to which therapy the patient receives. As such, these prognostic factors will require constant re‐evaluation as agents with new mechanisms of action are added into the myeloma treatment algorithm. This article summarises current concepts of prognostic markers in myeloma.     

Incidence of neutropenia and use of granulocyte colony-stimulating factors in multiple myeloma: is current clinical practice adequate?

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia.     

The future role of thalidomide in multiple myeloma

Treatment for multiple myeloma typically is chemotherapy, high-dose therapy with stem cell transplantation or radiation. Thalidomide shows promise, but to improve knowledge and understanding of this drug, more clinical data is required. Workshops designed to propose new studies providing much needed data on the use of thalidomide as first-line therapy, as maintenance therapy and as treatment for refractory or relapsed disease are reported here. Thalidomide has been shown to be effective in previously untreated patients as monotherapy (36% remission), although greater remission is seen in combination therapy, for example, thalidomide with dexamethasone (72% remission). Thalidomide is an interesting maintenance therapy. It has the advantages of being effective in the bone marrow and having a long-lasting effect but suffers because of its significant side-effect profile; however, it is tolerated by most patients. The adverse effects are thought to be dose-limiting, and most are seen in all patients at the beginning of treatment. Further clinical evidence is needed to determine the effectiveness of thalidomide as maintenance therapy in patients with multiple myeloma, having been shown to be active against refractory multiple myeloma, even in patients who relapse after high-dose chemotherapy. The workshop acknowledged the problems associated with designing a phase III study, and it is clear that many areas need to be addressed in the use of thalidomide for the treatment of multiple myeloma.     

Cytomegalovirus vaccine in renal transplants.

The frequency of solid tumors was evaluated in 628 consecutive patients with multiple myeloma who had been treated with various melphalan-prednisone combinations. Among those patients who lived at least 2 months, the incidence and diversity of second tumors were similar to those in normal persons of the same age and duration at risk. The diagnosis was usually made within 2 years after the start of chemotherapy for the myeloma. Long-term melphalan therapy did not seem to contribute to the pathogenesis of second solid tumors in patients with multiple myeloma.     

Re-use of the original infusional induction chemotherapy as salvage therapy in myeloma patients relapsing after one autograft

If standard infusional therapy (IC) has been used to treat myeloma at presentation, it is a matter of debate whether patients should receive the original induction therapy or a different drug combination in first relapse. Instinctively, most clinicians may switch treatment, particularly since the advent of new drugs for the treatment of myeloma. Hitherto, there has been no data on the efficacy of repeating standard IC in the salvage setting.

We studied 62 myeloma patients whose initial treatment consisted of C-VAMP and a single high dose melphalan procedure and who were retreated with C-VAMP at the time of first relapse. Response to salvage C-VAMP was seen in 50% (95% confidence interval = 0.37–0.62) but we were unable to identify any predictors for response to salvage C-VAMP. Only patients resistant to salvage C-VAMP benefited from a second autograft. The survival of patients who responded to salvage C-VAMP was not prolonged by a second transplant.

In conclusion, our data supports the use of C-VAMP for patients with myeloma in first relapse and suggest that only patients resistant to salvage C-VAMP should be offered a second autograft.     

Re-use of the original infusional induction chemotherapy as salvage therapy in myeloma patients relapsing after one autograft

If standard infusional therapy (IC) has been used to treat myeloma at presentation, it is a matter of debate whether patients should receive the original induction therapy or a different drug combination in first relapse. Instinctively, most clinicians may switch treatment, particularly since the advent of new drugs for the treatment of myeloma. Hitherto, there has been no data on the efficacy of repeating standard IC in the salvage setting.We studied 62 myeloma patients whose initial treatment consisted of C-VAMP and a single high dose melphalan procedure and who were retreated with C-VAMP at the time of first relapse. Response to salvage C-VAMP was seen in 50% (95% confidence interval = 0.37-0.62) but we were unable to identify any predictors for response to salvage C-VAMP. Only patients resistant to salvage C-VAMP benefited from a second autograft. The survival of patients who responded to salvage C-VAMP was not prolonged by a second transplant.In conclusion, our data supports the use of C-VAMP for patients with myeloma in first relapse and suggest that only patients resistant to salvage C-VAMP should be offered a second autograft.     

Outcome of COVID-19 in multiple myeloma patients in relation to treatment

COVID-19 has emerged as a global pandemic. Cancer patients have been reported to be at higher risk for adverse outcome of COVID-19. Studies are ongoing to decipher the risk factors and risk groups among cancer patients as well as strategies to refine treatment approaches. Here, we report eight patients with multiple myeloma that underwent immunomodulatory therapies with daratumumab or lenalidomide-based combination treatments and one patient with smoldering multiple myeloma, all of which presented with symptomatic COVID-19. We report that patients that succumbed to COVID-19 presented with either progressive tumor disease under daratumumab treatment or were in remission under lenalidomide-dexamethasone treatment.     

Maintenance therapy and need for cessation studies in multiple myeloma: Focus on the future

With ten years of follow-up since the advent of the modern paradigm of combination induction therapy, consolidative autologous stem-cell transplant, and lenalidomide maintenance, median survival for multiple myeloma has increased to almost 50% at 10 years. Given this outlook, the overarching goal of maintenance therapy is to spare patients from the toxicities of aggressive or otherwise intrusive therapies while ideally extending survival or, at the least, extending progression-free survival or time until next treatment. This review will focus on the current landscape of maintenance therapies for multiple myeloma. The historical context and evidence for choice of agent, duration of treatment, and current strategies and ongoing trials will be discussed – as well as a focus on unmet needs. The case for studies investigating cessation of therapy and risk and response-adapted approaches will be underscored given that the current paradigm likely results in overtreatment for some patients.     

Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations

Multiple myeloma is the second most common hematologic malignancy in the United States and the most common hematologic malignancy among Blacks/African Americans. Delay in diagnosis is common and has been associated with inferior disease-free survival and increased rates of myeloma-related complications. Despite a roughly 2-times higher risk of multiple myeloma, diagnostic delay appears more common, and improvements in 5-year survival rates have been slower among Blacks/African Americans than their White counterparts. When patient symptoms and basic laboratory findings are suggestive of multiple myeloma, the primary care provider should initiate extended laboratory work-up that includes serum protein electrophoresis, serum immunoglobulin free light chain assay, and serum immunofixation. Heightened awareness within high-risk populations such as Blacks/African Americans may help to eliminate racial disparities in the diagnosis and treatment of multiple myeloma.     

夫妻同患多发性骨髓瘤2例报道并文献复习

目的:探讨夫妻同患多发性骨髓瘤的相关危险因素.方法:报告1对夫妻同患多发性骨髓瘤的诊治经过,并结合文献复习夫妻同患癌症的相关危险因素.结果:病例1免疫球蛋白固定电泳呈IgG/LAM型,左胸壁包块免疫组化:瘤细胞EMA(+)、CD138(+)、MUM-1(+)、λ(+)、Ki-67 LI 80％;骨髓瘤细胞64.3％;流式细胞学免疫分型结果:表达lambda,部分表达CD38,CD138.行MPT、TD方案并联合中草药治疗可达非常好的部分缓解(VGPR).病例2免疫球蛋白固定电泳呈IgA/LAM型;骨髓瘤细胞51％;流式细胞学免疫分型结果:表达lambda,部分表达CD38,CD56,CD138;FISH:GLP RB1位点缺失,D13S319位点缺失,JGH基因异位,lq21位点扩增,p53位点缺失可疑.行VD方案不能耐受,改为MPT方案并联合中草药治疗后可达接近完全缓解(nCR).近10年的国内外文献中,未检索到夫妻同患多发性骨髓瘤的病例报道.夫妻癌的发生与环境、饮食、致病微生物,情志因素,基因融合,偶然性等因素相关.结论:夫妻同患多发性骨髓瘤与其长期共同的生活环境相关可能性大,但不能排除二者独立发病的巧合性.     

Bone Marrow Transplantation in Three Patients with Multiple Myeloma

ABSTRACT. Three patients with multiple myeloma received bone marrow grafts from HLA-identical sibling donors. One of the patients, with IgA kappa myeloma, refractory to alkeran-prednisone therapy, is well and still without sign of disease 26 months post transplantation. A second patient with Bence-Jones kappa myeloma is well, and sceletal pain and Bence-Jones proteinuria has disappeared 2 months after transplantation. A third patient with IgG-lambda myeloma died of effusive pericarditis shortly after transplantation. Bone marrow transplantation may be indicated in a selective group of patients with multiple myeloma.     

Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients

Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used population-based data from Sweden to identify all multiple myeloma patients (n=9253) diagnosed from 1988 to 2004 with follow up to 2007 and 34,931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8–7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8–7.4), and for viral infections 10-fold (10.0; 8.9–11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (P<0.001). At one year of follow up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed.     

Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma

Therapeutic options for patients with multiple myeloma whose disease has relapsed after a prior auto-SCT include novel biologic therapies, traditional chemotherapy or a second transplant, with no clear standard of care. Few published studies address the safety and efficacy of a second auto-SCT for relapsed disease. We reviewed the Abramson Cancer Center experience with salvage auto-SCT for relapsed multiple myeloma. Forty-one patients had received a salvage auto-SCT at our institution; the median time between transplants was 37 months (range 3-91). The overall response rate in assessable patients was 55%, and treatment-related mortality was 7%. With a median follow-up time of 15 months, the median PFS was 8.5 months and the median overall survival (OS) was 20.7 months. In a multivariate analysis of OS, independent prognostic factors were >or=5 prior lines of therapy and time to progression after initial auto-SCT of 相似文献   

Myélome multiple indolent

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell neoplasia, characterized by monoclonal plasma cell proliferation in the absence of end-organ damage, but with a high risk of progression to multiple myeloma. It has therefore to be distinguished from monoclonal gammapathy of undetermined significance (MGUS), which has a much lower risk of progression, but also from multiple myeloma, which remains an incurable disease and requires a specific treatment. The critical question in the management of SMM is whether an early therapeutic strategy could help delaying the progression to multiple myeloma, in order to lower the risk of serious complications related to this progression, or even to cure the disease. This early treatment could not be proposed to all SMM patients, who are indeed asymptomatic, and in whom the risk of toxicity could make it difficult to justify the potential benefit obtained. The challenge is to target early at diagnosis SMM patients with a high risk of progression, using available routine tests sufficiently reliable to warrant the therapeutic sanction which relies on it. Today however, apart from randomized studies, recommendations are to maintain therapeutic abstention in SMM patients.     

MRD Testing in Multiple Myeloma: The Main Future Driver for Modern Tailored Treatment

The past decade, several highly efficacious drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are less toxic than older chemotherapy drugs. Using modern combination therapy in newly diagnosed multiple myeloma patients, high proportions of newly diagnosed multiple myeloma patients obtain minimal residual disease (MRD) negativity and MRD testing has rapidly become an integral part of clinical trials focusing on patients in this setting. Only recently, MRD negativity was reported in clinical trials focusing on older newly diagnosed multiple myeloma patients (ie, nontransplant candidates), as well as studies focusing on patients with relapsed or refractory multiple myeloma. In the past, deeper responses were rarely seen in these patient categories due to inferior therapies and lack of MRD assays. The reason for the rapidly increased interest in MRD testing in all types of clinical trials is the fact that MRD negativity is closely correlated with longer progression-free survival which has been documented in recent meta-analyses. Consequently, MRD negativity has the potential to soon become a regulatory surrogate end-point for drug approval. This review dissects and discusses current data on MRD in multiple myeloma, it outlines new hypotheses, which can be tested in future clinical studies, and it discusses opportunities and future avenues for translational research. The goal of this article is to stimulate critical analysis of our current treatment landscape and development of future translational research involving MRD testing.