Novel therapies in myeloma

PURPOSE OF REVIEW: Several novel therapies have been licensed for the treatment of myeloma in recent years. We summarize some of the trials leading to their approval and the current evidence for their clinical use. A number of promising agents undergoing phase I/II trial evaluation are also discussed. RECENT FINDINGS: The immunomodulatory drugs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib, have been shown to be effective agents, both alone and as part of combination regimens, for the treatment of myeloma. Studies are now focusing on the optimal sequencing of these drugs throughout the disease course, with a view to maximizing antitumor efficacy and minimizing overlapping toxicities. New protocols are increasingly based on preclinical evidence of synergy. The incorporation of these agents into transplant-based treatment protocols has improved outcomes. Other examples of novel agents undergoing assessment at present include arsenic trioxide, hsp90 inhibitors and histone deacetylase inhibitors. Future developments are likely to include individualized treatment plans based on patient-specific parameters including cytogenetic analysis and gene expression profiling. SUMMARY: Thalidomide, lenalidomide and bortezomib can now be considered as standard options both as first-line agents and beyond for the treatment of myeloma, with respective combinations also emerging as valid choices for all stages of the disease.     

New treatment of multiple myeloma

PURPOSE: After decades of minimal progress, two new classes of drugs with novels mechanisms of action: immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) have shown great activity for the treatment of multiple myeloma. CURRENT KNOWLEDGE AND KEY POINTS: Thalidomide acts by a variety of mechanisms; its efficacy is well known in disease relapse especially associated with dexamethasone. Recent results prove that combination of thalidomide with melphalan and prednisone should be considered as the first line standard of care in elderly patient. The main side effects are peripheral neuropathy and deep-vein thrombosis. Bortezomib is the first proteasome inhibitor. It is approved for the treatment in first disease relapse. The combination with glucocorticoids is synergistic. This combination in induction treatment before autologous stem cell transplantation is promising, as well as the combination with melphalan and prednisone in elderly patient. The main toxicities are fatigue and peripheral neuropathy. Lenalidomide is a structural analogue of thalidomide. Its efficacy in combination with dexamethasone has been proved in relapsing patients. The main toxicity is hematologic. Utilisation as first line treatment is also promising. FUTURE PROSPECTS AND PROJECTS: These three drugs have toxicities predictable and manageable and can be used successively or in combination for greater effectiveness. They have an impact on the multiple myeloma treatment strategies and on the disease course itself.     

Development of leukocytoclastic vasculitis in a patient with multiple myeloma during treatment with thalidomide

Thalidomide, an agent with antiangiogenic and immunomodulatory properties, is therapeutically effective in multiple myeloma, leprosy, and autoimmune diseases. The most common clinical toxicities of thalidomide are constipation, neuropathy, fatigue, sedation, rash, tremor, and edema. We here describe for the first time a patient who developed leukocytoclastic vasculitis during therapy with thalidomide. Of the 260 patients treated with thalidomide in our institution, this is the first patient who developed autoimmune disease. We conclude that patients with malignant disorders who are treated with thalidomide should be carefully monitored for the development of autoimmune disorders. Whether autoimmune phenomena also occur during treatment with new drugs such as PS-341 or potent immunomodulatory agents remains to be evaluated.     

Current status of new drugs for the treatment of patients with multiple myeloma

Multiple myeloma, a malignant disorder of plasma cells, is the second most common haematological malignancy. Although treatable, multiple myeloma remains incurable in virtually all cases, with a median survival of 3-4 years. Fortunately for patients with this disease, traditional treatment paradigms have been challenged with the emergence of a number of new therapies entering clinical practice over the last 6 years. In this review, we focus on the use of thalidomide (Thalidomide Pharmion; Boulder, CO, USA), lenalidomide (Revlimid; Celgene Corporation, Summit, NJ, USA) and bortezomib (Velcade; Janssen Pharmaceutica N.V., Belgium) in the treatment of myeloma. We present the current clinical experience with respect to efficacy and toxicity of these promising new agents and how the incorporation of these drugs with traditional therapies may improve the outcome for patients with multiple myeloma.     

Emerging combination treatment strategies containing novel agents in newly diagnosed multiple myeloma

Treatment strategies for multiple myeloma have changed substantially over the past 10 years following the introduction of bortezomib and the immunomodulatory drugs thalidomide and lenalidomide. In the front-line setting, combination regimens incorporating these novel agents are demonstrating substantial activity, which is translating into improved outcomes compared with previous standards of care. Response rates and depth of response that were previously only seen with high-dose therapy plus stem-cell transplantation (HDT–SCT) can now be achieved with new induction regimens utilizing these novel agents. This has raised the need for trials that will determine the clinical benefit of early SCT in patients that have already achieved a high quality of response. Here, we review the improvements in response and outcome that are seen with these novel-agent regimens, both as induction therapy prior to HDT–SCT and in non-transplant patients, and highlight the latest data from key studies of various novel combinations, including regimens featuring bortezomib plus thalidomide or lenalidomide. We also review data on response and outcomes in patients with poor prognostic characteristics that indicate that the adverse impact typically seen with these factors may be overcome using novel-agent therapy.     

Bendamustine in multiple myeloma

The advent of high‐dose melphalan with autologous stem‐cell transplantation (ASCT), the availability of novel agents such as thalidomide, lenalidomide (immunomodulatory drugs or IMiDs) and bortezomib (proteasome inhibitor) and improvements in supportive care have allowed to increase overall survival in multiple myeloma (MM) patients; nevertheless, MM remains an incurable pathology. For this reason, newer agents are required for continued disease control. Bendamustine is an old drug rediscovered in the last decade. In fact, its unique mechanism of action with structural similarities to both alkylating agents and antimetabolities, but which is not cross‐resistant to alkylating agents, has reawakened interest in the use of this drug in the treatment of MM. Studies have proven the safety and efficacy of bendamustine administered alone or in combination with new drugs in both upfront and relapse/refractory settings of MM patients, including those with renal impairment. Moreover, bendamustine has been successfully used as conditioning for autologous stem‐cell transplantation. Finally, the use of bendamustine does not compromise peripheral blood stem‐cell collection. This drug is generally well tolerated, with the majority of adverse events being due to myelosuppression. Non‐haematological adverse events are infrequent and usually mild.     

Management of older patients with multiple myeloma

For many years, the oral combination melphalan-prednisone (MP) has been considered the standard of care for patients with multiple myeloma (MM) not eligible for autologous stem cell transplantation. In the era of novel agents, the introduction of immunomodulatory drugs and proteasome inhibitors has challenged the role of MP and led to new standards of care for this disease. Five randomized phase III studies compared the traditional MP with the MP plus thalidomide (MPT). All these studies showed a prolonged time to progression (TTP) with the 3-drug combination. However, in only two of these trials this advantage translated into an improvement in overall survival (OS). In another randomized trial, MP plus bortezomib (VMP) was correlated with an increase in both TTP and OS compared with MP. Preliminary data showed the superiority of the association of VMP plus thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) vs VMP and melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) compared to MP. Promising results have also been reported with the combination of lenalidomide plus low-dose dexamethasone. The availability of different efficacious regimens provided clinicians with the opportunity of tailoring the proper and specific approach for each patient. The choice should be based on patients' comorbidities and biologic age, while taking into account the expected toxicity profiles of each treatment regimen. Moreover, an accurate management of therapy-related adverse events and a gentler approach, particularly for patients older than 75 years, with appropriate age-adjusted dose reductions, should be considered to further improve outcome.     

Multiple myeloma: chemotherapy or transplantation in the era of new drugs

Objective: To review the current results of studies incorporating novel agents in multiple myeloma (MM) and discuss the role of autologous stem‐cell transplantation (ASCT) in the era of new active drugs for the treatment of this disease. The outlook for patients with symptomatic MM is changing with the introduction of bortezomib, thalidomide, and lenalidomide into the repertoire of available chemotherapeutic agents. Compared with standard chemotherapy, a survival benefit has been reported for the first time in 30 yrs. Methods: Articles published in English between 1969 and 2008 were identified by searching PubMed for ‘myeloma’, ‘diagnosis’, ‘thalidomide’, ‘bortezomib’, ‘lenalidomide’, ‘dexamethasone’, ‘prednisone’, ‘doxorubicin’, ‘cyclophosphamide’, ‘melphalan’, ‘combination chemotherapy’, and ‘autologous transplantation’. Results: In randomized studies, bortezomib, thalidomide, and lenalidomide have each been combined with dexamethasone, alkylating agents, or doxorubicin, and such combinations resulted in significant improvement in progression‐free survival. Conclusions: The incorporation of new drugs as induction therapy along with ASCT appears to produce very good partial response rates, slightly superior to those achieved by conventional chemotherapy with new drugs. How to best optimize induction, consolidation, and maintenance therapy and how to best select and prepare patients for ASCT are still to be determined. Randomized trials are needed to directly compare the current best chemotherapeutic approach with best ASCT strategies and to guide clinical practice for patients with MM.     

Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs

The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression‐free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front‐line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review.     

Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies

The introduction of thalidomide, lenalidomide, and bortezomib has changed the way that multiple myeloma (MM) is treated and has greatly improved survival outcomes. These novel agents are often used in combination with conventional drugs, such as dexamethasone, to optimize clinical responses; however, they are also being evaluated as part of novel treatment combinations to build upon the success of available treatment regimens. Lenalidomide-based combinations are a focus of clinical research due to the high efficacy, good tolerability, and lack of cumulative toxicity associated with lenalidomide. Lenalidomide is an IMiDs? immunomodulatory compound with a dual mechanism of action - tumoricidal effects rapidly reduce MM burden while long-term immunomodulatory actions maintain tumor suppression. Several new agents with antimyeloma effects have been identified including: epigenetic agents (e.g. histone deacetylase inhibitors); novel proteasome inhibitors; novel immunomodulatory compounds; cyclin-dependent kinase inhibitors; interleukin-6 inhibitors; and other experimental agents such as heat-shock protein 90 inhibitors and monoclonal antibodies targeting MM cell surface receptors (e.g. anti-CS1 and anti-CD40). Many of these new agents, in combination with lenalidomide, are in early phases of clinical evaluation. Early clinical results are promising, indicating that the novel lenalidomide-based drug combinations are effective and generally well tolerated in patients with MM; future research will continue to evaluate these novel combinations and help to identify the optimal setting (e.g. induction, salvage, or maintenance) in which they may provide the greatest impact on the disease course.     

Risk of thrombosis with lenalidomide and its prevention with aspirin

Lenalidomide, an analog of thalidomide, is an effective new treatment for multiple myeloma. Both compounds are associated with an increased risk of venous thromboembolism, particularly when used in combination with high-dose dexamethasone. As new trials with lenalidomide are being planned and performed, investigators are placing high importance on reducing the risk of thrombosis by incorporating an antithrombotic agent into the therapeutic regimen. Low-molecular-weight heparin, warfarin, and aspirin have all been suggested as candidate drugs for thromboprophylaxis, but none of these agents have been evaluated in randomized clinical trials. A body of opinion has evolved that aspirin is very effective in preventing venous thrombosis in myeloma patients treated with lenalidomide. If correct, this view has important implications, because aspirin is inexpensive and is safer and more convenient than anticoagulants. On the other hand, aspirin is less effective than anticoagulants for preventing venous thrombosis in other high-risk groups, and therefore might not be the most appropriate choice for preventing of venous thrombosis in myeloma patients. This commentary examines the strength of the evidence supporting the effectiveness of aspirin in preventing venous thrombosis in multiple myeloma patients treated with lenalidomide. It is concluded that the evidence that aspirin is efficacious in preventing venous thrombosis in myeloma patients is based on "before/after" and retrospective studies, with potential for bias and confounders. There is, therefore, a critical need to incorporate a randomized comparison of aspirin with an anticoagulant in future trials evaluating lenalidomide in multiple myeloma.     

�෢�Թ��������Ʋ��Խ�չ

多发性骨髓瘤仍是一种不可治愈的血液肿瘤,近10年的治疗突破很大程度上依赖新药的研发,主要包括蛋白酶体抑制剂硼替佐米、免疫调节剂如来那度胺和沙利度胺等。力求达到完全缓解(CR)是目前的治疗目标,因为CR意味着无进展生存期(PFS)甚至总生存期(OS)的延长。以新药为基础的不同诱导方案显著提高一线治疗缓解率。缓解后或移植后进行巩固和维持治疗显著延长PFS。文章主要对包含新药的诱导方案进行总结,并简要讨论难治复发骨髓瘤患者的治疗。     

Hypercoagulability in multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance

Patients with multiple myeloma are at an increased risk of venous thromboembolism (VTE), especially when treated with the immunomodulatory drugs, thalidomide and lenalidomide, in combination with dexamethasone and/or chemotherapy. Several studies have shown that patients with multiple myeloma precursor disease (monoclonal gammopathy of undetermined significance [MGUS]) also have a higher risk of thrombosis compared to the general population. The underlying mechanisms for the hypercoagulable state are not completely understood. In this review, we discuss risk factors for thrombosis in multiple myeloma, as well as prophylactic strategies, the evidence for thrombosis among patients with MGUS, and proposed mechanisms for the hypercoagulability.     

Modern multiple myeloma therapy: deep,sustained treatment response and good clinical outcomes

In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib). In 2015 and 2016, expanded label indications were approved by the FDA for lenalidomide and carfilzomib, respectively. The recent increase in approved, highly effective combination therapies for patients with multiple myeloma has led the way to redefining the goals of therapy. Here, we review and provide a clinical perspective on the treatment goals and management of multiple myeloma in the era of modern therapy. Recent meta‐analyses show that minimal residual disease (MRD) negativity is associated with longer progression‐free and overall survival in patients with multiple myeloma. With the use of modern combination therapy, large proportions (>60–70%) of newly diagnosed multiple myeloma patients achieve complete responses and MRD negativity. Modern combination therapies induce rapid, deep and sustainable responses (including MRD negativity), supporting a treatment paradigm shift away from palliative two‐drug combinations towards the use of modern, potent, three‐ or four‐drug combination regimens in early lines of therapy. Data support the use of modern therapy upfront rather than reserving it for later stages of the disease. As survival time increases with modern combination therapies, development of early reliable surrogate end‐points for survival, such as MRD negativity, are needed for expedited read‐out of future randomized clinical trials.     

Lenalidomide mode of action: linking bench and clinical findings

New effective strategies are required that specifically address the challenges of multiple myeloma (MM) treatment, namely, disease recurrence, immunosuppression, and treatment-related toxicities. Recent preclinical and clinical findings suggest that the IMiDs? immunomodulatory compound lenalidomide has a dual mechanism of action, involving both a direct tumoricidal activity and immunomodulation, which may result in rapid and sustained control of MM, respectively. The tumoricidal effect of lenalidomide occurs through several mechanisms, including disruption of stromal support, induction of tumor suppressor genes, and activation of caspases. The immunomodulatory effects of lenalidomide, including T-cell and natural killer (NK)-cell activation, and increased expression of death effector molecules, lead to enhanced immune cell function and may explain the beneficial effects of this agent in the maintenance setting. Lenalidomide appears to be effective regardless of prior thalidomide treatment, which may reflect mechanistic differences - lenalidomide has greater immunomodulatory properties than thalidomide, whereas thalidomide has greater antiangiogenic activity. Recent studies also suggest that the concomitant use of dexamethasone may influence lenalidomide's direct and immunomodulatory effects. Lenalidomide in combination with dexamethasone synergistically inhibits proliferation and induces apoptosis; however, dexamethasone appears to antagonize the immune-enhancing effect of lenalidomide. A study has demonstrated that a regimen of lenalidomide in combination with an optimal dose and schedule of dexamethasone may increase survival by allowing synergistic antiproliferative effects, without affecting immunomodulatory activity. As preclinical and clinical research continue, additional insights into the dual mechanism of action of lenalidomide will help to further optimize the use of lenalidomide in MM.     

Management of older adults with multiple myeloma

Two-thirds of patients with multiple myeloma are aged 65 years or more and the prevalence of multiple myeloma in elderly patients is expected to rise in the next future. Patients older than 65 years are usually considered ineligible for transplantation. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, combined with conventional chemotherapy, has radically changed the treatment paradigm of elderly patients and improved outcome. 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. Novel agents associated with reduced-intensity autologous transplant showed to be safe and effective in fit elderly patients. Patients older than 75 years or vulnerable ones are more susceptible to adverse events that negatively affect treatment adherence and outcome. In this setting, less toxic regimens and appropriate dose reductions should be adopted. Here we provide an overview of novel agent-based treatment strategies for elderly patients with multiple myeloma.     

Adverse effects of thalidomide administration in patients with neoplastic diseases

Thalidomide, a glutamic acid derivative, was withdrawn from clinical use in 1962 due to its severe teratogenic effects. Its recent reinstitution in clinical practice was related to its benefits in leprosy and multiple myeloma. Moreover, the antiangiogenic and immunomodulatory properties of thalidomide have led to its evaluation in several malignant diseases, including myelofibrosis, renal cell cancer, prostate cancer, and Kaposi sarcoma. However, thalidomide use is associated with several side effects: somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious. A combination of thalidomide with steroids or chemotherapy is being evaluated in several phase 2 studies. While it is not yet clear whether these combinations will enhance efficacy, they appear to increase the toxicity of thalidomide, and thalidomide analogs are being developed to minimize this toxicity. Ongoing studies will clarify the potential advantages of these agents in the treatment of neoplastic diseases.     

Clinical impact of chromosomal aberrations in multiple myeloma

Chromosomal aberrations are frequently found in multiple myeloma cells and play a major role in patient outcome and management of the disease. The most important chromosomal aberrations associated with poor outcome are del(17p), t(4;14), t(14;16) and t(14;20). Others that may be associated with adverse prognosis include amp(1)(q21), del(1p32), del(13), del(8p21) and hypodiploidy. Many chromosomal aberrations have no or uncertain impact; for example, t(11;14), t(8;14) and hyperdiploidy. Attempts have been made to overcome the negative prognostic impact of chromosomal aberrations using autologous or allogeneic transplantation or new immunomodulatory drugs such as thalidomide, lenalidomide and the proteasome inhibitor bortezomib, but the results are controversial. Data suggest that allogeneic transplantation and treatment with bortezomib or lenalidomide may help to overcome the negative effect of del(13) on prognosis, whereas bortezomib may have some influence on reducing the impact of del(17p), t(4;14) and t(14;16). Chromosome analysis should always be performed at diagnosis of multiple myeloma to improve the prediction of outcome and to aid treatment decision-making.     

Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short‐term induction therapy, frontline therapy in patients ineligible for ASCT, or long‐term maintenance treatment.     

Treatment of patients with multiple myeloma who are eligible for stem cell transplantation: position statement of the Myeloma Foundation of Australia Medical and Scientific Advisory Group

The survival of patients with multiple myeloma (MM) has improved substantially since the introduction in the late 1980s of high‐dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT). Further improvements have been observed following the availability of immunomodulatory drugs (IMiD) such as thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib. Here, we summarise the recommendations of the Medical Scientific Advisory Group to the Myeloma Foundation of Australia for patients considered suitable for HDT + ASCT as part of initial therapy. These recommendations incorporate the various phases of treatment: induction, HDT conditioning and maintenance therapy.