PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1067108)

Clipboard (0)
None

Related Articles

1.  The Cost-Effectiveness of Initial Treatment of Multiple Myeloma in the U.S. With Bortezomib Plus Melphalan and Prednisone Versus Thalidomide Plus Melphalan and Prednisone or Lenalidomide Plus Melphalan and Prednisone With Continuous Lenalidomide Maintenance Treatment 
The Oncologist  2013;18(1):27-36.
A detailed pharmacoeconomic analysis was conducted to estimate the incremental cost-effectiveness of bortezomib, melphalan, and prednisone versus thalidomide, melphalan, and prednisone versus lenalidomide, melphalan, and prednisone with lenalidomide maintenance as therapy for previously untreated transplant-ineligible multiple myeloma patients. Bortezomib, melphalan, and prednisone was found to be the cost-effective option in the U.S. setting.
The outlook for transplant-ineligible multiple myeloma patients has improved enormously over recent years with the incorporation of new agents into standard regimens. Novel regimens combine melphalan and prednisone (MP) with bortezomib (VMP), with thalidomide (MPT), and with lenalidomide with (MPR-R) and without (MPR) lenalidomide maintenance. The efficacy, safety, and cost-effectiveness of these regimens have not yet been compared; therefore, we conducted a pharmacoeconomic analysis using data from randomized controlled trials versus MP.
Using a Markov model developed from a U.S. payer's perspective, we compared VMP with MPT and MPR-R over a lifetime horizon. MPT and MPR-R were chosen because, like VMP, they are superior to MP in response and outcomes. Data from the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA; VMP), Intergroupe Francophone du Myelome (IFM) 99–06 (MPT), and MM-015 (MPR-R) trials were used. The IFM 99–06 study was selected because of the superior activity in this study compared with other MPT studies. Using patient-level (VMP) and published (MPT, MPR-R) data, we estimated the health-state transition and adverse event probabilities for each regimen, related costs, and state-specific utility estimates. Costs (in 2010 U.S. dollars) and health outcomes were discounted at 3%.
Discounted lifetime direct medical costs were lowest with VMP at $119,102. MPT cost $142,452 whereas MPR-R cost $248,358. Incremental cost-effectiveness ratio calculations projected that VMP would confer cost savings and better health outcomes relative to MPT and MPR-R. We conclude that VMP is highly likely to be cost-effective compared with MP, MPT, and MPR-R.
doi:10.1634/theoncologist.2011-0380
PMCID: PMC3556252  PMID: 23299777
Bortezomib; Lenalidomide; Thalidomide; Multiple myeloma; Cost-effectiveness
2.  Current Multiple Myeloma Treatment Strategies with Novel Agents: A European Perspective 
The Oncologist  2010;15(1):6-25.
This review presents an overview of the most recent data using the novel agents thalidomide, bortezomib, and lenalidomide in the treatment of multiple myeloma and summarizes European treatment practices incorporating these novel agents.
The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.
doi:10.1634/theoncologist.2009-0203
PMCID: PMC3227886  PMID: 20086168
Multiple myeloma; Thalidomide; Bortezomib; Lenalidomide
3.  Front line treatment of elderly multiple myeloma in the era of novel agents 
Melphalan combined with prednisone (MP) has long been the historical treatment of reference for a large proportion of elderly myeloma (MM) patients ineligible for autologous stem cell transplantation, and is still the backbone of new regimens that include the new era of novel agents. Melphalan–prednisone–thalidomide (MPT) and melphalan–prednisone–bortezomib (Velcade®, MPV), proved superior to MP, currently appear to be the treatments of choice for this population. In the near future melphalan–prednisone–lenalidomide (Revlimid®, MPR) will also provide a third therapeutic option (MPT, MPV, and MPR), in elderly multiple myeloma, eventually. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. Dexamethasone-based regimen is another option and questions regarding the relative efficacy of melphalan-based versus low-dose dexamethasone-based regimens will require randomized phase III trials. More intensive approaches with new drug combinations or with the incorporation of polyethylene glycolated (PEGylated) liposomal doxorubicin will also require additional studies. Additionally, the important issue of maintenance treatment needs to be further investigated. These new and emerging therapies offer multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians.
PMCID: PMC2726063  PMID: 19707399
multiple myeloma; elderly; bortezomib; thalidomide; revlimid; IMiDs; supportive care
4.  Post-Autologous (ASCT) Stem Cell Transplant Therapy in Multiple Myeloma 
Advances in Hematology  2014;2014:652395.
Autologous stem cell transplant (ASCT) is the standard of care in transplant-eligible multiple myeloma patients and is associated with significant improvement in progression-free survival (PFS), complete remission rates (CR), and overall survival (OS). However, majority of patients eventually relapse, with a median PFS of around 36 months. Relapses are harder to treat and prognosis declines with each relapse. Achieving and maintaining “best response” to initial therapy is the ultimate goal of first-line treatment and sustained CR is a powerful surrogate for extended survival especially in high-risk multiple myeloma. ASCT is often followed by consolidation/maintenance phase to deepen and/or maintain the response achieved by induction and ASCT. Novel agents like thalidomide, lenalidomide, and bortezomib have been used as single agents or in combination. Thalidomide use has been associated with a meaningful improvement in PFS and EFS, however, with substantial side effects. Data with lenalidomide maintenance after-ASCT is favorable, but the optimal duration of lenalidomide maintenance is still unclear. Bortezomib use has been associated with superior outcomes, predominantly in high-risk myeloma patients. Combination regimens utilizing a proteasome inhibitor (i.e., bortezomib) with an immunomodulatory drug (thalidomide or lenalidomide) have provided the best outcomes. This review article serves as a review of the best available evidence in post-ASCT approaches in multiple myeloma.
doi:10.1155/2014/652395
PMCID: PMC4265378  PMID: 25525435
5.  New therapies in multiple myeloma 
The melphalan-prednisone regimen has been considered as standard therapy for patients with multiple myeloma (MM) for many years. Recently, high-dose chemotherapy with stem-cell support has extended progression-free survival and increased overall survival, and it is now considered conventional therapy in younger patients. However, most patients relapse and the salvage treatment is not very effective. New active drugs, including immunomodulatory agents, thalidomide (Thal) and lenalidomide, and the proteasome inhibitor bortezomib, have shown promising anti-myeloma activity. These novel treatments are aimed at overcoming resistance of tumour cells to conventional chemotherapy, acting both directly on myeloma cells and indirectly by blocking the interactions of myeloma cells with their local microenvironment and suppressing growth and survival signals induced by autocrine and paracrine loops in the bone marrow. Thal has been widely studied, mostly in combination regimens in patients with relapsed MM and, more recently, in front-line therapy, showing efficacy in terms of response rate and event-free survival. Bortezomib has been found to possess remarkable activity, especially in combination with other chemotherapeutic agents, in relapsed/refractory and newly diagnosed MM, as well as in patients presenting adverse prognostic factors. Lenalidomide, in combination with dexamethasone, is showing high overall response rates in relapsed and refractory MM and promising results also in first-line therapy. In this paper, the results of the most significant trials with Thal, bortezomib and lenalidomide are reported. Several ongoing clinical studies will hopefully allow the identification of the most active combinations capable of improving survival in patients with MM.
doi:10.1007/s10238-007-0134-y
PMCID: PMC2779346  PMID: 17972050
Multiple myeloma; Therapy; Thalidomide; Lenalidomide; Bortezomib
6.  Treatment of Multiple Myeloma: A Comprehensive Review 
Clinical lymphoma & myeloma  2009;9(4):278-288.
Multiple myeloma (MM) is a neoplastic plasma cell disorder that results in end-organ damage (hypercalcemia, renal insufficiency, anemia, or skeletal lesions). Patients should not be treated unless they have symptomatic (end-organ damage) MM. They should be classified as having high-risk or standard-risk disease. Patients are classified as high risk in the presence of hypodiploidy or deletion of chromosome 13 (del[13]) with conventional cytogenetics, the presence of t(4:14), t(14;16), t(14;20) translocations or del(17p) with fluorescence in situ hybridization. High-risk disease accounts for about 25% of patients with symptomatic MM. If the patient is deemed eligible for an autologous stem cell transplantation (ASCT), 3 or 4 cycles of lenalidomide and low-dose dexamethasone, or bortezomib and dexamethasone, or thalidomide and dexamethasone are reasonable choices. Stem cells should then be collected and one may proceed with an ASCT. If the patient has a complete response or a very good partial response (VGPR), the patient may be followed without maintenance therapy. If the patient has a less than VGPR, a second ASCT is encouraged. If the patient is in the high-risk group, a bortezomib-containing regimen to maximum response followed by 2 additional cycles of therapy is a reasonable approach. Lenalidomide and low-dose dexamethasone is another option for maintenance until progression. If the patient is considered ineligible for an ASCT, then melphalan, prednisone, and thalidomide is suggested for the standard-risk patient, and melphalan, prednisone, and bortezomib (MPV) for the high-risk patient. Treatment of relapsed or refractory MM is covered. The novel therapies—thalidomide, bortezomib, and lenalidomide—have resulted in improved survival rates. The complications of MM are also described. Multiple myeloma is a plasma cell neoplasm that is characterized by a single clone of plasma cells producing a monoclonal protein (M-protein). The malignant proliferation of plasma cells produces skeletal destruction that leads to bone pain and pathologic fractures. The M-protein might lead to renal failure, hyperviscosity syndrome, or through the suppression of uninvolved immunoglobulins, recurrent infections. Anemia and hypercalcemia are common complications.
doi:10.3816/CLM.2009.n.056
PMCID: PMC3910142  PMID: 19717377
Autologous stem cell transplantation; Bortezomib; Lenalidomide; Thalidomide
7.  The Treatment of Multiple Myeloma Patients Not Eligible for Asct 
Advances in therapies for younger patients with multiple myeloma have resulted in significant improvements in outcome over recent years, on the contrary the progress in treatments for elderly patients has remained more modest. Traditionally, patients who are not eligible for transplantation, like the older patients, have been treated with the combination of melphalan plus prednisone (MP), which leads to responses in approximately 50% of patients; however, patients rarely achieve a complete response (CR) and long-term outcomes are disappointing, with a relapse-free survival of approximately 18 months and an overall survival (OS) of approximately 3 years.
With the arrival of novel agents, including the first–in-class proteasome inhibitor, bortezomib, and the immunomodulatory agents, thalidomide and lenalidomide, a shift in the management of older patients and/or those not eligible for transplantation has taken place. Increasingly, novel agents are now being incorporated into therapy, based on the positive findings from clinical trials in this setting, and outcomes have improved accordingly.
doi:10.4084/MJHID.2010.009
PMCID: PMC3033138  PMID: 21415962
8.  New Treatment Approaches for Older Adults with Multiple Myeloma 
Journal of geriatric oncology  2012;3(3):279-290.
The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20 years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens which include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient's comorbidities and goals of care.
doi:10.1016/j.jgo.2012.02.001
PMCID: PMC3458649  PMID: 23024730
multiple myeloma; geriatrics; aging; chemotherapy; immunomodulatory agents; proteosome inhibitors
9.  Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline 
Current Oncology  2006;13(5):160-172.
Questions
In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?
What is the toxicity associated with the use of bortezomib?
Which patients are more or less likely to benefit from treatment with bortezomib?
Perspectives
Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback.
Outcomes
Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events.
Methodology
A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc.
Results
The literature review found one randomized controlled trial (rct)—the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma.
The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation.
Practice Guideline
This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status.
Recommendations
Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations:
For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.
Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.
For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent–based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent–based chemotherapy is recommended.
Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials.
Qualifying Statements
Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg.
For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes.
Dosage
Bortezomib 1.3,g/m2 is given as a rapid intravenous bolus over 3–5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed.
Response to Treatment
Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone.
The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent–based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.
PMCID: PMC3394599  PMID: 22792013
Bortezomib; Velcade; multiple myeloma; lymphoma; clinical practice guideline; systematic review
10.  Efficacy and Safety of Busulfan-Based Conditioning Regimens for Multiple Myeloma 
The Oncologist  2013;18(5):611-618.
This literature review focuses on the efficacy and safety of busulfan (BU)-based conditioning regimens for autologous stem cell transplantation in patients with multiple myeloma. A BU-melphalan regimen demonstrated superior efficacy and a satisfactory safety profile, particularly when the i.v. formulation of BU was used.
Multiple myeloma is a malignancy of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. In the past 20 years, the use of high-dose therapies and novel agents has resulted in significant and meaningful improvements in survival. Autologous stem cell transplantation (auto-SCT) following a high-dose melphalan-conditioning regimen represents the standard of care for younger patients as well as older patients with a good performance status. A number of strategies have been proposed to improve the outcome of auto-SCTs, including the incorporation of new agents such as thalidomide, lenalidomide, and bortezomib into the induction regimen administered before auto-SCT; the administration of maintenance therapy after auto-SCT; the incorporation of novel agents into chemotherapeutic regimens after transplantation as consolidation therapy; and the use of reduced-intensity allogeneic transplantation after an initial autograft. Although these approaches have demonstrated some success in improving responses after auto-SCT, none of these strategies are curative. An additional strategy to improve outcomes after auto-SCT is to enhance the immediate pretransplant conditioning regimens by either increasing the dose of melphalan or by incorporating novel agents, such as busulfan. This literature review focuses on the efficacy and safety of busulfan-based conditioning regimens for auto-SCT in patients with multiple myeloma.
doi:10.1634/theoncologist.2012-0384
PMCID: PMC3662853  PMID: 23628980
Multiple myeloma; Conditioning regimens; Hematopoietic stem cell transplantation; Melphalan; Busulfan
11.  Autologous Stem Cell Transplantation in Elderly Patients with Multiple Myeloma: Past, Present, and Future 
BioMed Research International  2014;2014:394792.
High-dose melphalan (200 mg/m2) as conditioning regimen followed by autologous stem cell transplantation (ASCT) rescue has been established as a standard treatment for patients with multiple myeloma (MM) younger than 65 years of age. However, the role of ASCT in elderly patients older than 65 years remains controversial in the era of novel agents such as thalidomide, bortezomib, and lenalidomide. The efficacy and feasibility of ASCT have been shown in elderly patients by reducing the dose of melphalan to 100–140 mg/m2. Although the clinical benefit of reduced-intensity ASCT in elderly patients has not been clearly established in comparison with that of novel agent-based induction therapy, recent studies have demonstrated that sequential strategies of novel agent-based induction therapy and reduced-intensity ASCT followed by consolidation/maintenance with novel agents translate into better outcome in the management of elderly patients. Thus, ASCT could also be a mainstay in the initial treatment of elderly MM patients, and its indication should be evaluated based on performance status and the presence of complications and/or comorbidities of each elderly patient with MM.
doi:10.1155/2014/394792
PMCID: PMC3956410  PMID: 24719860
12.  Novel Therapies in Multiple Myeloma for Newly Diagnosed Non-Transplant Candidates 
In the 21st Century, melphalan-prednisone can no longer be regarded as the standard treatment of multiple myeloma patients not eligible for high-dose melphalan followed by autologous stem cell transplantation. The introduction of thalidomide, lenalidomide and bortezomib has improved the arsenal of therapeutic options in multiple myeloma. Indeed, randomized studies have shown that melphalan-prednisone-thalidomide and melphalan-prednisone-bortezomib are superior to melphalan-prednisone alone. Additionally, other combinations, including lenalidomide are under study. In this review we discuss the role of novel therapies in multiple myeloma in elderly multiple myeloma patients. Important aspects, such as toxicity and the role of prognostic factors, are also addressed.
doi:10.1097/PPO.0b013e3181c60f08
PMCID: PMC2818857  PMID: 20010166
13.  Induction Therapy and Stem Cell Mobilization in Patients with Newly Diagnosed Multiple Myeloma 
Stem Cells International  2012;2012:607260.
Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients.
doi:10.1155/2012/607260
PMCID: PMC3369512  PMID: 22701493
14.  Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials 
Seminars in oncology  2013;40(5):10.1053/j.seminoncol.2013.07.007.
The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free and overall survival in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next five years.
doi:10.1053/j.seminoncol.2013.07.007
PMCID: PMC3819933  PMID: 24135408
15.  Treatment of newly diagnosed myeloma 
Leukemia  2008;23(3):449-456.
The introduction of thalidomide, bortezomib and lenalidomide has dramatically changed the treatment paradigm of multiple myeloma (MM). In patients eligible for autologous stem cell transplant (ASCT), combinations including thalidomide/dexamethasone (Thal/Dex) or bortezomib/dexamethasone (Bort/Dex) or lenalidomide/dexamethasone (Rev/Dex) have been introduced as induction regimens in patients eligible for ASCT. New induction regimens have significantly increased complete response rate before and after ASCT with a positive impact on progression-free survival. Maintenance therapy with thalidomide, under investigation with lenalidomide, may further prolong remission duration. In patients not eligible for ASCT, randomized studies have shown that melphalan, prednisone, thalidomide (MPT) and melphalan, prednisone and bortezomib (MPV) are both superior to melphalan and prednisone (MP), and are now considered standard of care. Ongoing trials will soon assess if MP plus lenalidomide may be considered an attractive option. More complex regimens combining thalidomide or bortezomib or lenalidomide with cyclophosphamide or doxorubicin have been also tested. In small cohorts of patients bortezomib or lenalidomide may overcome the poor prognosis induced by deletion 13 or translocation t(4;14) or deletion 17p13. If these data will be confirmed, a cytogenetically riskadapted strategy might become the most appropriate strategy.
doi:10.1038/leu.2008.325
PMCID: PMC3923468  PMID: 19005483
new drugs; therapy; diagnosis; myeloma
16.  Current approaches to the initial treatment of symptomatic multiple myeloma 
International journal of hematologic oncology  2013;2(1):10.2217/ijh.13.3.
SUMMARY
The treatment of newly diagnosed multiple myeloma has dramatically changed since the emergence of proteasome inhibitors and immunomodulatory drugs. Front-line combination regimens incorporating novel drugs such as thalidomide, bortezomib and lenalidomide, have significantly improved response rates and are the standard of care for induction regimens. Although the timing and role of autologous stem cell transplant are now being questioned, it remains an important part of the treatment paradigm in eligible patients. In addition, the concept of extended sequential therapy has recently emerged, including consolidation and/or maintenance in both the post-transplant setting and in nontransplant candidates. In this article we focus on management strategies in newly diagnosed multiple myeloma, including choice of induction regimens in transplant-eligible and -ineligible patients, as well as the role of autologous stem cell transplant, consolidation therapy and maintenance therapy.
doi:10.2217/ijh.13.3
PMCID: PMC3839860  PMID: 24286003
17.  Tretatment Approach of Nontransplant Patients with Multiple Myeloma 
Materia Socio-Medica  2014;26(5):348-351.
Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient's characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients.
doi:10.5455/msm.2014.26.348-351
PMCID: PMC4272840  PMID: 25568637
multiple myeloma; treatment; transplant noneligible patients
18.  Multiple Myeloma Treatment Transformed: A Population-Based Study of Changes in Initial Management Approaches in the United States 
Journal of Clinical Oncology  2013;31(16):1984-1989.
Purpose
Despite improved outcomes for multiple myeloma, little is known about changes in initial treatment at the population level for US patients. We report trends in treatment practices.
Patients and Methods
Patients (n = 1,976) with newly diagnosed myeloma in 1999, 2003, and 2007 were examined by using the National Cancer Institute's Patterns of Care Studies. We assessed use of common chemotherapies (melphalan, vincristine, and doxorubicin), novel agents (thalidomide, bortezomib, or lenalidomide), or hematopoietic stem-cell transplantation (HSCT) during the first year after diagnosis. By using logistic regression, we evaluated the association of race and insurance status with receipt of high-cost treatments—transplantation or novel agents.
Results
From 1999 to 2007, use of melphalan alone dropped from 32.0% to 4.1%, and vincristine and doxorubicin use declined from 18.2% to 0.4%. The percentage of patients receiving any novel agent rose from 3.9% in 1999 to 75.5% in 2007. HSCT increased from 11.1% in 1999 to 21.7% in 2007. For white patients, use of novel agents was lower for those with Medicare only (42.6%) than for those with private insurance (50.2%). For patients of other races, those with Medicare only or Medicaid were less likely to receive novel agents or transplantation compared with those with private insurance.
Conclusion
Initial treatment for multiple myeloma has changed markedly. Most patients now receive novel agents, with a decline in the use of traditional chemotherapy. Use of transplantation and novel agents varies with race and insurance. These findings document rapid changes in patterns of care and highlight addressable disparities in myeloma care.
doi:10.1200/JCO.2012.46.3323
PMCID: PMC3661935  PMID: 23569317
19.  Myeloma (multiple) 
Clinical Evidence  2006;2006:2403.
Introduction
Multiple myeloma is the most common primary cancer of the bones in adults, representing about 1% of all cancers diagnosed in the US in 2004, and 14% of all haematological malignancies. In the UK, multiple myeloma accounts for 1% of all new cases of cancer diagnosed each year.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment in people with asymptomatic early stage multiple myeloma (stage I)? What are the effects of first-line treatments in people with advanced stage multiple myeloma (stages II and III)? What are the effect of salvage treatments, or supportive therapy, in people with advanced stage multiple myeloma (stages II and III)? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: allogenic transplant (non-myeloablative), autologous stem cell transplant (early or late transplantation, double or single, purging of), bisphosphonates, bone marrow stem cells, bortezomib, chemotherapy (combination, conventional dose, intermediate dose plus stem cell rescue, high-dose plus stem cell rescue), combination chemotherapy plus corticosteroids, deferred treatment (in stage I disease), early chemotherapy plus corticosteroids (in stage I disease), epoetin alpha, first-line treatments, infection prophylaxis, interferon, maintenance therapy (in advanced multiple myeloma), melphalan (normal dose, high dose before autologous stem cell transplantation, plus total body irradiation), optimum priming regimen, peripheral blood stem cells, plasmapheresis, salvage therapy regimens, single-agent chemotherapy (adding prednisolone), single-agent chemotherapy (bendamustine, melphalan, cyclophosphamide, lomustine, carmustine) with or without corticosteroid (prednisolone, dexamethasone), syngeneic transplantation, and thalidomide (and derivatives).
Key Points
Multiple myeloma is a neoplastic proliferation of plasma cells, mainly within the bone marrow, causing anaemia, renal dysfunction, infections and bone lesions. Monoclonal protein is found in serum and/or urine in 97% of people.
Early chemotherapy plus corticosteroids have not been shown to improve survival in people with asymptomatic, early stage multiple myeloma.
In people with advanced multiple myeloma, combination chemotherapy or single agent chemotherapy plus prednisolone improves survival more effectively than single agent chemotherapy alone, and adding corticosteroids to combination chemotherapy is more effective still High or intermediate dose chemotherapy with bone marrow or peripheral blood stem cell rescue improves progression free and overall survival compared with conventional dose chemotherapy. Syngeneic (from a twin) or autologous stem cell transplantation may increase event free, but not overall, survival if given early rather than late.An optimum priming regimen with stem cell factor may increase the yield of CD34+ cells for transplantation, but increases the risk of adverse effects. Very high dose melphalan may increase overall survival and have fewer adverse effects compared with high dose melphalan plus total body irradiation.
Adding interferon to chemotherapy increases response rates and progression free, but not overall, survival, but increases toxicity. We don't know which are the most effective salvage regimens,or if thalidomide increases survival, but bortezomib may increase response rates and overall short term survival.
In people with advanced disease, bisphosphonates reduce skeletal fractures and pain, epoetin alpha may improve anaemia, prophylactic treatment with antibiotics and immunoglobulin may reduce infections, and plasmapheresis may improve renal function when added to forced diuresis plus chemotherapy. However, we don't know whether any of these treatments improve survival, and they may increase adverse effects.
PMCID: PMC2907638
20.  Addition of lenalidomide to melphalan in the treatment of newly diagnosed multiple myeloma: the National Cancer Institute of Canada Clinical Trials Group MY.11 trial 
Current Oncology  2007;14(2):61-65.
Oral melphalan and prednisone remain an effective and tolerable treatment for patients with multiple myeloma. For approximately 40 years, this combination has been the standard of care for patients not proceeding to stem cell transplant. Within the last 10 years, new agents have been found to be efficacious in the relapsed/refractory setting. Within the last year, two trials of added thalidomide in the newly diagnosed setting have demonstrated outcomes superior to those achieved with melphalan and prednisone alone. This improved outcome comes at the cost of increased toxicity.
The National Cancer Institute of Canada Clinical Trials Group (ncic ctg) has recently developed a randomized phase ii trial (MY.11) that uses a combination of lenalidomide with melphalan for patients with newly diagnosed multiple myeloma. Lenalidomide is a thalidomide analogue and, like thalidomide, is thought to work through immunomodulatory effects. It was shown to have activity in patients with relapsed or refractory disease and, in combination with dexamethasone, is superior to dexamethasone alone. Lenalidomide holds promise as a more effective and potentially less toxic derivative of thalidomide. Experience with lenalidomide in combination with chemotherapy is very limited, and the purpose of MY.11 is to establish tolerability and to gain knowledge about efficacy. The information gained from MY.11 is expected to help inform dosing levels and schedules for a large phase iii trial being developed by the Eastern Cooperative Oncology Group that will include participation by the ncic ctg.
PMCID: PMC1891198  PMID: 17576467
Multiple myeloma; newly diagnosed; melphalan; thalidomide; lenalidomide
21.  Multiple myeloma 
Summary
Multiple myeloma accounts for 10% of all hematologic cancers. Median age at diagnosis is 69 years for men and 72 years for women. The incidence of MM has remained relatively stable, but the associated mortality has declined since the early 1990s. The knowledge acquired about the bone marrow microenvironment in MM and the availability of new drugs has significantly improved patients survival in the past 10 years. Immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, carfilzomib) can induce apoptosis of myeloma plasma cells and suppress cytokine release and metabolic ways which sustain the disease. These novel agents demonstrate substantial activity either alone or as part of a range of combination regimens. MM therapy is now based on 1 or 2 new drugs plus standard chemotherapy. Induction is patient tailored and first of all it depends on eligibility for stem-cell transplantation and key presenting features of the patients and the disease. Noteworthy, novel agent-based combination therapies may overcome most of poor prognostic factors. Up to 80% of newly diagnosed MM patients present with osteopenia, osteolysis and fractures. Thalidomide, lenalidomide and bortezomib have a beneficial effect on myeloma-related bone disease. Thalidomide reduces bone resorption, lenalidomide and bortezomib inhibit osteoclast growth and survival, and specifically target key factors in osteoclastogenesis, preventing development of osteolytic lesions. Noteworthy, new therapies offer higher complete response rates than previously reported with standard regimens.
PMCID: PMC3536006  PMID: 23289028
multiple myeloma; immunomodulatory drugs; myeloma bone disease
22.  Lenalidomide in the Treatment of Young Patients with Multiple Myeloma: From Induction to Consolidation/Maintenance Therapy 
Advances in Hematology  2012;2012:906247.
Multiple myeloma is the second most common hematologic malignancy. It accounts for 20,580 new cancer cases in the USA in 2009, including 11,680 cases in men, 8,900 cases in women, and 10,580 deaths overall. Although the disease remains still incurable, outcomes have improved substantially over recent years thanks to the use of high-dose therapy and the availability of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Various trials have shown the advantages linked to the use of novel agents in the transplant and not-transplant settings. In particular, this paper will present an overview of the results achieved with lenalidomide-containing combinations in patients eligible for high-dose therapies, namely, young patients. The advantages obtained should always be outweighed with the toxicity profile associated with the regimen used. Therefore, here, we will also provide a description of the main adverse events associated with lenalidomide and its combination.
doi:10.1155/2012/906247
PMCID: PMC3400298  PMID: 22829835
23.  Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma 
OncoTargets and therapy  2013;6:531-538.
Multiple myeloma remains an incurable disease despite the introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib that have improved the outcome of patients with both newly diagnosed and relapsed/refractory disease. However, patients who relapse after treatment with these agents or are refractory to them represent an unmet need and highlight the necessity for the development of novel anti-myeloma agents. Pomalidomide is an IMiD, structurally related to thalidomide, with enhanced antiangiogenic, antineoplastic, and anti-inflammatory properties and exhibiting potent anti-myeloma activity in vitro and in vivo. Pomalidomide has shown remarkable activity in patients who were refractory to both bortezomib and lenalidomide in Phase II and III studies. This paper reviews the chemistry and mechanisms of action of pomalidomide as well as all the available data from clinical trials on pomalidomide use in patients with refractory/relapsed multiple myeloma.
doi:10.2147/OTT.S34498
PMCID: PMC3656921  PMID: 23690693
immunomodulatory drugs; cereblon; angiogenesis; lenalidomide; refractory
24.  Advances in multiple myeloma therapy during two past decades 
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by aberrant expansion of plasma cells within bone marrow and extramedullary sites. It is one of the most common haematological malignancies; it accounts for 1.4% of all tumours and is responsible for 2% of cancer-related mortality. Over the last decades, the paradigm of MM therapy has changed dramatically - from the conventional combination of oral melphatan + prednisone, high-dose chemotherapy with stem cell (ASCT) support for younger patients to the present paradigm with the use of one (or more) of 3 major new targeted agents - the first-in class proteasome inhibitor bortezomib, the immunomodulatory drug thalidomide, and its more potent derivative lenalidomide. Their use as a part of initial therapy is associated with high overall response rates as well as high rates of complete response (CR), both for elderly patients unable to undergo ASCT and for younger patients treated prior to ASCT. Altogether, the advent of novel agents has resulted in a 50% improvement in median survival. Moreover, the development of new drug classes based on preclinical rationale and the introduction of next-generation agents are likely to further expand treatment options and improve outcomes for especially relapsed MM. This review highlights important historic landmarks as well as more recent events that have played an important role in the evolution of myeloma targeted therapy.
doi:10.1016/j.csbj.2014.05.005
PMCID: PMC4151869  PMID: 25210597
Multiple myeloma; Bortezomib; Lenalidomide; ASCT
25.  Association of response endpoints with survival outcomes in multiple myeloma 
Leukemia  2013;28(2):258-268.
Since the introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, more patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. These improvements have afforded more robust analyses of the relationship between response and survival. Generally, these studies have demonstrated that improvements in the quality of response across all stages of treatment are associated with better disease control and longer survival. Thus, achievement of maximal response should be strongly considered, particularly in the frontline setting, but must also be balanced with tolerability, quality of life and patient preferences. In select patients, achievement of a lesser response may be adequate to prolong survival, and attempts to treat these patients to a deeper response may place them at unnecessary risk without significant benefit. Maintenance therapy has been shown to improve the quality of response and disease control and, in some studies, survival. Studies support maintenance therapy for high-risk patients as a standard of care, and there are emerging data supporting maintenance therapy in standard-risk patients to improve progression-free and possibly overall survival. Multidrug regimens combining a proteasome inhibitor and an IMiD have shown exceptional response outcomes with acceptable increases in toxicity in both the frontline and salvage settings, and are becoming a standard treatment approach. Moving forward, the use of immunophenotypic and molecular response criteria will be essential in better understanding the impact of highly active and continuous treatment regimens across myeloma patient populations. Future translational studies will help to develop antimyeloma agents to their fullest potential. The introduction of novel targeted therapies, including the IMiD pomalidomide and the proteasome inhibitors carfilzomib and ixazomib (MLN9708), will provide greater options to individualize treatment and help patients achieve a clinically meaningful response.
doi:10.1038/leu.2013.220
PMCID: PMC3918869  PMID: 23868105
myeloma; depth of response; durability of response; survival; minimal residual disease; multidrug treatment

Results 1-25 (1067108)