ࡱ> KNDEFGHIJ (bjbj .cRhh!!&&&o'o'o'g(L,,o'2N-7Ly7y7C8F_KdL  ZX U&hCFhh !#Xy7C8 `h#$Vy7&C8 h xU&C8Po'g$v0@TTHT&Ѻ$wM W]tEcwMwMwM wMwMwMhhhhTwMwMwMwMwMwMwMwMwMh q :  VHA Clinical Guidance for the Initial Management of Adults with Multiple Myeloma Pharmacy Benefits Management Services Medical Advisory Panel and VACO Oncology Service Consultants Veterans Health Administration Department of Veterans Affairs Version: 1 August 2009 Executive Summary Multiple Myeloma (MM) is part of a spectrum of diseases that involves the neoplastic proliferation of a monoclonal clone of plasma cell that produces immunoglobulins. MM is the second most frequent hematologic malignancy in the United States after non-Hodgkins lymphoma. Patients with asymptomatic myeloma may not require immediate treatment. The choice of initial therapy for symptomatic patients depends on whether or not the patient is a candidate for stem cell transplantation (SCT). Patients who are candidates for SCT receive a short (4 course) induction like therapy to determine initial response and to allow for collection of stem cells. Patients may go immediately to transplant or may continue with the initial therapy and delay transplant. Patients who are not transplant candidates are also evaluated for an initial response and continue initial therapy if at least a partial response is achieved. The length of therapy in this population is not well defined. The overall goal is to prolong overall survival and improve quality of life; however, long-term disease-free survival has not been observed. The choice of the initial drug regimen is first based on SCT eligibility, and then on a complex of disease related, treatment related, and patient related factors. Consideration is given to renal function, risk for thrombosis, pre-existing neuropathy, past compliance with oral medications, and distance to travel to the treatment site. For patients who are eligible for SCT, alkylating agents should be avoided in initial therapy as they impair the ability to adequately harvest stem cells for transplant. In this population, the three newer agents produce high response rates before transplantation. There is no standard initial therapy for patients who are candidates for SCT. The choice of initial therapy is based on the above-named factors and individualization for each patient. Bortezomib-dexamethasone and lenalidomide-low-dose dexamethasone are combinations with high level evidence for efficacy. Single agent dexamethasone plays a very limited role in this setting, and thalidomide-dexamethasone may be considered in a select population. For patients who are not transplant candidates, there is a wider array of regimens to choose from. Alkylating agents can be utilized in this population. There is no one standard initial therapy for patients who are not transplant candidates. The choice of therapy is based on disease, treatment, and patient related factors. The regimens with the highest level of evidence to date are the triplet regimens of melphalan plus prednisone and either thalidomide or bortezomib. The addition of thalidomide or bortezomib to melphalan plus prednisone is associated with additional toxicity. Preliminary reports of two and three year survival data with lenalidomide plus dexamethasone has consistently shown good results; while the data is encouraging, further follow-up is needed as well as publication in peer-reviewed journals. Melphalan and prednisone, alone, may be used in patients who do not tolerate the novel agents but response rates are lower than with triplet therapies or lenalidomide plus dexamethasone. On disease progression, these patients should be offered one of the three newer agents; otherwise, their overall survival may be compromised. For patients who are co-managed, please refer to the Dual Care Policy at HYPERLINK "http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=2058"Dual Care When used in combination with lenalidomide, a lower dose of dexamethasone produced higher response rates and lower rates of toxicity than standard dose dexamethasone in a phase III trial. Consensus opinion and single institution practice endorse the low-dose dexamethasone combination. Risks of therapy with the newer agents include thrombosis with lenalidomide and thalidomide when combined with standard dose dexamethasone, and peripheral neuropathy with bortezomib. The duration of initial treatment for patients who are not transplant candidates should continue until disease plateau, at which time treatment should stop. Maintenance treatment is not recommended; however, patients should be observed for disease progression and offered subsequent treatment. Guidance for thrombosis prophylaxis is based on a current consensus statement and not on a randomized clinical trial. A randomized trial of prophylactic therapy required in this population is currently on-going. Until that data is available, utilization of the consensus recommendations with careful patient evaluation should be considered. Because most regimens include glucocorticoids, consider prophylaxis for opportunistic infections (PCP and fungus) and reactivation of varicella. A select population of VA patients may also be at risk for latent infection with strongyloides and/or tuberculosis and should be carefully evaluated. VA Pharmacy Benefits Management Services VHAs Pharmacy Benefits Management Services (PBM) has been directed by the Under Secretary for Health to coordinate the development of guidance for the pharmacologic management of common diseases treated within the VA, establish a national VA formulary, manage pharmaceutical costs and utilization, and measure outcomes as they apply to patient care. The Medical Advisory Panel (MAP) provides support and direction to the PBM Staff, located in Washington, DC and Hines, IL. Michael Valentino, RPh, MHSA Chief Consultant, PBM Joseph J. Canzolino, RPh Deputy Chief Consultant, PBM Virginia S. Torrise, PharmD Deputy Chief Consultant, PBM Ken Siehr, RPh, MS Deputy Chief Consultant, PBM Timothy Stroup, RPh Deputy Chief Consultant, PBM Lou Cobuzzi, RPH, MS Associate Chief Consultant, PBM Jeff Ramirez, PharmD Associate Chief Consultant, PBM Puri Subramaniam, PharmD, MS Associate Chief Consultant, PBM John Lowe, RPh Associate Chief Consultant, PBM Vincent Calabrese, PharmD Associate Chief Consultant, PBM Fran Cunningham, PharmD Director, Center for Medication Safety Program Manager, Outcomes Research, PBM  Janet Dailey, PharmD Clinical Pharmacy Specialist Elaine Furmaga, PharmD Clinical Pharmacy Specialist Mark Geraci, PharmD Clinical Pharmacy Specialist Francine Goodman, PharmD Clinical Pharmacy Specialist Bernadette Heron, PharmD Clinical Pharmacy Specialist Cathy Kelley, PharmD Clinical Pharmacy Specialist Deborah Kachikian, PharmD Clinical Pharmacy Specialist Lisa Longo, PharmD Clinical Pharmacy Specialist Melinda Neuhauser, PharmD Clinical Pharmacy Specialist Todd Semla, MS, PharmD Clinical Pharmacy Specialist Kathy Tortorice, PharmD Clinical Pharmacy Specialist Medical Advisory Panel Mission The role of the Medical Advisory Panel (MAP) in the PBM is to consult on the development and refinement of evidence-based pharmacologic management guidance for the VHA. These guidances are intended to promote provision of quality, cost-effective care. The MAP is composed of practicing VA physicians from facilities across the nation: Barry Cusack, MD Boise VAMC Professor, Division of Gerontology & Geriatric Medicine, University of Washington, School of Medicine, Seattle, WA Sylvan DeLisle, MD, MBA VA Maryland HCS Associate Professor of Medicine and Physiology University of Maryland School of Medicine Baltimore, MD Thomas Dickinson, MD Associate Chief, Primary Care Brocton Division VA Boston HCS Clinical Instructor in Medicine Harvard Medical School Boston, MA John Downs, MD Medicine Service South Texas Veterans HCS Chief, General Medicine & Associate Professor of Medicine University of Texas HSC San Antonio, TX Peter Glassman, MBBS, MSc Greater Los Angeles HCS Professor, University of California (UCLA) Los Angeles, CA Matthew Goetz, MD Greater Los Angeles HCS Chief, Infectious Diseases Professor of Clinical Medicine David Geffen School of Medicine at UCLA Chester B. Good, MD, MPH VA Pittsburgh HCS Chief, Section of General Medicine Professor of Medicine University of Pittsburgh Pittsburgh, PA Robert Harriman, MD Director, Cardiac Electrophysiology James Haley Veterans Hospital Professor of Medicine Loyola University Stritch School of Medicine Maywood, IL Lori Highberger, MD Chief of Psychiatry Carl T. Hayden VAMC Phoenix, AZ William Korchik, MD Medical Director, Extended Care & Rehab Gerontology VAMC Minneapolis Assistant Professor of Medicine University of Minnesota, Minneapolis, MN Suzanne Quinn, MD Gainesville VAMC Robert Rosenstein, MD Section of Cardiology West Palm Beach VAMC Alexander Shepherd, MD, PhD Professor and Chief, Div. of Clinical Pharmacology, Departments of Medicine and Pharmacology University of Texas HCA San Antonio, TX Los Angeles, CA Acknowledgements This guideline was developed in consultation with the PBM-MAP. The following clinicians assisted in developing, researching, writing, and preparation of the final document. The list does not include all clinicians in the field who reviewed the document and provided comments. Mark Geraci, PharmD Clinical Pharmacy Specialist, PBM Suman Kambhampati, MD Oncology Consultant, PBM-MAP Staff Physician Kansas City VA Medical Center Associate Professor of Medicine University of Kansas Medical Center Kansas City, KS Jeffrey Kanofsky, MD, PhD Staff Physician Section of Hematology/Oncology Medical and Neurology Service Line Edward Hines, Jr. VA Hospital Hines IL Professor of Medicine and of Cell Biology, Neurobiology and Anatomy Loyola University Stritch School of Medicine Maywood, IL  Beth A. Martin-Kool, MD Staff Physician, Transfusion Service Director Palo Alto VAMC Clinical Assistant Professor Stanford School of Medicine Stanford, CA Nikhil Munshi, MD Boston VAMC Associate Professor of Medicine Harvard Medical School Associate Director, Jerome Lipper Myeloma Center, Dana Farber Cancer Institute Boston, MA Table of Contents  TOC \o "1-3" \h \z \u HYPERLINK \l "_Toc238980953"List of Abbreviations  PAGEREF _Toc238980953 \h 7 HYPERLINK \l "_Toc238980954"Definitions  PAGEREF _Toc238980954 \h 8 HYPERLINK \l "_Toc238980955"Goals of the Guidance  PAGEREF _Toc238980955 \h 10 HYPERLINK \l "_Toc238980956"Guidance Development Process  PAGEREF _Toc238980956 \h 10 HYPERLINK \l "_Toc238980957"Algorithm 1 VHA Clinical Guidance on the Initial Management of Adults with Multiple Myeloma  PAGEREF _Toc238980957 \h 14 HYPERLINK \l "_Toc238980958"Annotations  PAGEREF _Toc238980958 \h 15 HYPERLINK \l "_Toc238980959"A. Adults with untreated symptomatic multiple myeloma  PAGEREF _Toc238980959 \h 15 HYPERLINK \l "_Toc238980960"B. Is the patient a candidate for stem cell transplantation?  PAGEREF _Toc238980960 \h 15 HYPERLINK \l "_Toc238980961"C. Pre-existing co-morbid diseases/factors that affect the choice of initial therapy  PAGEREF _Toc238980961 \h 16 HYPERLINK \l "_Toc238980962"D. Begin initial therapy in patients who ARE candidates for stem cell transplantation  PAGEREF _Toc238980962 \h 18 HYPERLINK \l "_Toc238980963"Dexamethasone  PAGEREF _Toc238980963 \h 18 HYPERLINK \l "_Toc238980964"Thalidomide-Dexamethasone (TD)  PAGEREF _Toc238980964 \h 20 HYPERLINK \l "_Toc238980965"Lenalidomide-Dexamethasone (RD or Rd for low dose dexamethasone)  PAGEREF _Toc238980965 \h 21 HYPERLINK \l "_Toc238980966"Bortezomib-Dexamethasone (BD)  PAGEREF _Toc238980966 \h 24 HYPERLINK \l "_Toc238980967"Bortezomib-Thalidomide-Dexamethasone (VTD)  PAGEREF _Toc238980967 \h 24 HYPERLINK \l "_Toc238980968"Bortezomib-Adriamycin-Dexamethasone (PAD)  PAGEREF _Toc238980968 \h 24 HYPERLINK \l "_Toc238980969"Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD)  PAGEREF _Toc238980969 \h 24 HYPERLINK \l "_Toc238980970"E. Early Versus Delayed Stem Cell Transplantation  PAGEREF _Toc238980970 \h 27 HYPERLINK \l "_Toc238980971"F. Secondary Induction Therapy for Transplant Candidates/ Alternative Drug Therapy in Non-Transplant Patients  PAGEREF _Toc238980971 \h 27 HYPERLINK \l "_Toc238980972"G. Select Initial Therapy in Patients Who Are NOT Transplant Candidates  PAGEREF _Toc238980972 \h 28 HYPERLINK \l "_Toc238980973"Dexamethasone  PAGEREF _Toc238980973 \h 28 HYPERLINK \l "_Toc238980974"Thalidomide-Dexamethasone (TD)  PAGEREF _Toc238980974 \h 29 HYPERLINK \l "_Toc238980975"Lenalidomide-Dexamethasone (RD or Rd for low dose dexamethasone)  PAGEREF _Toc238980975 \h 30 HYPERLINK \l "_Toc238980976"Melphalan-Prednisone (MP)  PAGEREF _Toc238980976 \h 32 HYPERLINK \l "_Toc238980977"Melphalan-Prednisone-Thalidomide (MPT)  PAGEREF _Toc238980977 \h 32 HYPERLINK \l "_Toc238980978"Melphalan-Prednisone-Bortezomib (MPV)  PAGEREF _Toc238980978 \h 35 HYPERLINK \l "_Toc238980979"H. Initial Response in Patients Who Are NOT Transplant Candidates  PAGEREF _Toc238980979 \h 36 HYPERLINK \l "_Toc238980980"I. Continuation of Therapy in Patients Who Are NOT Transplant Candidates  PAGEREF _Toc238980980 \h 37 HYPERLINK \l "_Toc238980981"References  PAGEREF _Toc238980981 \h 38  List of Abbreviations CI = 95% Confidence Interval CR = Complete Response EFS = Event Free Survival FISH = Fluorescent In-situ Hybridization FLC = Free light chains GIMEMA = Gruppo Italiano Malattie EMatologiche dell'Adulto HR = Hazard Ratio IFM = Intergroupe Francophone du Myelome IMWG = International Myeloma Working Group ISS = International Staging System LVEF = Left ventricular ejection fraction MR = Minor Response nCR = near Complete Response OS = Overall Survival PCP = Pneumocystis carinii pneumonia PJP = Pneumocystis jiroveci pneumonia PFS = Progression Free Survival PR = Partial Response RR = Response Rate SCT = Stem Cell Transplant TTP = Time to Progression VGPR = Very Good Partial Response VTE = venous thromboembolism Definitions Complete Response = No M protein in serum and urine; negative immunofixation and disappearance of any soft-tissue plasmacytomas and<5% plasma cells in bone marrow Event Free Survival = The time span that follows therapy for a malignancy, during which there are no objective signs of recurrence High-risk Cytogenetics = t(4:14), t(14:16), or del(17p) by FISH and/or conventional cytgenetics, 13q deletion by conventional cytogenetics Multiple Myeloma = A clonal B-cell malignancy characterised by abnormal proliferation of plasma cells able to produce a monoclonal immunoglobulin (M protein). Some myelomas only produce light chains, and a small percentage are non-secretory. near Complete Response = Normal electrophoresis but a positive immunofixation is defined as near-CR (n-CR) Overall Survival = The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease. Usually reported as months of time since diagnosis or treatment Progression Free Survival = The length of time during and after treatment in which a patient is living with a disease that does not get worse Partial Response = e"50% reduction of serum M protein and reduction in 24 h urine M-protein by e"90% or to <200 mg 24 h. If the serum and urine M-protein are unmeasurable, a e"50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, e"50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was e"30%. In addition to the above criteria, if present at baseline, e"50% reduction in the size of soft-tissue plasmacytomas is also required Response Rate = The percentage of patients whose cancer shrinks or disappears after treatment. Revlimid = lenalidomide Stem Cell Transplant = The use of stem cells as a treatment for diseases Thalomid = thalidomide Velcade = bortezomib VGPR = Serum and urine M-component detectable by immunofixation but not on electrophoresis or e"90% or greater reduction in serum M protein plus urine M-protein <100 mg per 24 h Introduction The Initial Therapy of Adults with Multiple Myeloma Multiple myeloma (MM) is part of a spectrum of diseases involving the neoplastic proliferation of a single clone of plasma cells that produce immunoglobulins. Included in this spectrum of diseases are benign conditions such as monoclonal gammapathy of undetermined significance (MGUS), rare disorders such as Castlemans disease, indolent conditions such as Waldenstroms macroglobulinemia, and the aggressive plasma cell leukemia. Chemotherapy was first successfully to treat MM in 1958 using a racemic mixture of D- and L-phenylalanine mustard. Subsequent investigations found the antimyeloma activity was due to the L-isomer, which came to be known as melphalan. Later, in 1967, high doses of glucocorticoids were shown to induce remissions in relapsing or refractory MM. Data from the SEER program shows that MM accounts for about 1% of all malignancies in whites and 2% of all malignancies in blacks in the United States. It is the second most frequent hematologic malignancy in the US after non-Hodgkins lymphoma. Multiple myeloma is a service connected disease related to exposure to Agent Orange. It is unknown if the treatment or outcomes of treatment are different for Agent-Orange related disease. Goals of the Guidance The goal of evidence-based guidance in the Veterans Health Administration (VHA) is to improve patient outcomes. The desired outcome of successful implementation of this guidance is to provide a framework for selecting the initial treatment of symptomatic multiple myeloma with consideration given to disease-related prognostic indicators and patient factors that may affect efficacy, safety, and quality of life. To achieve this goal, this guidance addresses the following points: Identifying patients who are or are not potential candidates for stem cell transplantation Identifying disease-related prognostic factors and patient factors to be considered in selecting initial therapy. Develop a plan for monitoring efficacy and toxicity to minimize complications. Guidance Development Process Whenever possible, the PBMMAP relies upon evidence-based, multidisciplinary, nationally recognized consensus statements and randomized trials published in peer-reviewed journals for the basis of clinical practice guidance. Relevant literature was reviewed and assessed with consideration given to the VA population. Drafts of the full guideline or only the treatment algorithm were sent to VA hematologists and oncologists and members of the PBM-MAP for comment and to identify pivotal decision points in treatment pathways. The present guidance relied primarily on evidence-based publications on the diagnosis and management of Multiple Myeloma. Sources of Evidence Literature searches were performed to obtain updated, general information on the management of Multiple Myeloma and to obtain problem-directed evidence to support decision points and treatment pathways. Electronic searches were performed on all Evidence Based Medicine reviews available on OVID (included the Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effectiveness, and Cochrane Controlled Trials Register) and the National Library of Medicines (NLMs) MEDLINE/PubMed database (1966 to May 2009). Preference was given to meta-analyses, systematic reviews, and randomized controlled trials. The Clinical Queries service of PubMed was used for focused searches for well-designed (e.g., double-blind or placebo-controlled) trials on therapy, diagnosis, or prognosis. Relevant articles were also obtained from reference lists of retrieved articles. In an attempt to find other up-to-date evidence-based clinical practice guidelines on the initial management of Multiple Myeloma the Web sites of the Agency for Healthcare Research and Quality (http://www.ahcpr.gov), the National Guideline Clearinghouse (http://www.guidelines.gov), and the National Institute for Clinical Excellence (http://www.nice.org.uk) were searched. A complete list of references used in the development of the treatment algorithm and annotations starts on page 38. Literature Evaluation: The following questions were used to evaluate published clinical trials used in this document. Were patients randomized (centrally for multi-site studies)? Was everyone blinded (including radiology and data committee)? Were treatment and control groups similar at the start of the study? Were all patients accounted for at the end? Were missing patients addressed or adjusted for? Was data analyzed on an intent-to-treat basis? Were groups treated similarly during the study except for study treatment? How was study funded? What was the primary endpoint? Secondary endpoints? Was there a difference between treatments? Statistically different? Clinically different? Does the study have outcomes important to VA patients? Were the patients similar to VA patients? Do the benefits outweigh the risks? Rating the Evidence Articles supporting initial therapeutic interventions were reviewed for relevance and graded according to the U.S. Preventive Service Task Force. Ratings were based on the level of evidence (LE), the overall quality of the evidence (OQ), the net benefit of the intervention, and the grade of the strength of the recommendation (SR). (See tables #1 to #3.) The SR depends on the OQ of the evidence and on the net benefit) Table 1 Level of Evidence (LE) Rating Scale I Evidence obtained from at least one properly randomized controlled trial II-1 Evidence obtained from well-designed controlled trials without randomization II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferablyfrom more than one center or research group. II-3 Evidence obtained from multiple time series with or without the intervention. Dramaticresults in uncontrolled experiments (such as in the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees Table 2 Overall Quality (OQ) Good High-grade evidence (I or II-1) directly linked to health outcome Fair High-grade evidence (I or II-1) linked to intermediate outcome OR Moderate-grade evidence (II-2 or II-3) directly linked to health outcome Poor Level III evidence or no linkage to health outcome % Insufficient Evidence Table 3 Grade for Strength of Recommendation (SR) Overall Quality of EvidenceNet benefit of interventionSubstantialModerateSmallZero or NegativeGood Fair Poor InsufficientA B C IB B C IC C C ID D D DKey: A A strong recommendation that the intervention is always indicated and acceptable B A recommendation that the intervention may be useful/effective C A recommendation that the intervention may be considered D A recommendation that a procedure may be considered not useful/effective, or may be harmful I Insufficient evidence to recommend for or against-use clinical judgment Treatment Algorithm and Annotations Algorithm 1 VHA Clinical Guidance on the Initial Management of Adults with Multiple Myeloma    No     Yes     No    Yes    No   Yes  VHA Clinical Guidance on the Initial Management of Multiple Myeloma Annotations A. Adults with untreated symptomatic multiple myeloma Annotation Multiple myeloma is one disease in the spectrum of plasma cell neoplasms affecting adults. It is characterized by a clonal proliferation of immunoglobulin producing B cells with features that include over production of immunoglobulin and immunosuppression. Although intact immunoglobulins are usually secreted by plasma cells, there may be a discrepancy in the production of heavy and light chains, with an excess of light chains excreted in the urine (Bence Jones proteinuria). In a small percentage of patients, myelomas do not secrete immunoglobulins or light chains (non-secretory myeloma). Patients with smoldering (asymptomatic) myeloma (M protein e"3 g/dL or >10% bone marrow plasma cells without lytic lesions, hypercalcemia, renal insufficiency, anemia, or end-organ damage) do not require immediate therapy as there is no clear benefit in this population. Clinical manifestations, including anemia, bone pain, pathologic fractures, infections, hypercalcemia, renal failure, and coagulopathy are the result of tumor involvement in the bone marrow, the effect of myeloma protein on various end organs, cytokine production by tumor cells or by the bone marrow microenvironment, and deficiencies in humoral and cellular immunity. Diagnostic evaluation includes a complete blood count with differential, complete skeletal radiographic survey, serum and urine electrophoresis and immunofixation, quantitative immunoglobulin levels, 24 hour urinary protein excretion, beta-2 microglobulin, and bone marrow aspiration and biopsy. Part of the bone marrow aspirate is sent for standard cytogenetics and a myeloma FISH panel. Following the initial evaluation, more detailed cellular and molecular studies may be considered to evaluate prognostic variables affecting outcomes. An in-depth review of the initial diagnostic evaluation is beyond the scope of this guidance. Intravenous bisphosphonate therapy with either pamidronate or zoledronic acid prolongs the time to the first skeletal-related event (pathologic fracture, radiotherapy to bone, spinal cord compression, orthopedic surgery, hypercalcemia). The American Society of Clinical Oncology guidelines on the use of intravenous bisphosphonates in multiple myeloma recommend use in patients with lytic bone lesions or compression fractures. All patients should have a dental exam and preventive dental procedures before starting bisphosphonate therapy. Serum creatinine should be checked prior to each dose to monitor for renal toxicity and make any needed dose adjustment. The ASCO guideline suggests a duration of bisphosphonate therapy of 2 years in patients with responsive or stable disease; further use is at the discretion of the physician. B. Is the patient a candidate for stem cell transplantation? Annotation,,,,,,,, Eligibility for stem cell transplantation (SCT) in multiple myeloma (MM) typically includes high performance status, acceptable major organ function, acceptable neuropsychiatric function, a reliable caregiver, acceptable social circumstances, lack of drug/alcohol addiction, and an age not exceeding 70 years. Some centers do not have age limits, and rely on organ function and response to therapy, rather than chronological age, when considering patients for transplant. Generally, autologous SCT is utilized in MM. While immediate transplantation is not required in MM, when SCT is chosen as an early therapy, the concept of viewing pre-transplant chemotherapy as induction therapy, which is intended to rapidly reduce disease burden, is a widely used practice. The impact of induction therapy using novel agents, such as bortezomib, lenalidomide, and thalidomide, on the outcome from SCT is under investigation. Achieving CR/VGPR from treatment given before SCT may confer significant prognostic value (Attal et al, 1996; Morris et al, 2004; Kim JS et al, 2009). Treatment planning for the transplant eligible patient should be done in conjunction with the VHA transplant center of choice. This collaborative assessment, usually by telephone, should occur after risk factors have been assessed, preferably prior to initiating induction therapy or, at least, within the first cycle of therapy. For example, patients with very high risk cytogenetics such as t (4;14) or del (17p) have traditionally had a poor outcome even with tandem autologous transplantation. Use of newer agents, particularly bortezomib, may improve the results obtained in this patient population. Additionally, if the transplant specialist considers incorporating an allogeneic transplant in the treatment plan, a donor search needs to be initiated promptly. Other examples of how initial regimen components can impact transplant methods and outcomes include the duration of lenalidomide and post-transplant maintenance. General agreement exists to support limitation on the pre-SCT duration of lenalidomide (Kumar et al, 2009; Mark et al, 2008; Paripati et al, 2008) and to avoid melphalan prior to SCT. Initial therapy with lenalidomide, as well as the duration of lenalidomide therapy, could adversely affect the ability to collect stem cells for transplant (Kumar et al, 2007; Popat et al, 2009). If post-SCT maintenance therapy is planned, the induction regimen components may affect the medication choices following transplantation. C. Pre-existing co-morbid diseases/factors that affect the choice of initial therapy Annotation,,,,,,,,,,,,,60,61,74,81 Determination of the optimal treatment plan for a given multiple myeloma (MM) patient, including the initial regimen and the role for stem cell transplantation (SCT), requires a complex assessment and decision-making process. The most common pertinent factors related to the choice of regimen include age, cytogenetic abnormalities (assessed by both FISH and conventional cytogenetics), renal function, co-morbidities (neuropathy, neuromuscular diseases, diabetes), and ability to adhere to a treatment regimen. Given that high dose and prolonged corticosteroid therapy is a common component of the treatment regimen, assessment for risk of infection, particularly tuberculosis and strongyloides, is especially important in patients with risk factors for latent infections including homelessness, wartime service in Asian countries/tropics, and Filipino origin. Other general considerations are the need for prophylactic antibiotics to prevent opportunistic infections (PCP and fungal infections) and antiviral prophylaxis for varicella reactivation. Disease related factors and treatment related factors play a role in susceptibility to infection. During induction therapy, high dose dexamethasone therapy is associated with increased rates of infection in multiple myeloma patients, including PCP pneumonia (Oken et al, 1996; Hernandez et al, 2004; Facon et al, 2005; Palumbo et al, 2006). Reactivation of varicella zoster has been reported with bortezomib (San Miguel, et al. 2008). The following table provides a framework for choosing drugs and combinations based on a number of patient and disease characteristics. This table is based on published literature as well as expert opinion. Each patient case must be evaluated on an individual basis. Table #4 Multiple Myeloma Risk Stratification for Initial Chemotherapy Risk FactorBortezLenalidLen/DexThal/DexDoxCytMelphalanDexAge >75YesCYes#CCCYesCPre-existing neuropathy e" Grade 2NoYesYesNoYesYesYesYesTransplant candidateYesYes#Yes#YesYesYesNoYesDiabetesYesYesYes#Yes#YesYesYesCRenal FailureYesCCYesYesCCYesThrombosis Risk YesYesCCYesYesYesYesHigh-risk cytogeneticsYesNoCNoYesYesNoYesPoor medication complianceYesNoNoNoYesYesNoCTravel barrierNoYesYesYesNoYes (oral)YesYesConcurrent radiationNoNoNoNoNoNoNoYesLow LVEFYes#YesYesCNoCYesYesKey: Yes = acceptable; Yes# = limited data, careful monitoring required; No = avoid; C = Caution Bortez=bortezomib; Lenalid=lenalidomide; Len/Dex=lenalidomide + dexamethasone; Thal/Dex=thalidomide + dexamethasone; Dox=doxorubicin or any anthracycline; Cyt=cyclophosphamide; Dex=dexamethasone While this table does not provide specific guidelines for patients with multiple risk factors, the choice of therapy is made based on a risk-benefit evaluation. For example, consider a patient who has co-existing renal failure and peripheral neuropathy. Bortezomib should not be used in patients with pre-existing neuropathy and lenalidomide is used with caution in patients with renal failure. In this case, the benefit of lenalidomide outweighs the risk and a reduced dose is prescribed based on package insert recommendations. Neither the short term or long term safety and efficacy of novel agents (bortezomib, lenalidomide, and thalidomide) has been fully evaluated and reported in the elderly, particularly for patients over the age of 75. Example of expert consensus in the use of a risk table to decide initial therapy for a patient who is NOT a transplant candidate (adapted from Blade et al. 2009): Risk FactorYes (risk present)No (risk not present)Therapy Choice(s)Aggressive DiseaseMPVMPTHigh risk cytogeneticsMPV or Rd*MPT or MPRenal FailureBDMPV or MPT or Rd or MPSystemic anticoagulation contraindicatedMPV or MP or BDMPT or RdGrade e"2 NeuropathyRdMPV or MPT or Rd or MPe"75 year oldMPT or MPV or RdMPV or MPT or Rd or MPTravel issuesMPT or RdMPVMPV=melphalan, prednisone, Velcade; MPT=melphalan, prednisone, thalidomide; Rd=Revlimid, low-dose dexamethasone; MP=melphalan, prednisone; BD=bortezomib, dexamethasone;*Patients with either del(13q) or t(4;14) could benefit, whereas patients with del(17p13) had a significantly worse outcome with Revlimid and dexamethasone22 While lenalidomide or thalidomide alone as induction or maintenance after chemotherapy is associated with low risk (<5%) of venous thromboembolism, the risk of thromboembolism significantly increases when lenalidomide is used in combination with dexamethasone, doxorubicin, erythropoietin, or multi-agent chemotherapies and when thalidomide is used in combination with dexamethasone, Doxil, or multi-agent chemotherapies. A risk assessment model and prevention strategies have been proposed, however these strategies are only now being tested in a randomized trial comparing lenalidomide with and without prophylaxis. Anticoagulant prophylaxis is not recommended for patients receiving single-agent lenalidomide. A risk assessment model (Palumbo et al, 2008) based on expert opinion has been proposed by the International Myeloma Working Group (IMWG) for the management of VTE in myeloma patients treated with lenalidomide or thalidomide. There is an on-going randomized trial for VTE prophylaxis through GIMEMA comparing aspirin, warfarin and LMWH for prophylaxis in patients receiving lenalidomide or thalidomide. Results are not yet published. Thrombosis Prevention: Risk Stratification if initial therapy contains thalidomide or lenalidomide in combination with either dexamethasone or traditional chemotherapy agents (Adapted from Palumbo et al, 2008) Level of Risk*TherapyNo risk factor or one risk factorAspirin 81-325 mg dailyTwo or more risk factorsLMWH prophylactic dose or Warfarin with target INR 2-3Myeloma therapy with high dose dexamethasone, doxorubicin, or multi-agent chemotherapyLMWH prophylactic dose, or Warfarin with target INR 2-3 *Risk Factors for venous thromboembolism: Obesity (BMI 30 or higher)HyperviscosityPrevious DVT or PECentral Venous CatheterPacemakerCardiac DiseaseChronic Renal FailureDiabetesAcute InfectionImmobilizationErythropoetin therapyDiagnosis of myelomaType of myeloma therapy: Dexamethasone > 479mg per month, Doxorubicin Multi-agent chemotherapySurgery: General surgery or trauma surgery with any anesthesiaInherited or acquired tendency for thrombosisInstitutionalization within previous 90 days (with or without surgery) D. Begin initial therapy in patients who ARE candidates for stem cell transplantation Regimens (Strength of Recommendation) Dexamethasone (B) Thalidomide-Dexamethasone (B) Lenalidomide-Dexamethasone (B) Bortezomib-Dexamethasone (B) Bortezomib-Thalidomide-Dexamethasone (B) Bortezomib-Adriamycin-Dexamethasone (B) Cyclophosphamide-Bortezomib-Dexamethasone (B) Dexamethasone Annotation:,, Table #5 Dexamethasone InterventionReferencePrimary OutcomeCR + nCRe"PRPFS (mos)OS (mos)D vs VADKumar et al, 2004Response to transplant, OS and PFS 1 year post transplant0% vs 0%65% vs 75%D=20 VAD=29D=85% at 2 years VAD=78% at 2 yearsD vs TDRajkumar et al, 2006Best RR within 4 cycles of Treatment0% vs 4%41% vs 63%Not reportedNot reportedD vs VAD, TD, RDKumar et al, 2008 OS and PFSNot reportedNot reportedD=24.7 VAD=27.1 TD=21.1 RD=not reached (P=0.11)D=69.6 VAD=62 TD=not reached RD=not reached (P=0.2) (post ASCT)D= dexamethasone; OS=overall survival; PFS= progression-free survival; RR=response rate; TD=thalidomide+dexamethasone; VAD= vincristine, Adriamycin, dexamethasone The study reported by Kumar et al (2004) was a retrospective study in which 35 patients receiving induction therapy with dexamethasone were compared with 72 patients receiving VAD. All patients went to transplant after induction therapy. The study patients were a consecutive cohort. While the two groups of patients did not appear to be dissimilar, there was no attempt at matching the two groups. There was no explanation provided about how the treatments were selected for each patient. There were no differences in overall and complete response to transplant. There were also no differences in progression-free survival and in overall survival one year post transplant. The quality of the study is fair. The paper by Rajkumar et al (2006) was a randomized clinical trial involving 207 patients. The response rate to thalidomide-dexamethasone was higher than dexamethasone alone (P=0.0017). Toxicity was higher in patients receiving thalidomide-dexamethasone. Deep venous thrombosis and neuropathy (e" grade 3) were more common in the thalidomide-dexamethasone arm. Stem cell collection was successful in 90% of patients in each arm. The quality of the study is fair as the primary endpoint is not OS. The paper by Kumar et al (2008) was a retrospective study of 472 patients who underwent stem cell transplantation within 12 months of diagnosis. The purpose of the study was to determine if the type of initial chemotherapy affected the post-transplant outcome. There were four treatment groups: VAD, dexamethasone alone, thalidomide + dexamethasone and lenalidomide + dexamethasone. No differences in survival or time to progression were found. The major weakness of this study is that it is retrospective and the different treatment groups were not matched. Thus, the quality of the study is fair. In summary, induction chemotherapy with dexamethasone appears to be effective, but the pre-transplant response rates are lower than newer combinations therapies, such as thalidomide plus dexamethasone. However, the toxicity associated with dexamethasone induction is lower than the combination regimens. Further, it is uncertain how much the type of induction therapy affects the post- transplant outcomes. Induction therapy with dexamethasone alone would be most appropriate for patients who cannot tolerate combination regimens. InterventionReference(s)LEOQSRDexamethasoneKumar et al (2004) Rajkumar et al (2006) Kumar et al (2008) II-2 I II-2 FairB Thalidomide-Dexamethasone (TD) Annotation:31,32,,,,,, Table #6 Thalidomide and Dexamethasone InterventionReferencePrimary OutcomeCR + nCRe"PRPFS (mos)OS (mos)TDRajkumar et al, 2002RR30%64%Not reportedNot reportedTDWeber et al, 2003 RR16%72%Not reportedNot reportedTD vs VADCavo et al, 2005 RR and Reduction in Immunoglobulins13% vs 13%76% vs 52%Not reportedNot reportedTD vs DRajkumar et al, 2006, Best RR within 4 cycles of Treatment4% vs 0%63% vs 41%Not reportedNot reportedTD vs VAD, D, RDKumar et al, 2008 OS and PFSNot ReportedNot ReportedD=24.7 VAD=27.1 TD=21.1 RD=not reached (P=0.11)D=69.6 VAD=62 TD=not reached RD=not reached (P=0.2) (post ASCT)TDHussein et al, 2009OS and EFS27%66%50% at 4 years64% at 4 yearsD= dexamethasone; T=thalidomide; TD=thalidomide+dexamethasone; VAD=vincristine, Adriamycin, dexamethasone; RD=lenalidomide+dex The study by Rajkumar et al (2002) was an uncontrolled study of 50 patients. The response rate was high (e"PR 64%). Stem cells were collected for 31 patients of which 26 proceeded to transplant and 64% of patients proceeded to transplant. Deep venous thrombosis was seen in 6 patients. The quality of this moderately sized study was fair. The study by Weber et al (2003) was uncontrolled and involved only 40 patients. Twenty-eight additional patients were treated with thalidomide alone. Only 21 patients actually proceeded to transplant. Since this is a relatively small uncontrolled study, the quality of the study is fair. The paper by Cavo et al (2005) is a retrospective case control study with two hundred patients. The response rate was higher for thalidomide-dexamethasone than for VAD. Thalidomide-dexamethasone also produced larger reductions in immunoglobulin levels for patients with both IgG myelomas (P=0.02) and IgA myelomas (P=0.03). Deep venous thromobosis was more frequent in the thalidomide-dexamethasone arm (15% versus 2%). Granulocytopenia was more common in the VAD arm (12% versus 0%). P values were not reported for toxicity. The quality of the study is fair with no major design flaws. The paper by Rajkumar et al (2006) was a randomized clinical trial involving 207 patients. The response rate to thalidomide-dexamethasone was higher than dexamethasone alone (P=0.0017). Toxicity was higher in patients receiving thalidomide-dexamethasone. Deep venous thrombosis and neuropathy (e" grade 3) were more common in the thalidomide-dexamethasone arm. Stem cell collection was successful in 90% of patients in each arm. The quality of the study was fair. The paper by Kumar et al (2008) was a retrospective study of 472 patients who underwent stem cell transplantation within 12 months of diagnosis. The purpose of the study was to determine if the type of initial chemotherapy affected the post-transplant outcome. There were four treatment groups, VAD, dexamethasone alone, thalidomide + dexamethasone and lenalidomide + dexamethasone. No difference in survival or time to progression was found. The major weakness of this study is that it is retrospective and the different treatment groups were not matched. Thus, the quality of the study was fair. The paper by Hussein et al (2009) was a phase II study with 142 patients treated. Collection of stem cells sufficient for two transplantations was achieved in 88% of 111 patients. Patients treated on the S9321 protocol were used as historic controls. Two analyses were carried out. The first was for all patients on each protocol. In the second analysis, 121 patients were matched for ISS stage and LDH with 363 control patients. The overall survival (P=0.0002) and event-free survival (P<0.0001) for patients treated with thalidomide-dexamethasone were both superior to patients treated with VAD. This study has a major flaw because there were differences in the two treatment protocols in addition to differences in induction chemotherapy. The type of transplant used in each arm was different (tandem versus single transplant) and the type of post-transplant maintenance therapy was different (thalidomide versus interferon or no treatment). Thus, the quality of the study is poor. In summary, induction chemotherapy with thalidomide-dexamethasone consistently provides a high response rate prior to transplantation. There are also a significant number of complete remissions and near complete remissions. Consistently, stem cell collection is also adequate. Further, patients are able to undergo transplantation successfully. In contrast to VAD induction chemotherapy, the thalidomide-dexamethasone regimen is oral and does not require a hospital stay. Thalidomide-dexamethasone has a higher response rate than dexamethasone alone, but is associated with higher toxicity. The use of thalidomide-dexamethasone is associated with an increased risk of deep vein thrombosis and pulmonary embolism, but the incidence of these complications can be reduced by the prophylactic use of anticoagulants. Less certain is the impact of thalidomide-dexamethasone induction on the post- transplant outcomes. The post-transplant results are inconsistent. In the study by Kumar et al(2008), the survival and progression-free survival were independent of the induction regimen. In contrast, Hussein et al did report a significantly improved survival and event-free survival with thalidomide-dexamethasone induction. However, this study had a major design flaw. The strength of recommendation is given as a B rather than an A because of this uncertainty in post-transplant benefit and due to availability of more effective therapies. InterventionReference(s)LEOQSRThalidomide Plus DexamethasoneRajkumar et al (2002) Weber et al (2003) Cavo et al (2005) Rajkumar et al (2006) Kumar et al (2008) Hussein et al (2009) II-3 II-3 II-2 I II-2 II-2FairB Lenalidomide-Dexamethasone (RD or Rd for low dose dexamethasone) Annotation5,6,7,8,,,, Lenalidomide is not FDA approved for use as first-line therapy in multiple myeloma. To date, there are no randomized controlled trials of lenalidomide in combination with dexamethasone published in manuscript form in a peer reviewed journal as an induction regimen prior to stem cell transplantation (SCT). However, expert consensus (NCCN) and a large single institution program (Mayo Clinic at www.mSmart.org) consider this to be an appropriate first line therapy in the transplant eligible patient. While these consensus statements did not specifically address the needs of a Veteran population, the studies on which these are based (Tables 7 and 8) are applicable to VA patients who are transplant candidates. Table #7 Pre-transplantation Outcomes from Lenalidomide and Dexamethasone Induction Therapy RegimenReferencePrimary OutcomeCR + nCRe"PRLDLacy et al, 2007RR at 4 months8%100%RD vs RdRajkumar et al, 2008RR at 4 months 82% vs 70%BiRDNiesvizky et al, 2009RR toxicity39%91% Table #8 Post- transplantation Outcomes from Lenalidomide and Dexamethasone Induction Therapy RegimenReferencePrimary OutcomeCR + nCRe"PREFS or PFSOSLDLacy et al, 2007RRNot reportedNot reported83% at 2 years (transplant)92%* at 2 and 3 years (transplant)RD vs RdRajkumar et al, 2008RR Not reportedNot reportedNot reportedAt 1 year 99% At 2 years 94% (combined data)BiRDNiesvizky et al, 2009RR Toxicity#Not reported Not reported85%Not reportedL= lenalidomide; R= Revlimid; D=dexamethasone; Bi= Biaxin (clarithryomycin) #Described in annotation The paper by Lacy et al in 2007 report on 34 newly diagnosed patients treated in 2004 in a Phase II trial of lenalidomide and dexamethasone. The regimen used in this study was lenalidomide 25 mg daily for 21 days on a 28 day cycle with dexamethasone 40 mg for 12 doses/cycle for the first four cycles. After 4 cycles of therapy, patients were allowed to discontinue treatment to pursue SCT. Treatment beyond 4 cycles was permitted at the physicians discretion. Dexamethasone was reduced to four doses in subsequent cycles. Aspirin was used for thrombosis prophylaxis. The outcomes for the 13 patients who proceeded to SCT were reported. The median age of the entire cohort of patients was 64 years, and the characteristics related to advanced Salmon-Durie stage and disease activity appeared to be comparable between the transplant and no transplant groups but exact stage distribution was not reported. Serum creatinine was less than 2.5 mg/dL in the cohort. Cytogenetic and molecular analysis is not reported. Of note, 41% of the entire study cohort was ISS I and 12% Salmon-Durie Stage I but the exact stage of the transplant group is not reported. Grade three or higher toxicities were detected in 55% of the 34 patients, with fatigue being the most common grade 3/4 toxicity. Two patients in the no transplant group died of infection. Although 15 patients of the cohort, in a nonrandomized fashion, proceeded to stem cell mobilization, 13 proceeded to SCT. They received filgrastim for mobilization in all but 2 who received both cyclophosphamide and filgrastim. Stem cell collection was adequate in all. The number of transplant procedures was not specified. The rates of CR, VGPR, and PR prior to SCT were 8%, 31%, and 62%, respectively. Post SCT response rates were not reported. Notably, the patients in the no transplant group were noted to have increase depth of response with time and received a median of 19 cycles of therapy. PFS was 29 months in the no transplant group and was not reached in the transplant group. The 2 year PFS for the transplant group was 83% and 59% for the no transplant group. Three year OS for no transplant and transplant groups was at 85% and 92%, respectively. Comparison of the transplant and no transplant groups was not performed. Although there is extended follow-up on the cohort and the overall response rate is high, this is a relatively small, uncontrolled trial without a primary endpoint related to transplantation and with inadequate information on the transplant patient characteristics. Additionally, the use of more than 4 doses of dexamethasone 40 mg per cycle may confer excess toxicity which was later addressed by the Phase III ECOG study between lenalidomide with high or low dose dexamethasone. Therefore, although the quality of the information reported by the two papers on the use of lenalidomide and high-doses of dexamethasone as an induction regimen is fair, its applicability in light of E4A03 study results are limited. More recently, the ECOG study, E4A03, by Rajkumar et al (2008) was updated at the American Society of Hematology/American Society of Clinical Oncology Joint Symposium during the 50th Annual Meeting on December 7, 2008. In the study design, RD regimen consisted of four 28-day cycles of lenalidomide 25 mg/day PO on days 121 plus dexamethasone 40 mg on days 1 to 4, 9 to 12, and 17 to 20. Rd regimen consisted of four 28-day cycles of lenalidomide 25 mg/day PO on days 121 plus dexamethasone 40 mg on days 1, 8, 15, and 22. A total of 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. The primary objective was response and safety after 4 cycles. The E4A03 study also evaluated patient outcomes after 4 cycles of RD or Rd, defined as primary therapy, comparing (1) patients who completed 4 cycles of primary therapy and did not undergo ASCT, (2) patients who underwent ASCT after completing 4 cycles of primary therapy, (3) patients who continued RD beyond 4 cycles of primary therapy, and (4) patients who continued Rd beyond 4 cycles of primary therapy. In this study, grade >3 toxicities occurred with more frequency in the RD arm than in the Rd arm within first 4 cycles (50% vs 30% respectively, p<0.001). One hundred forty nine patients underwent stem cell mobilization, although regimen was not specified, and 97% were successful. PR or higher within the first 4 cycles was higher in the RD arm than in the Rd arm (82% vs 70%, p=0.007). CR+VGPR rates were 52% vs 42%, respectively (p=0.06). Overall survival was superior with Rd at 1 year (96% vs. 88%) and at 2 years (87% vs. 75%). There were no significant differences in 3-year OS rates among patients (n=102) who received RD versus Rd and ASCT (3 year OS = 92%). The quality of the study is good with no major design flaws. However, only a portion of patients were eligible for SCT, as the decision for SCT was left to physician or patient choice, which introduces considerable selection bias. Full publication of this study is not yet available. The paper by Niesvizky et al (2009) reports on a Phase II trial of 72 newly diagnosed patients, treated with a regimen of clarithromycin (Biaxin) 500 mg BID, lenalidomide 25 mg days 1-21, and dexamethasone 40 mg weekly on a 28 day cycle. The cohort included patients with only Salmon-Durie Stage II, III disease and serum creatinine less than 2.5 gm/dL. Cytogenetic analysis was abnormal in 12% and molecular abnormalities were detected in 72%. The proposed mechanisms of action of clarithromycin include pharmacological alteration in glucocorticoid kinetics, immunomodulation, and antineoplastic activity. The pre-transplantation response rates for the BiRD regimen for the cohort which proceeded to transplant were not separately reported but the median time to first response was 54 days (range 21-816 days) and the median time to maximal response was 209 days (range, 27-850 days). The rates of CR+nCR, VGPR, and PR were 53%, 21%, and 17%, respectively, for an ORR of 90%. The most common grade toxicities were neutropenia, anemia, thrombocytopenia, myopathy, and thrombosis. Relative dose intensity was maintained for all agents at 75% or greater. After a median time on treatment of 353 days (range, 137-651 days), 18 patients underwent stem cell mobilization: 9 with a combination of bortezomib, cyclophosphamide, and filgrastim, and 9 with a combination of cyclophosphamide and filgrastim, all with adequate stem cell collection. Number of transplants was not specified. Time to platelet and neutrophil recovery was comparable to historical controls. One patient died due to non-engraftment. Actuarial 2 year PFS for the transplant group was reported as 85% and for the nontransplant group 75% (P value not reported). Although the response rates to the regimen in the first line setting are high and are comparable to the results reported by Lacy et al, 2007, this moderately-sized, uncontrolled trial had only a small proportion of the patients undergo SCT. Inadequate information was reported on the transplant patients characteristics and specific response rates before and after SCT. Additionally, an unspecified dose of bortezomib was utilized in 50% of the transplanted patients during stem cell mobilization. Therefore, the quality of the information reported on the use of BiRD as an induction regimen is fair. In summary, lenalidomide and dexamethasone induction is associated with high response rates. Based on early studies and retrospective analyses, an important concern about the impact of lenalidomide and dexamethasone induction on stem cell mobilization for SCT was raised. These doubts, however, have been addressed in the recent consensus statement published by the IMWG on stem cell collection following induction therapy inclusive of novel agents. This new evidence suggests that mobilization with Cytoxan and GCF and, in specific instances, addition of plerixafor to GCSF seems to overcome the negative impact of lenalidomide on stem cell collection (Kumar et al, 2009). Nonetheless, until the issue of optimal number of cycles of the medications prior to stem cell mobilization and transplantation is addressed, the duration of lenalidomide therapy prior to stem cell mobilization should be typically limited to 4 months, with the length of pre-transplant therapy discussed with the transplant center. The overall recommendation of lenalidomide and dexamethasone as induction chemotherapy for myeloma is rated as B. InterventionReference(s)LEOQSRLenalidomide Plus DexamethasoneLacy et al (2007) Rajkumar et al (2008) Niesvizky et al (2008) II-3 I II-3FairB Bortezomib-Dexamethasone (BD) Bortezomib-Thalidomide-Dexamethasone (VTD) Bortezomib-Adriamycin-Dexamethasone (PAD) Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) Annotation,,,,,,,,, In general, the results of the studies of bortezomib-containing induction regimens used pre-autologous stem cell transplantation (SCT) are applicable to Veterans with multiple myeloma (MM) who are eligible for transplantation and who do not have grade 2 or higher peripheral neuropathy. Bortezomib-containing regimens may be preferred for Veterans with MM with adverse cytogenetics and/or renal failure. Bortezomib is approved for first-line use in patients with newly diagnosed multiple MM and for use in relapsed MM. Table #9 Bortezomib and Dexamethasone: Pre-transplant Outcomes InterventionReferencePrimary OutcomeCR + nCRe"PRBDHarousseau et al, 2006CR post 4 cycles33%84%B and D, alternatingRosinol et al, 2007ORR12.5%65%BD vs VADHarousseau et al, 2008 CR+nCR Before SCT21% vs 8%VGPR 47% vs 19% Table #10 Bortezomib, Dexamethasone, and Additional Agent: Pre-transplant Outcomes InterventionReferencePrimary OutcomeCR + nCRe"PRVTD vs TD Cavo et al, 2008CR38% vs 7%92% vs 79PAD1 Oakervee et al, 2005CD34 yield29%95%PAD2Popat et al, 2008CD34 yield14%89%CBDKropf et al, 2009Cy dose8%92%CyBorDReeder et al, 2009VGPR or better39%61%B=bortezomib; Bor=bortezomib; V=Velcade; D= dexamethasone; VAD=vincristine, Adriamycin, dexamethasone; C=cyclophosphamide; Cy= Cyclophosphamide; VTD=Velcade, thalidomide, dexamethasone; PAD=PS-341(bortezomib), Adriamycin, dexamethasone Bortezomib carries a significant risk of neurotoxicity and dose modification guidelines were strictly followed in these studies. Additionally, multiple studies suggest that bortezomib containing regimens result in better outcomes in patients with MM who possess adverse cytogenetics as compared to regimens which do not contain bortezomib (Jagannath et al, 2007). While bortezomib is considered to be a suitable agent for MM patients with severe renal insufficiency and renal failure (Gertz et al, 2008), patients with these conditions were excluded from these studies. The chemotherapy regimens for MM appear to confer an increased risk for opportunistic infections, pneumonia, and varicella zoster reactivation. These studies do not share a common infection prophylaxis regimen. Bortezomib containing induction regimens are associated with high response rates and adequate stem cell collection. These studies used filgrastim-based mobilization regimens, with or without cyclophosphamide. In contrast to the CR rates reported from these studies, the highest CR rate reported with VAD chemotherapy induction is 13% (Cavo et al, 2005). The addition of other agents is currently under investigation in hopes improving response rates to VGPR or better such that a second SCT and/or post-transplant maintenance therapy would not be needed. Achieving CR/VGPR from induction appeared to confer prognostic value in past studies (Attal et al, 1996; Morris et al, 2004) and is suggested in these studies. The comparison of VTD to TD (Cavo et al, 2008) suggest the addition of bortezomib resulted in increased pre-transplant and post transplant complete remission rates which resulted in improved PFS in the preliminary report with a median follow-up of 15 months. Table #11 Phase III randomized controlled trials bortezomib containing regimens: Post transplant outcomes Intervention ReferenceCRCR/nCRe"VGPRNNTT toe"VGPRPFSBD vs VADHarousseau et al, 2008n/a35% vs 24%62% vs 42%* 5n/aVTD vs TDCavo et al, 2008 41% vs 20%*54 vs 29%*75% vs 53%* 4.5 93% vs 86% at 15 months***P<0.0001 **P=0.04 n/a=not available In a small, industry-sponsored trial of 52 patients with over 90% of patients proceeding to SCT, Harousseau et al found high response rates to BD with successful stem cell mobilization using filgrastim alone in 93% of patients after 3 cycles of BD. Stem cell collections were adequate for one transplant in all and adequate for two transplants in 73%. While this is a Phase II study, it is published as a full manuscript with ITT analysis, and the quality of the data is good. Rosinol et al (2007) reported a small, Phase II, industry sponsored trial of 40 patients of a short induction with alternating therapy with B and D. All patients had serum creatinine less than 1.9 gm/dL. The goals include rapid response kinetics and reduction in toxicity, particularly neuropathy. Twelve doses of dexamethasone 40 mg were administered in each cycle. Toxicity was very low with no patients having grade 4 or 5 toxicity and neurotoxicity was grade II or less. CR rate pre-transplant was 12.5% with CR rate following a single melphalan-based SCT of 33%. A small study of novel medication sequencing, the quality of the data is rated as fair. Harousseau et al (2008) subsequently published, in abstract form, the preliminary results of a large Phase III trial involving 482 patients, sponsored by the IFM, comparing BD to VAD. Interpretation of the results of this trial is confounded by an additional randomization to therapy with DCEP (dexamethasone, Cytoxan, etoposide, cisplatin). While all grades of neurotoxicity were higher with BD, adverse events leading to death were lower and pre and post transplant CR rates higher with BD. Stem cell collections were equivalent. These results are considered preliminary and the overall quality is therefore considered fair. Oakervee et al and Popat et al published, in 2005, with follow up in 2008, single institution results from two Phase II industry- sponsored trials of two PAD regimens, PAD 1 and PAD 2. PAD 1 regimen included bortezomib at the dose of 1.3 mg/m2 while PAD 2 regimen utilized bortezomib at the dose of 1 mg/m2. Fifty per cent of the PAD 2 patients had Stage I disease. The primary goals of these studies were stem cell mobilization using cyclophosphamide and filgrastim and time to recovery of counts following SCT. Secondary endpoints were toxicity and response rates. Rates of grade 3 and 4 neuropathy were lower with PAD 2. All other endpoints, including PFS and OS at 36 months, were equivalent. The quality of the data related to the studys primary goals is rated as good. Cavo et al (2008) in a large Phase III trial of VTD vs. TD sponsored by GIMEMA, published the results of the first 187 patients in abstract form in 2007 with a subsequent update in abstract form in 2008 on 399 patients out of 480 enrolled. The primary endpoints were CR rate and nCR rate after 3 cycles of therapy. The secondary endpoints were toxicity, PFS, OS, and CR rate following SCT. Toxicity was low, particularly with grade 3/4 peripheral neuropathy in 8% of VTD treated patients and 2% of TD treated patients. CR and nCR rates pre SCT, published in the abstract, were 33% for VTD and 12% for TD (p<0.001). Disease progression pre transplant occurred in 4.5% of TD patients and none in the VTD arm (p=0.005). PFS at 15 months was 93% for VTD and 86% for TD (p=0.04) While this is a large phase III study, the results are considered preliminary given abstract publication only and are rated as fair. There are few publications in manuscript form in peer reviewed publications on additional bortezomib containing regimens to date. The addition of cyclophosphamide to BD has been reported by two groups. Kropf et al (2009) in a small Phase I/II trial sponsored by cooperative group, evaluated induction therapy with three cycles of BD with cyclophosphamide. The primary endpoint was to determine the maximally tolerated dose of cyclophosphamide, which was 900 mg/m2 administered as one dose per cycle. Supportive care included antibiotics for prophylaxis of PJP, virus, and fungus. Using a dose of bortezomib of 1.3 mg/m2, 53% of patients had grade 1/2 peripheral neuropathy and 10% had grade 3. Grade 3/4 leucopenia was seen in 46% of patients. Stem cell mobilization efficacy was comparable to historical controls. Pre-SCT CR rate 8% with a 92% ORR. The overall quality of the data for this phase I/II design is good. Reeder et al (2009) also evaluated the combination of BDC, named CyBorD, in a small Phase II study of 31 patients with Stage II/III myeloma and creatinine up to 3.5. Four cycles were administered and the cyclophosphamide was dosed at 300 mg/m2 weekly for four doses per 28 day cycle. Grade 3/4 toxicities were thrombocytopenia (25%), neutropenia (13%), hyperglycemia, neuropathy, and thrombosis (7% each). Two SCTs were planned and stem cell mobilization was adequate in 81%. Ten of 33 patients had proceeded to SCT at the time of publication and, following one SCT, CR/nCR rates were 70% with ORR rates 100%. The overall quality for this small study of a novel regimen is fair. In summary, induction therapy with bortezomib and dexamethasone based regimens is consistently highly responsive and these responses may be higher than thalidomide and dexamethasone alone. The preliminary evidence suggests that addition of cyclophosphamide is safe and may improve response rates to induction. The reported outcomes of BD compared to VAD are congruent with previous publications on the VAD regimen. Consistently, stem cell collection following bortezomib appears to be adequate. Neuropathy is a significant toxicity and the regimens are intravenous. At this time, the impact of an induction regimen containing bortezomib on improved post-transplant PFS awaits longer follow-up and published analysis. While the quality of the data is impaired by relatively small Phase II studies and publication of the larger Phase III studies in abstract form only, the reported response and toxicity rates are consistent across studies. The strength of the recommendation is B. InterventionReference(s)LEOQSRBortezomib Plus DexamethasoneHarousseau (2006) Rosinol (2007) Harousseau (2008)II-1 II-1 IFairBBortezomib, Dexamethasone, plus Additional AgentCavo (2008) Oakervee (2005) Popat (2008) Kropf (2009) Reeder (2009)I II-1 II-2 II-1 II-1FairB E. Early Versus Delayed Stem Cell Transplantation Annotation9,,,,, Stem cell transplantation (SCT) has changed the natural history of MM by improving patient survival. Improved survival reported with SCT is subsequent to improved rates of CR and VGPR in patients with newly diagnosed MM (Attal et al, 1996; Child et al, 2003; Lahuerta et al, 2000; Alexanian et al, 2001). Typically, patients with myeloma may undergo SCT immediately following 46 cycles of induction therapy. However, evidence on optimal timing of SCT (early versus delayed) was lacking until the publication by Fermand et al in 1998. In this study design, among 202 enrolled patients who were up to 56 years old, 185 were randomly assigned to receive high-dose therapy (HDT) and peripheral blood SCT (early HDT group, n=91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n=94). In the late HDT group, HDT and transplantation were performed as rescue treatment, in case of primary resistance to CCT or at relapse in responders. When analyzed on an intent-to-treat basis, OS was similar in the two groups, with a median duration exceeding 5 years. Because of improved EFS in the early SCT arm, time spent off chemotherapy was longer in the early HDT group. Subsequent study by the intergroup, S9321, in the USA (Barlogie et al, 2006), also yielded comparable response rates and PFS and OS durations in patients offered early versus delayed SCT. With the introduction of novel agents in MM treatment, information regarding impact of early versus delayed SCT on OS of patients is lacking. Therefore, decision making regarding early versus delayed SCT should be done in consultation the VHA transplant centers. Even in cases where delayed AST is considered, early harvesting and cryopreservation of stem cells is encouraged after 4-6 cycles of induction chemotherapy. Currently, there is a joint study by IFM and the Dana Farber Cancer Institute evaluating early versus delayed autologous transplant utilizing a combination chemotherapy regimen; all patients have peripheral blood stem cells harvested even if transplantation is delayed. F. Secondary Induction Therapy for Transplant Candidates/ Alternative Drug Therapy in Non-Transplant Patients Annotation,69,70,71,81 Treatment selection considerations for patients who fail initial induction therapy are similar for both transplant eligible and non-transplant eligible patients with the exception that melphalan is not recommend prior to transplant. Disease-related factors include the rate of progression of disease, duration of response to initial therapy, and adverse risk factors (e.g. t(4:14), t(14:16), or del(17p) by FISH, 13q deletion by conventional cytogenetics). Treatment-related factors include prior drug exposure, anticipated regimen toxicity (e.g. peripheral neuropathy or myelosuppression), route of drug administration, and the need for VTE prophylaxis. Patient-related factors include pre-existing organ dysfunction (e.g. thrombocytopenia or peripheral neuropathy), co-morbid medical conditions (e.g. diabetes or renal insufficiency), tolerance to prior therapy, and goals of care. Most patients should have the option of receiving novel agents at some point in their treatment course in case of disease progression or relapse. Otherwise, their overall survival or survival from relapse may be short-lived (Facon et al, 2007; Palumbo et al, 2008, San Miguel et al, 2008; Hulin et al, 2009, see Section G). G. Select Initial Therapy in Patients Who Are NOT Transplant Candidates Regimens (Strength of Recommendation) Dexamethasone (D) Thalidomide-Dexamethasone (D) Lenalidomide-Dexamethasone (B) Melphalan-Prednisone (C) Melphalan-Prednisone-Thalidomide (A) Melphalan-Prednisone-Bortezomib (A) Refer to Section C for evaluating of pre-existing comorbid factors which affect initial therapy and the guidelines for thrombosis prophylaxis. Dexamethasone Annotation,,,, High-dose dexamethasone is recognized as one of the most active single agents for induction of responses in both refractory myeloma patients (Alexanian etal, 1986) and untreated myeloma patients (Alexanian etal, 1992). These reports led to phase III comparisons between dexamethasone-based regimens and melphalan and prednisone (MP). Table #12 Dexamethasone regimens in patients who are not transplant candidate InterventionReferencePrimary OutcomeMP vs MD MP vs Melphalan plus Dexamethasone (MD) Hernandez et al, 2004 RR (%) at 6 cycles RR (%) at 12 cycles 67.9 vs 64.5 2.6 vs 7.9 (CR) 38.5 vs 51.3 (PR) 26.9 vs 5.3 (MR) 49.4 vs 46.1 9.1 vs 22.4 (CR) 26 vs 22.4 (PR) 14.3 vs 1.3 (MR)MP vs Dexamethasone vs Dexamethasone-based regimensFacon et al, 2006 OS, m 34 vs 33.4 (MP vs Dexamethasone alone) MP vs MDShustik et al, 2007OS, yrs2.5 vs 2.7M = melphalan; P=prednisone; MP =melphalan plus prednisone; The trial by Hernandez et al (2004) compared MP with a combination of melphalan with a double pulse of dexamethasone (MD; dexamethasone was given 20mg/m2 on days 1 4 every 4weeks) in elderly (age e"70 years) patients. In this randomized trial, a total of 201 patients treated at Spanish Institutions were included. Due to protocol violations and/or loss to follow-up before 6 months, only 170 (87 MP and 83 MD) were evaluable for response. The first and second response evaluations were performed at 6 and 12 months, respectively. As summarized in the results table, the overall RR was similar at six months and after 12 months. Although, the proportion of CR was higher in the MD arm, the median OS in months was almost identical (MP 29.4 vs 27.2). More non-hematological toxicity was reported with MD, mainly being increased incidence of antibiotic-requiring infections and hyperglycemia. This study confirmed MP as the gold standard for MM treatment. The quality of the study is good with no major design flaws. Mature results from the IFM 9501 study were reported by Facon et al in 2006. In this randomized clinical trial in newly diagnosed MM patients, a total of 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Dexamethasone was given as 40mg/day on days 14, 912 and 1720 every 6weeks. Results from this study show that there was no significant difference in OS (primary end-point) among the 4 treatment groups. Response rates (secondary end-point) at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone. However, the progression-free survival (secondary end-point) was significantly better among patients receiving melphalan then those receiving dexamethasone alone or dexamethasone-based regimens (p < .001, for both comparisons). Most significantly, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone (28% vs 16%, respectively), especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. The IFM 95-01 trial reaffirmed MP as the best conventional treatment choice in elderly patients with MM. This was a good quality study with no major design flaws. The results from the non-blinded randomized-controlled trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) were reported by Shustik et al (2007). This study compared the effectiveness of melphalan plus dexamethasone (MD) with melphalan plus prednisone (MP) as induction therapy and dexamethasone with observation as maintenance therapy. Induction doses of dexamethasone were 40mgper day for 4days every 14days for the first 3 treatment cycles and then every 28days with remaining cycles. Five hundred and ninety-five patients with previously untreated, symptomatic stage I or stages IIIII myeloma were randomized. Randomization to the M-Dex arm was stopped as a result of an analysis performed which met a predetermined event-related criterion. Of 466 patients randomized to MP or MD, no differences were detected in the OS (2.5 vs 2.7years; p=03). Thus, dexamethasone did not improve clinical outcome when combined with melphalan during induction. The quality of the study is good with no major design flaws. In summary, when efficacy and patient tolerability is concerned, MP is superior to melphalan-dexamethasone in the treatment of elderly patients with MM providing equal efficacy with less toxicity. Dexamethasone alone or dexamethasone-based induction containing conventional agents is not advised for elderly myeloma patients. MP remains the best choice of conventional chemotherapy in elderly patients with MM. However, dexamethasone could be offered to patients in selected situations such as cord compression or in clinical situations requiring concomitant use of radiation in MM. Data regarding the safety of other novel and/or conventional chemotherapy agents given concomitantly with radiation is sparse in MM. InterventionReference(s)LEOQSRDexamethasone-based regimens Hernandez et al (2004) Facon et al (2006) Shustik et al (2007) I I I Good D  Thalidomide-Dexamethasone (TD) Annotation32,,, Thalidomide was introduced for relapsed/refractory MM in 1998 (Singhal et al, 1999). Later on, thalidomide was combined with corticosteroids, which resulted in high response rates in young patients with untreated myeloma (Rajkumar et al, 2006 and 2008). Since MP is used as a standard regimen in elderly myeloma patients, a phase III study was designed to evaluate the therapeutic efficacy and the toxicity of thalidomide with dexamethasone (TD) in comparison with MP as upfront treatment for patients ineligible for high-dose therapy (Ludwig et al, 2009). Table #13 Thalidomide-dexamethasone in patients who are not transplant candidates InterventionReferencePrimary OutcomeTD vs MPTD vs MP Ludwig et al, 2009 PFS, m Tolerance16.7 vs 20.7 HR 1.30 (95%CI 0.95-1.78) Grade 3 or 4 leukopenia (3% vs 15%) Grade 3 or 4 thrombocytopenia (1% vs 12%) Thromboembolic complications (15% vs 8%)T=thalidomide; D=dexamethasone; M=melphalan; P=prednisone The trial by Ludwig et al (2009) was the first trial to compare TD with MP in elderly or transplant ineligible patients. In this randomized, phase III study, 289 patients were randomized to either TD or MP. The TD group showed a significantly higher rate of very good responses (CR and VGPR) as compared to MP (26% vs 13%, respectively, p=.006). However, median PFS (primary endpoint) was 16.7 months and 20.7 months in the respective groups (p = .10). Median OS (secondary end-point) was also shorter, being 41.5 months in patients treated with TD and 49.4 months in patients treated with MP (p = .024). In term of toxicity (primary endpoint), number of deaths was slightly higher with TD (45%) vs MP (33%); p = .051). Additionally, early deaths within the first year were significantly higher with TD (28%) vs MP (16%; p = .014). Toxicities were selective for TD and MP, with more hematological toxicity noted with MP than in TD. As expected, the cumulative incidence of thromboembolic events was higher with TD (summarized in results). The quality of the study is good with no major design flaws. In summary, as compared to MP treatment in elderly, TD is associated with poorer survival. TD is not advised for elderly myeloma patients. Use of thalidomide is best recommended with MP (MPT). InterventionReference(s)LEOQSRThalidomide and DexamethasoneLudwig et al (2009) I GoodD Lenalidomide-Dexamethasone (RD or Rd for low dose dexamethasone) Annotation36,41,,, Lenalidomide, a novel analogue of thalidomide, first received approval for treatment of relapsed/refractory multiple myeloma (MM) (Weber et al, 2007; Dimopoulos et al, 2007). Lenalidomide is not FDA approved for use as first-line therapy in multiple myeloma. Subsequently, phase II (Lacy et al, 2007) and phase III studies were designed to evaluate the efficacy of lenalidomide-based induction in treatment nave MM. The phase III randomized controlled study, Southwest Oncology Group (SWOG) S0232, compared dexamethasone, with a combination of dexamethasone and lenalidomide in newly diagnosed patients with MM who were either ineligible for, or declined autologous stem cell transplant (ASCT) (Zonder et al, 2008). Another landmark study that evaluated lenalidomide-based induction in myeloma was the Eastern Cooperative Oncology Group (ECOG) study, E4A03. This phase III randomized study compared lenalidomide plus high (standard) dose dexamethasone (RD) versus lenalidomide plus low dose dexamethasone (Rd) in newly diagnosed, untreated MM (Rajkumar et al 2008). Table #14 Lenalidomide-dexamethasone in patients who are not transplant candidates InterventionReferencePrimary OutcomeCR + nCRe"PRPFSOSRDLacy et al, 2007RR 18%91%29 mos90% at 2 yrs 85% at 3 yrs (no transplant)RD vs DZonder et al, 2008 RR 15% vs 2%75% vs 48%RD vs RdRajkumar et al, 2008RR at 4 months 79% vs 68%Not reportedRD 96% at 1 yr 80% at 2 yrs Rd 99% at 1yr 91% at 2 yrsR = Revlimid; D= dexamethasone; RD = Revlimid plus high dose dexamethasone; Rd = Revlimid plus low dose dexamethasone The study by Lacy et al (2007) was a phase II study to evaluate the response rate and the long-term effects of lenalidomide and dexamethasone on time to progression, progression-free survival, and overall survival in patients with MM. A total of 34 patients were registered for the study. The combination of lenalidomide and dexamethasone resulted in an overall response rate of 91% with a 3-year survival rate of 88%. Despite impressive results, the major weaknesses of this study are that it was single-institutional and a small, non-randomized study. Hence, the quality of the study is fair. The SWOG 0232 study by Zonder et al (2008) was a randomized clinical trial comparing lenalidomide-dexamethasone with dexamethasone alone. A total of 198 patients were enrolled in this study. Complete remission (CR) and very good partial remission (VGPR) rates were higher with lenalidomide-dexamethasone versus dexamethasone alone (75% vs 48%, respectively). This superior response also translated into improved remission duration of 77% and 55%, respectively. However, 1-year overall survival (OS) was similar in both arms (93% vs 91%). Higher rates of thromboembolism (27% vs 8.5%) and infection (51.4% vs 28%) were seen with lenalidomide-dexamethasone compared to dexamethasone alone (HYPERLINK "http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=55&trackID=111&sessionID=375&sortBy=PS"ASCO Virtual Meeting). This study was halted at interim analysis and patients on dexamethasone alone were switched to lenalidomide with dexamethasone. The SWOG data and safety monitoring committee based its recommendation to permanently close this study enrollment based on the preliminary 1-year survival results from the ECOG study, E4A03. Thus, the quality of the study is fair. The ECOG study (E4A03) by Rajkumar et al (2008) was first presented at the 49th American Society of Hematology meeting on December 8, 2007. Study results were later updated at the American Society of Hematology/American Society of Clinical Oncology Joint Symposium during the 50th Annual Meeting on December 7, 2008. In the study design, RD regimen consisted of four 28-day cycles of lenalidomide 25 mg/day PO on days 121 plus dexamethasone 40 mg on days 1 to 4, 9 to 12, and 17 to 20. Rd regimen consisted of four 28-day cycles of lenalidomide 25 mg/day PO on days 121 plus dexamethasone 40 mg on days 1, 8, 15, and 22. A total of 445 pts (median age, 65 yrs) were accrued, with 223 randomized to RD, and 222 to Rd. At a median follow-up of 36 months, patients who received RD demonstrated a superior overall response rates versus patients who received Rd (79% versus 68%, respectively; p=.008). Although Rd had lower response rates than RD, it was within the 15% limit that was defined in study design as clinically equivalent. Nevertheless, better RR with RD did not translate into an improvement in OS at 3 years (RD 75% versus Rd 74%, p=.46) or time to progression (p value not significant). The survival equivalency for the low dose dexamethasone regimen held true for patients < 65 years old and those ( 65 years old. There was also a trend toward improved progression free survival (PFS) in the Rd arm (p=.08). Most significantly, major grade 3 or higher toxicities, including DVT/PE and infections/pneumonia, were significantly higher in the high dose dexamethasone arm (27% vs 17% with Rd). DVT risk was 5%8% with Rd with routine aspirin prophylaxis. The increased mortality in RD arm was due to disease progression (myeloma deaths) as well as increased toxicity (5% vs 0.5% with Rd). The quality of the study is good with no major design flaws. The above summarized clinical evidence suggests that lenalidomide plus dexamethasone produces a superior response rate compared to dexamethasone alone. This higher response rate is associated with a longer progression-free survival but has not been shown to improve overall survival. Lenalidomide-dexamethasone combinations induction presents a valuable oral, outpatient therapy to VA patients with MM. The ECOG study provides a basis for the optimal dosing of dexamethasone in combination with lenalidomide, particularly in elderly patients who are generally poor candidates for high doses of cyclical dexamethasone. Interestingly, although better responses were seen with RD (high dose dexamethasone), rates of certain toxicities associated with RD, notably infections, venous thromboembolism (VTE) and infections/pneumonia, may be reduced by lowering the dose of dexamethasone in Rd. The overall survival (OS) rates with RD and Rd were equivalent at 3 years. Moreover, in a landmark analysis of patients who continued RD or Rd beyond 4 cycles, the overall response rate improved to 89%, including 22% complete remissions. The 3-year OS rate of patients was 79%, regardless of the regimen they received. This data indicates that prolonged treatment with lenalidomide-dexamethasone leads to durable responses. In summary, lenalidomide plus low-dose dexamethasone (Rd) is as an induction option for the treatment of transplant ineligible or elderly patients, although there is a limited amount of data in patients >75 years old. However, a randomized study comparing lenalidomide-dexamethasone with another induction therapy, principally MPT (Melphalan + Prednisone + Thalidomide), is still not available. The IFM 07-01 study is evaluating lenalidomide plus low-dose dexamethasone versus MPT. Until that information is available, the results of this trial cannot be applied to the entire population of untreated myeloma. Rd presents an oral chemotherapy regimen for Veterans with MM who are limited in their ability to attend VA appointments due to travel distance and/or physical limitations. An alternative to this form of oral chemotherapy is MPT (Melphalan + Prednisone + Thalidomide). Rd may be favored over MPT in patients who have preexisting severe neuropathy using the neuropathy assessment tools (Tariman et al, 2008). Additionally, Rd may be favored over MPT for the patient who has contraindications to systemic anticoagulation or only one risk factor for thrombosis (see Section C). Altogether, the unprecedented short-term OS rates seen with lenalidomide and dexamethasone make this approach very attractive without upfront SCT. The strength of recommendation is B. InterventionReference(s)LEOQSRLenalidomide Plus DexamethasoneLacy et al (2007) Zonder et al (2008) Rajkumar et al (2008) II-3 III IFairBA*= Unpublished data, but recommended by expert consensus based on high-level evidence directly linked to health outcome Melphalan-Prednisone (MP) Melphalan-Prednisone-Thalidomide (MPT) Annotation20,61,,,,,,,,,,,, Melphalan plus prednisone (MP) is considered the first induction therapy that improved MM associated survival (Alexanian et al, 1972). There have been many efforts to improve upon the results achieved with MP by the use of combination chemotherapy. However, complex combinations of chemotherapy have often resulted in toxicity and inconvenience without providing a survival advantage (Gregory et al, 1992; Myeloma collaborative trials, 1998), thereby making MP the most widely accepted treatment choice in elderly patients (Facon et al, 2006). This acceptance has led to randomized comparisons of MP with MP plus new agents. Thalidomide was initially approved in relapsed/refractory MM (Singhal et al, 1999). Given its unique mechanism of actions, it is acknowledged as a "novel agent" in myeloma (Rajkumar et al, 2004). MP plus thalidomide (MPT) was one of the original combinations to incorporate a novel agent within the framework of traditional myeloma chemotherapy, ushering a new approach to clinical trial design in MM. Three randomized studies comparing MP with MPT have been published. Two other studies are reported as abstracts. Results from these studies are summarized below. Table #15 Melphalan containing regimens for patients who are not transplant candidates InterventionReferencePrimary OutcomeCR + nCRe"PRPFS (mos)OS (mos)MPT vs MPFacon et al, 2007OS, m 47% vs 7% P<0.000176% vs 35% P<0.0001MPT vs MP HR 0.51 CI 0.39-0.66 P<0.0001 51.6 vs 33.2 HR 0.56 P=0.002MPT vs MPPalumbo et al, 2008 RR (%) PFS, m15.6% vs 3.7% P<0.00168.9% vs 47.6% P<0.00121.8 vs 14.5 HR 0.63 CI 0.48-0.81 P<0.00145 vs. 47.6 HR 1.04 CI 0.76-1.44 P=0.79MPT vs MPHulin et al, 2009OS, m44 (CI 33.4-58.7) vs 29.1 (CI 26.4-34.9) HR 0.68 P=0.028MPT vs MPWaage et al, 2007OS29 vs 33MPT vs MPWijermans et al, 2008OS63% vs. 47%P=0.08 37 vs 30 P=0.28M=melphalan; p=prednisone; T=thalidomide; MPT=melphalan plus prednisone and thalidomide Since the peak incidence of myeloma occurs between the sixth and seventh decade of life, data from the IFM99-06 study, by Facon et al (2007) carry significant weight in guiding choice of therapy for elderly Veterans with MM. In this study dedicated to age group of 65-75 years, 447 untreated myeloma patients were randomly assigned to receive MP, MPT, or reduced-intensity autologous stem cell transplant using 100 mg/m2 of melphalan (MEL100). After a median follow-up of 51.5 months, median OS was 51.6 months with MPT, 33.2 months for MP, and 38.3 months for ASCT. These results indicate that patients receiving the combination of MPT had significantly prolonged OS and PFS as compared with MP and patients receiving MEL100 followed by ASCT. The quality of the study is good with no major design flaws, except for criticisms regarding dose selection of high dose melphalan prior to ASCT. That said, given the unquestionable superiority of MPT over MP, MPT is endorsed as one of the standard therapies in the 65-75 years age group of myeloma patients. Evidence from the GIMEMA group study by Palumbo et al (2008) suggests that the overall survival on extended follow-up of patients treated with MPT versus MP failed to confirm any difference that was seen when first reported. This study randomly assigned 331 patients to receive either MPT or MP alone for 6 cycles, followed by thalidomide maintenance until disease relapse. Updated analysis was by intention to treat and included PFS, OS, and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). The authors pointed out the crossover of MP patients to thalidomide or bortezomib-based salvage regimens as a possible explanation for the lack of survival advantage with MPT. Moreover, in contrast to IFM 99-06 study, the GIMEMA study design employed a short course of MP-based induction of 6 cycles. The quality of the study is good with no major design flaws. More recently, mature results from the IFN 01/01 study by Hulin et al (2009) were published. This randomized, placebo-controlled, phase III trial investigated the efficacy of MPT in patients older than 75 years with newly diagnosed myeloma. A total of 232 patients were enrolled and 229 were randomly assigned to MPT versus MP. After a median follow-up of 47.5 months, OS was significantly longer in patients who received MPT compared with those who received MP plus placebo (median, 44.0 vs 29.1 months, P = 0.028). Progression-free survival was significantly prolonged in the MPT group (median, 24.1 vs 18.5 months, P = 0.001). This trial confirms the superiority of the MPT combination over MP alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable. The quality of the study is good with no major design flaws. The general theme evolving from phase III studies comparing MPT versus MP in elderly myeloma patients is that, the addition of thalidomide to melphalan and prednisone results in significant improvements in RR and PFS. However, the impact of MPT on survival is unclear. Significant OS benefit with MPT has been reported from the two IFM studies out of the five randomized trials presented so far. Nonetheless, taking into account of improved RR and PFS with MPT, the first advancement in MM treatment has come from the addition of thalidomide to MP. While MPT offers greater responses in myeloma, it is important to keep in mind that not all elderly patients might be able to tolerate MPT as it is associated with greater toxicity than MP. For instance, grade III to IV adverse events were more reported in the MPT arms (48%), compared to 25% who were offered MP (Palumbo et al, 2006). Peripheral neuropathy (PN) was distinctively noted in more than half of the patients who were offered MPT (Palumbo et al, 2006). Hence, caution is advised before offering thalidomide to Veterans with pre-existing peripheral neuropathy or those having risk factors for PN (e.g., long-standing history of diabetes mellitus or history of trauma to the peripheral nervous system). It is also worth noting that clinically significant PN is present in about 10% of myeloma patients while up to one third have subclinical neuropathy based on neurophysiologic nerve conduction velocities studies or histopathologic findings (Kyle et al, 1992; Kissel et al, 1996). Other factors associated with thalidomide use include higher incidence of somnolence and constipation in the MPT group than in the MP group. High doses of thalidomide (400 mg per day) used in the IFM99-06 could have accounted for the high rates of those side effects. Therefore, use of a lower thalidomide dose (100 mg per day), as adopted by the GIMEMA group (Palumbo et al, 2006), could alleviate some of the intolerable side effects associated with it. Another notable event is the significant risk (20%) of venous thromboembolism (VTE) when thalidomide is used in combination with MP (Palumbo et al, 2006). This rate, however, dropped to ~3% with use of thromboprophylaxis (Palumbo et al, 2006). A risk assessment model (Palumbo et al, 2008) may be used for the management of VTE in myeloma patients treated with thalidomide. Using that model, LMWH or full-dose warfarin should be considered in patients who receive MPT (Palumbo et al, 2008). Patients in whom anticoagulant use is prohibited, alternative therapies for myeloma should be offered. Taking consideration of the above issues, it would be reasonable then to offer MP to transplant ineligible patients with slowly growing myeloma, where hemoglobin, renal function, and/or hypercalcemia are not seriously compromised. Recent evidence from the GIMEMA group suggests that the overall survival on extended follow-up of patients treated with MPT versus MP was similar. This experience is likely replicable in VA patients with an intrinsically good prognosis myeloma who are offered upfront MP with the option of receiving novel agents (Thalidomide, bortezomib, or lenalidomide) during their lifetime in case of disease progression or relapse. In patients with poor life expectancy (<1 year) due to non-myeloma factors, MP could be offered as palliation of myeloma. In summary, MPT is associated with superior response rates and PFS in the three published randomized studies (Palumbo et al, Facon et al, and Hulin et al) and significant OS benefit compared to MP in two of those studies (Facon et al, and Hulin et al) in newly diagnosed MM. Two additional randomized trials have been reported, but more mature data from these studies (Waage et al, and Wijermans et al) are pending. MPT offers an oral form of chemotherapy to untreated MM patients. MPT should only be utilized in patients who can comply with systemic anticoagulation. Since the selection of best induction therapy has yet to be determined in MM, MPT could be best offered to Veterans who are limited in their capacity to VA travel due to distance and/or physical incapacity. Those patients who are offered MP as frontline therapy should have the option of receiving novel agents at sometime during their treatment course in case of disease progression or relapse. Otherwise, their overall survival or survival from relapse may be short-lived, based on the aforementioned summary of evidence. The strength of recommendation for MPT and MP is A and C, respectively. InterventionReference(s)LEOQSRMelphalan and Prednisone plus Thalidomide Melphalan and PrednisoneFacon et al (2007) Palumbo et al (2008) Hulin et al (2009) Facon et al (2007) Palumbo et al (2008) Hulin et al (2009)I I I I I IGood GoodA C Melphalan-Prednisone-Bortezomib (MPV) Annotation,, Following the encouraging clinical experience and approval of bortezomib in relapsed/refractory MM (Kane et al, 2006), bortezomib was incorporated into the framework of melphalan and prednisone (MPV) for testing in transplant ineligible MM patients. After seeing impressive results in phase I/II testing of MPV in untreated MM (Mateos et al, 2008), an international collaboration between investigators led to the conduct of the Velcade as Initial Standard Treatment in Myeloma Assessment (VISTA) trial. VISTA was a randomized, international, multicenter, phase III trial of the use of melphalan-prednisone-Velcade (MPV) combination compared with melphalan-prednisone (MP) for front-line therapy in myeloma patients not eligible for transplant (San Miguel et al, 2008). Table #16 Bortezomib regimen in patients who are not transplant candidates InterventionReferencePrimary OutcomeMPV vs MPHR for deathMPV vs MPSan Miguel et al, 2008 TTP, m24 vs 16.6 MPV vs. MP 0.61 P=0.0008M=melphalan; P=prednisone; V=Velcade (bortezomib) The VISTA trial enrolled 682 patients with previously untreated myeloma, including a high proportion of patients with advanced and high-risk factors, making this the largest MP-based phase III study. The primary end-point was time to disease progression (TTP). In this study, MPV proved superior to MP with significant improvements in TTP (24 months vs 16.6 months, respectively; P=0.001). Moreover, all pre-specified secondary end-points, including the rate of CR (according to European Group for Blood and Bone Marrow Transplant [EBMT] criteria), the time to subsequent myeloma therapy, and OS, were significantly superior in the MPV arm compared to the MP arm. The 3-year OS was 72% for MPV versus 59% for MP and this survival advantage was maintained despite subsequent use of bortezomib in 45% of MP patients at disease progression, although this was a post-hoc analysis. Furthermore, better survival was seen in patients who received MPV as front-line therapy than in patients who received MP and were then treated with novel agents on disease relapse. Among evaluable patients, MPV reported very high overall response rates and CR of 71% and 30%, respectively, by EBMT criteria. In contrast, MP was associated with an ORR and CR of 35% and 4%, respectively. Responses to MPV were rapid, with median time to achieve the first response being 1.4 months. Median time to achieve CR was 4.2 months. There were also significant observations reported to correlate the magnitude of response with duration of response seen with MPV. Specifically, CR was associated with significantly longer TTP and treatment-free interval, irrespective of time to achieve CR with MPV. The high CR rates could be partly due to the efficacy of bortezomib in patients with poor risk features, including del 13 and t (4;14), t(14;16) chromosomal anomalies or a 17p deletion, where traditional therapies have proven ineffective in long lasting disease control. No significant differences in grade 4 events between MPV and MP were reported. The quality of the study was good with no major design flaws. In 2008, the Food and Drug Administration (FDA) approved front-line bortezomib for patients with previously untreated MM. In summary, MPV is associated with superior TTP, RR, PFS, and OS as compared to MP. The VISTA trial results establish MPV as a new standard of care for MM patients not eligible for ASCT. Although direct comparison between MPV and other MP-containing regimens has not been done in the transplant ineligible patients, indirect comparisons between studies suggests MPV being the most potent regimen in achieving high anti-myeloma responses. Furthermore, since more data on the ability of MPV to overcome the poor prognosis associated with high-risk cytogenetics is available, MPV could be best offered to patients with poor-risk disease (del 13q, t (4;14), t (14;16), del 17p, or hypodiploid karyotype). In addition, bortezomib can be safely administered to patient with renal failure, including those on hemodialysis. Like thalidomide, peripheral neuropathy is the major concern in bortezomib-containing regimens, whereas the risk of deep vein thrombosis is minimal with bortezomib-containing regimens as opposed to thalidomide. InterventionReference(s)LEOQSRMelphalan and Prednisone plus Velcade (bortezomib)San Miguel et al (2008) I GoodA H. Initial Response in Patients Who Are NOT Transplant Candidates Annotation 41,63,81,, Changes in the M-protein level are the principal components used for response evaluation in MM. With regimens containing novel agents, response may occur rapidly and can be substantial within 12 months (Rajkumar et al, 2008 EA403 study; San Miguel et al, 2008; Ludwig et al, 2009, Durie et al, 2006). Therefore, it is recommended that treatment decisions on patients who are not transplant candidates be done after 4 cycles with regimens containing one of the three newer agents (bortezomib, lenalidomide, thalidomide) (Rajkumar et al, 2008 EA403 study; San Miguel, 2008). The initial response for regimens not containing a newer agent, such as MP, should be done after 6 cycles (Palumbo et al, 2008). Response assessment should be done as per the International Myeloma Working Group Uniform Response Criteria listed in Table #17. Table #17 International Myeloma Working Group uniform response criteria: CR and other response categories (Durie et al, 2006) Response CategoryResponse Criteriaa sCRCR as defined below plus normal FLC ratio and absence of clonal cells in bone marrowb by immunohistochemistry or immunofluorescenceCRNegative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and d"5% plasma cells on bone marrowbVGPRSerum and urine M-component detectable by immunofixation but not on electrophoresis or e"90% or greater reduction in serum M protein plus urine M- protein <100 mg per 24 hPRe"50% reduction of serum M protein and reduction in 24 h urine M-protein by e"90% or to <200 mg 24 h. If the serum and urine M-protein are unmeasurable,d a e"50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, e"50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was e"30%. In addition to the above criteria, if present at baseline, e"50% reduction in the size of soft-tissue plasmacytomas is also requiredSD (not recommended for use as an indicator of response; stability of disease is best described by providing the time to progression estimates) Not meeting criteria for CR, VGPR, PR or progressive diseasePDIncrease of 25% from lowest response value in: Serum M protein (absolute increase must be e"0.5 100 ml) and/or urine M-component (absolute increase must be e"200 mg/24 h) and/or bone marrow plasma cell percentage (absolute % must be 10%) and/or only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg per 100 ml). OR Definite development of new bone lesions or soft-tissue plasmacytomas or definite increase in the size of existing bone lesions or soft-tissue plasmacytomas. OR Development of hypercalcemia (corrected serum calcium >11.5 mg per 100 ml) that can be attributed solely to the plasma cell proliferative disorder Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response. aAll response categories require two consecutive assessments made at anytime before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. bConfirmation with repeat bone marrow biopsy not needed. cPresence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is k/l of >4:1 or <1:2. I. Continuation of Therapy in Patients Who Are NOT Transplant Candidates Annotation Evidence regarding optimal duration of therapy in chemotherapy-responsive myeloma patients who are not transplant candidates is lacking. Nonetheless, there is evidence to suggest that prolonged length of therapy (i.e., over 6 months) with newer agents improves the duration and depth of responses (Facon et al, 2007; Palumbo et al, 2008; Rajkumar et al, 2008 EA403 study; San Miguel et al, 2008; Hulin et al, 2009 ). Although many physicians continue treatment with regimens containing a novel agent (bortezomib, lenalidomide, and thalidomide) until disease relapse, the survival advantage over MP in clinical trials was seen using fixed durations in all patients (54 weeks in the MPV trial, and 72 weeks in the MPT trials). The addition of a novel agent to MP produced a higher incidence of adverse events; no Quality of Life data are available. Although this guidance is limited in providing specific choices for maintenance therapy, expert consensus (NCCN and Mayo clinic) recommends use of bortezomib, lenalidomide and thalidomide in maintaining the clinical remission of myeloma. Factors such as patient preference, disease characteristics, toxicity to benefit evaluation must be considered in choosing the chemotherapy type, dose, and frequency. For instance, to avoid cumulative steroid toxicities, dexamethasone could be discontinued after first year of Rd (lenalidomide and low dose dexamethasone) in responding patients after the first year. Treatment with MP should generally be limited to a maximum of 12 6-week cycles to avoid prolonged myelosuppression and secondary malignancies such as myelodysplastic syndrome. 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Moore F, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. A randomized Southwest Oncology Group study comparing dexamethasone (D) to lenalidomide + dexamethasone (LD) as treatment of newly-diagnosed multiple myeloma (NDMM): Impact of cytogenetic abnormalities on efficacy of LD, and updated overall study results. J Clin Oncol 26: 2008 (May 20 suppl; abstr 8521).  Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America.N Engl J Med. 2007 Nov 22;357(21):2133-42.  Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Fo R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32.  Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Mylome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18.  Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. 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Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. [No authors listed]J Clin Oncol. 1998 Dec;16(12):3832-42.  Rajkumar SV. Thalidomide: tragic past and promising future. Mayo Clin Proc 2004;79:899903.  Waage A. Gimsing P, Juliusson G, et al. Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomized phase III trial [abstract]. Blood. 2007;110. Abstract #32.  Kyle RA. Monoclonal proteins in neuropathy. Neurol Clin. 1992 Aug;10(3):713-34.  Kissel JT, Mendell JR. Neuropathies associated with monoclonal gammopathies. Neuromuscul Disord. 1996 Jan;6(1):3-18.  San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17.  Mateos MV, Hernndez JM, Hernndez MT, Gutirrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, Garca-Laraa J, Garca-Sanz R, Blad J, Prsper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5  Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res. 2006 May 15;12(10):2955-60.  Durie BG, Harousseau JL, Miguel JS, Blad J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. Epub 2006 Jul 20. Erratum in: Leukemia. 2006 Dec;20(12):2220. Leukemia. 2007 May;21(5):1134. Adult with symptomatic MM [ HYPERLINK \l "Annotation_A" A] Is patient a transplant candidate? [ HYPERLINK \l "Annotation_B" B] Select Initial Therapy for patients who are NOT transplant candidates with consideration of pre-existing conditions affecting drug choices including thrombosis risk [ HYPERLINK \l "Annotation_C" C,  HYPERLINK \l "Annotation_G" G] Start Initial Therapy Select Initial Therapy for patients who ARE transplant candidates with consideration to pre-existing conditions affecting drug choices including thrombosis risk (Avoid alkylating agents) [ HYPERLINK \l "Annotation_C" C,  HYPERLINK \l "Annotation_D" D] e"Partial Response after 4 cycles for novel agents (bortezomib, lenalidomide, thalidomide) or after 6 cycles (melphalan/prednisone)? [ HYPERLINK \l "Annotation_H" H] [I] Switch to alternative drug regimen [ HYPERLINK \l "Annotation_F" F] Start Initial Therapy Continue therapy: For regimens containing novel agents (bortezomib, lenalidomide, thalidomide) continue until plateau or relapse (see text) For MP continue for a total of 12 cycles [ HYPERLINK \l "Annotation_I" I] Secondary Induction Therapy and discussion with transplantation specialist [ HYPERLINK \l "Annotation_F" F] 4@`abNOPʹʐxg\O\>!jh3?h{'$0JCJUaJhh{'$0J(CJaJhh{'$CJaJ!jhh{'$0JCJUaJhA=h{'$0J(CJaJhA=h{'$CJaJ!jhA=h{'$0JCJUaJhz`h{'$0J(CJaJhz`h{'$CJaJ!jhz`h{'$0JCJUaJh{'$h'"h{'$0J(CJaJh'"h{'$CJaJh{'$CJaJ!jh'"h{'$0JCJUaJOܗݗ-. +[$\$gd ,[$\$gd8% +[$\$gdp1$3$gdP01$3$gd)9 +[$\$gdTUėϗܗݗޗL ™5cZf鼱鈁peXeeh8%h{'$0J(CJaJh8%h{'$CJaJ!jh8%h{'$0JCJUaJ hh{'$ h=Ph{'$jh{'$0JUhmRh{'$0J(CJaJhmRh{'$CJaJhph{'$CJaJ!jhph{'$0JCJUaJhP0h{'$CJaJ!jhP0h{'$0JCJUaJh{'$h{'$CJaJh3?h{'$CJaJ"ߛʜ.cew-/02h"IKLʺʺzi!jh|h{'$0JCJUaJhmRh{'$0J( h4h{'$ hmRh{'$hh{'$0J(CJaJhh{'$CJaJ!jhh{'$0JCJUaJh]h{'$0J( hvh{'$ h]h{'$jh{'$0JU h*Ymh{'$jh*Ymh{'$0JU h{'$]h$h{'$]h{'$%./JK;<rstuڤ  Ŧ$a$gd f ,[$\$gdo -[$\$gdo +[$\$gd|Lz ;<=rstuȽ١p[pHp$h6h{'$0JCJ OJQJ^JaJ )jh{'$CJ OJQJU^JaJ #jh{'$CJ OJQJU^JaJ h{'$CJ OJQJ^JaJ hk~h{'$CJ OJQJ^JaJ hnchh{'$CJaJhoh{'$0J(CJaJhoh{'$CJaJ!jhoh{'$0JCJUaJh{'$h|h{'$0J(CJaJhS\h{'$CJaJh|h{'$CJaJۤܤǥȥɥʥ˥ͥΥɷpک[F)j2h{'$CJ OJQJU^JaJ )jh{'$CJ OJQJU^JaJ hk~h{'$CJOJQJ^JaJ$h6h{'$0JCJ OJQJ^JaJ )j<h{'$CJ OJQJU^JaJ h{'$CJ OJQJ^JaJ #jh{'$CJ OJQJU^JaJ hk~h{'$CJ OJQJ^JaJ h{'$ hy\;h{'$CJOJQJ^JaJ hWh{'$CJ OJQJ^JaJ   ƦǦ      HJLNPZ򥺒}lW)jh{'$CJ OJQJU^JaJ hdh{'$CJ OJQJ^JaJ )j(h{'$CJ OJQJU^JaJ $h6h{'$0JCJ OJQJ^JaJ )jh{'$CJ OJQJU^JaJ #jh{'$CJ OJQJU^JaJ hIh{'$CJ OJQJ^JaJ h{'$ h2h{'$CJ OJQJ^JaJ h{'$CJ OJQJ^JaJ ŦT\^"Ū7]^DF"$&(gdgd f$a$gd fZ\^ƪǪ89Wݶˣݒ݁lYH h'h{'$CJ OJQJ^JaJ $hNRh{'$0JCJ OJQJ^JaJ )jh{'$CJ OJQJU^JaJ hgh{'$CJ OJQJ^JaJ hj}h{'$CJ OJQJ^JaJ $h6h{'$0JCJ OJQJ^JaJ )jh{'$CJ OJQJU^JaJ #jh{'$CJ OJQJU^JaJ h{'$CJ OJQJ^JaJ h{'$ hC5h{'$CJ OJQJ^JaJ WXY[\]DF "$&(شؠؠzvmhBvhBvCJh Q h:xh{'$CJ OJQJ^JaJ )jh{'$CJ OJQJU^JaJ h{'$CJ OJQJ^JaJ Uh{'$ hTh{'$CJ OJQJ^JaJ $h6h{'$0JCJ OJQJ^JaJ #jh{'$CJ OJQJU^JaJ )jh{'$CJ OJQJU^JaJ e"Partial Response after 4 cycles? 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