Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease)

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The Centers for Medicare & Medicaid Services (CMS) will modify our existing National Coverage Determinations Manual to expand national coverage for allogeneic hematopoietic stem cell transplantation (HSCT) for three separate medical conditions: Multiple Myeloma Myelofibrosis, and Sickle Cell Disease. MULTIPLE MYELOMA CMS will cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with multiple myeloma (MM) using the Coverage with Evidence Development (CED) paradigm. We are finalizing the following decision: Allogeneic HSCT for multiple myeloma will be covered by Medicare only for beneficiaries with Durie-Salmon Stage II or III multiple myeloma, or International Staging System (ISS) Stage II or Stage III multiple myeloma who are participating in an approved prospective clinical study that meets the criteria below. There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, disease classification, International Myeloma Working Group (IMWG) classification, ISS staging, Durie-Salmon staging, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source. A prospective clinical study seeking Medicare coverage of allogeneic HSCT for multiple myeloma pursuant to CED must address the following question: Prospectively, compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with multiple myeloma who receive allogeneic HSCT have improved outcomes as indicated by: Graft vs. host disease (acute and chronic); Other transplant-related adverse events; Overall survival; and Quality of life (optional). MYELOFIBROSIS CMS will cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with myelofibrosis (MF) using the Coverage with Evidence Development (CED) paradigm. We are finalizing the following decision: Allogeneic HSCT for myelofibrosis will be covered by Medicare only for beneficiaries with Dynamic International Prognostic Scoring System (DIPSSplus) intermediate-2 or High primary or secondary MF and participating in an approved prospective clinical study. There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, disease classification, DIPSSplus score, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source. A prospective clinical study seeking Medicare coverage of allogeneic HSCT for myelofibrosis pursuant to Coverage with Evidence Development (CED) must address the following question: Prospectively, compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with MF who receive allogeneic HSCT have improved outcomes as indicated by: Graft vs. host disease (acute and chronic); Other transplant-related adverse events; Overall survival; and Quality of life (optional). SICKLE CELL DISEASE CMS will cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with Sickle Cell Disease using the Coverage with Evidence Development (CED) paradigm. We are finalizing the following decision: Allogeneic HSCT for sickle cell disease (SCD) will be covered by Medicare only for beneficiaries with severe, symptomatic sickle cell disease who participate in an approved prospective clinical study. There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source. A prospective clinical study seeking Medicare coverage of allogeneic HSCT for sickle cell disease pursuant to Coverage with Evidence Development (CED) must address the following question: Prospectively, compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with SCD who receive allogeneic HSCT have improved outcomes as indicated by: Graft vs. host disease (acute and chronic); Other transplant-related adverse events; Overall survival; and Quality of life (optional). All CMS-approved clinical studies and registries regarding allogeneic HSCT for the treatment of multiple myeloma, myelofibrosis, or sickle cell disease, must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects. The rationale for the study is well supported by available scientific and medical evidence. The study results are not anticipated to unjustifiably duplicate existing knowledge. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination. The study is sponsored by an organization or individual capable of completing it successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data. All aspects of the study are conducted according to appropriate standards of scientific integrity. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR). The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results). The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. We are finalizing changes to expand national coverage for allogeneic hematopoietic stem cell transplantation (HSCT) for these three separate medical conditions. See Appendix B for the manual language.

Decision Memo: TO: Administrative File: CAG-00444R FROM: Tamara Syrek Jensen, JD Director, Coverage and Analysis Group Joseph Chin, MD, MS Deputy Director, Coverage and Analysis Group James Rollins, MD, MSHA, PhD Director, Division of Items and Devices Lori Paserchia, MD Lead Medical Officer Cheryl Gilbreath, PharmD, MBA, RPh Lead Analyst Rosemarie Hakim, PhD Epidemiologist Xiufen Sui, MD, MS Biostatistician SUBJECT: Final National Coverage Decision Memorandum for Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease) DATE: January 27, 2016 I. Decision The Centers for Medicare & Medicaid Services (CMS) will modify our existing National Coverage Determinations Manual to expand national coverage for allogeneic hematopoietic stem cell transplantation (HSCT) for three separate medical conditions: Multiple Myeloma Myelofibrosis, and Sickle Cell Disease. MULTIPLE MYELOMA CMS will cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with multiple myeloma (MM) using the Coverage with Evidence Development (CED) paradigm. We are finalizing the following decision: Allogeneic HSCT for multiple myeloma will be covered by Medicare only for beneficiaries with Durie-Salmon Stage II or III multiple myeloma, or International Staging System (ISS) Stage II or Stage III multiple myeloma who are participating in an approved prospective clinical study that meets the criteria below. There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, disease classification, International Myeloma Working Group (IMWG) classification, ISS staging, Durie-Salmon staging, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source. A prospective clinical study seeking Medicare coverage of allogeneic HSCT for multiple myeloma pursuant to CED must address the following question: Prospectively, compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with multiple myeloma who receive allogeneic HSCT have improved outcomes as indicated by: Graft vs. host disease (acute and chronic); Other transplant-related adverse events; Overall survival; and Quality of life (optional). MYELOFIBROSIS CMS will cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with myelofibrosis (MF) using the Coverage with Evidence Development (CED) paradigm. We are finalizing the following decision: Allogeneic HSCT for myelofibrosis will be covered by Medicare only for beneficiaries with Dynamic International Prognostic Scoring System (DIPSSplus) intermediate-2 or High primary or secondary MF and participating in an approved prospective clinical study. There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, disease classification, DIPSSplus score, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source. A prospective clinical study seeking Medicare coverage of allogeneic HSCT for myelofibrosis pursuant to Coverage with Evidence Development (CED) must address the following question: Prospectively, compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with MF who receive allogeneic HSCT have improved outcomes as indicated by: Graft vs. host disease (acute and chronic); Other transplant-related adverse events; Overall survival; and Quality of life (optional). SICKLE CELL DISEASE CMS will cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with Sickle Cell Disease using the Coverage with Evidence Development (CED) paradigm. We are finalizing the following decision: Allogeneic HSCT for sickle cell disease (SCD) will be covered by Medicare only for beneficiaries with severe, symptomatic sickle cell disease who participate in an approved prospective clinical study. There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, comorbid conditions, type of preparative/conditioning regimen, graft vs. host disease (GVHD) prophylaxis, donor type and cell source. A prospective clinical study seeking Medicare coverage of allogeneic HSCT for sickle cell disease pursuant to Coverage with Evidence Development (CED) must address the following question: Prospectively, compared to patients who do not receive allogeneic HSCT, do Medicare beneficiaries with SCD who receive allogeneic HSCT have improved outcomes as indicated by: Graft vs. host disease (acute and chronic); Other transplant-related adverse events; Overall survival; and Quality of life (optional). All CMS-approved clinical studies and registries regarding allogeneic HSCT for the treatment of multiple myeloma, myelofibrosis, or sickle cell disease, must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects. The rationale for the study is well supported by available scientific and medical evidence. The study results are not anticipated to unjustifiably duplicate existing knowledge. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination. The study is sponsored by an organization or individual capable of completing it successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data. All aspects of the study are conducted according to appropriate standards of scientific integrity. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR). The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results). The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. We are finalizing changes to expand national coverage for allogeneic hematopoietic stem cell transplantation (HSCT) for these three separate medical conditions. See Appendix B for the manual language. II. Background The scope of this National Coverage Analysis (NCA) is limited to allogeneic stem cell transplantation for beneficiaries with multiple myeloma, for beneficiaries with myelofibrosis, and for beneficiaries with sickle cell disease. This NCA will not reconsider the current NCD for any other indications. Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations. Please find below a list of these acronyms and corresponding full terminology: ABMTR - Autologous Blood and Marrow Transplant Registry ACCE Model - a model process named for the four criteria in evaluating a genetic test: Analytic validity, Clinical validity, Clinical utility, and associated Ethical, legal and social implications AHRQ - Agency for Healthcare Research and Quality AHSCT - Allogeneic Hematopoietic Stem Cell Transplantation AlloSCT - Allogeneic Stem Cell Transplantation AML - Acute Myelogenous Leukemia ASBMT - American Society for Blood and Marrow Transplantation ATG - Anti-thymocyte Globulin AuSCT - Autologous Stem Cell Transplantation BMT - Bone Marrow Transplantation CALR - Calreticulin CBT - Cord Blood Transplantation CED - Coverage with Evidence Development CFR - Code of Federal Regulations CI - Confidence Interval CIBMTR - Center for International Blood and Marrow Transplant Research CMS - Centers for Medicare & Medicaid Services DFS - Disease-free Survival DIPSS - Dynamic International Prognostic Scoring System EBMT - European (Society for) Blood and Marrow Transplantation EFS - Event-free Survival ELN - European LeukemiaNet ESH - European School of Haematology ET - Essential Thrombocythemia ET—MF - Essential Thrombocythemia/Myelofibrosis FDA - Food and Drug Administration FISH - fluorescence in situ hybridization GvHD/GVHD - Graft Versus Host Disease h - Hour(s) HCT/Ps - human cells, tissues, and cellular-and tissue based products HLA - Human Leukocyte Antigen HPC - Hematopoietic stem/progenitor cells HR - Hazard Ratio HRSA - Health Resources and Services Administration HSCT - Hematopoietic Stem Cell Transplantation IBMTR - International Bone Marrow Transplant Registry Ig - Immunoglobulin IMWG - International Myeloma Working Group IPSS - International Prognostic Scoring System ISS - International Staging System JAK2 - Janus Kinase 2 LCD - Local Coverage Determination MA - Myeloablative MAC - Medicare Administrative Contractor MDS - Myelodysplastic Syndrome MF - Myelofibrosis MM - Multiple Myeloma MRA - Magnetic Resonance Angiography MRI - Magnetic Resonance Imaging NCA - National Coverage Analysis NCD - National Coverage Determination NHLBI - National Heart, Lung and Blood Institute NIH - National Institutes of Health NMDP - National Marrow Donor Program NRM - Non-relapsing Mortality OS - Overall Survival PedsQL - Pediatric Quality of Life Inventory PFS - Progression-free Survival PHS - Public Health Service PMF - Primary Myelofibrosis PV - Polycythemia Vera PV—MF - Polycythemia vera/Myelofibrosis QoL - Quality of Life RBC - Red Blood Cell RIC - Reduced-intensity Conditioning SCD - Sickle Cell Disease SCOTD - Stem Cell Therapeutic Outcomes Database SCT - Stem Cell Transplantation TCD - Transcranial Doppler TM - Thalassemia Major TRM - Transplantation-related Mortality URD - Unrelated Donor US - United States USPSTF - US Preventive Services Task Force WHO - World Health Organization STEM CELL TRANSPLANTATION (SCT) Hematopoietic stem cells are multi-potent cells that give rise to all the blood cell types; these stem cells produce blood and immune cells. Hematopoietic stem cells can be sourced from peripheral blood, bone marrow and umbilical cord blood. Stem cell transplantation (SCT) is a process that includes mobilization, harvesting, and transplant of stem cells and the administration of high dose chemotherapy and/or radiotherapy prior to the actual transplant. During stem cell transplantation, stem cells are harvested from either the patient (autologous) or a donor (allogeneic) and subsequently administered by intravenous infusion to the patient. For allogeneic transplants, the stem cell source may be a related or unrelated donor. In addition, the transplant can be HLA-identical (matched), unmatched or half-matched (also known as haplo-identical). The degree of matching is important because if the HLA match is not close, the donor’s immune cells, which are transplanted along with the donor’s stem cells, will attack the patient’s tissues; this is called graft versus host disease (GVHD). Allogeneic stem cell transplants (alloSCT) may be used to restore function in recipients having an inherited (such as Sickle Cell Disease) or acquired (such as occurs after severely myelotoxic doses of chemotherapy and/or radiotherapy, which are used to treat various malignancies) deficiency or defect. Autologous stem cell transplants (AuSCT) are used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy and/or radiotherapy. Until recently, the majority of patients who received a SCT were younger than 65 years and relatively free of concomitant morbidities such as cardiac disease. This is due to the high toxicity of the high intensity chemotherapy (referred to as myeloablative conditioning) administered prior to the transplantation and the inability of patients with concomitant morbidities to tolerate these pre-transplant chemotherapy-related toxicities. With the introduction of reduced-intensity conditioning (RIC) prior to transplantation, more patients with advanced age and/or concomitant morbidities are eligible for SCT. The scope of this decision memorandum is limited to the use of alloSCT for MM, the use of alloSCT for MF, and the use of alloSCT for SCD. The use of alloSCT for acute myelogenous leukemia (AML), which MF can transform into, is not within the scope of this review. MULTIPLE MYELOMA Multiple myeloma (also called Kahler disease or plasma cell myeloma) is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction (Kyle & Rajkumar, 2004). Characteristics of the disease include lytic bone lesions, anemia, loss of kidney function, immunodeficiency, and myeloma-associated amyloid light-chain (AL) amyloid deposits in various tissues. In this malignancy, there is an overproduction of light and heavy chain monoclonal immunoglobulins. The specific immunoglobulin secreted by the malignant cell is the M-protein, named in reference to its monoclonal characteristics. Epidemiology Multiple myeloma accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. In Western countries, the annual age adjusted incidence is 5.6 cases per 100,000 persons. The median age at diagnosis is approximately 66 years; 37% of patients are younger than 65 years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older. The incidence rates are higher among males than females, and highest among African Americans. In patients presenting at an age under 60 years, 10-year survival is approximately 30%. Multiple myeloma is the ninth most common cause of cancer death among US females and the fourteenth most common cause of cancer death among US males, accounting for about 2% of cancer deaths for each gender. A number of lifestyle, occupational as well as environmental risk factors have been explored to determine their association with MM. Lifestyle factors such as obesity, diet, tobacco and alcohol usage, reproductive as well as hormonal factors fail to reveal an association with MM. And when exploring occupational and environmental risk factors, most occupational cohort studies lack statistical power for rare outcomes such as MM. Many case-control studies suffer from small numbers of exposed subjects in specific occupation, job title or chemical exposure categories. And case-control studies may be hindered by bias due to differential recall of exposures between the cases and controls. Studies evaluating the association between asbestos exposure as well as other environmental risk factors and MM also do not support a causal link. In a meta-analysis of 18 cohort studies of chemical workers in the United States and western Europe, the authors found no excess of MM mortality (Greenberg et al., 2001). When exploring family history and genetic influences, several studies have reported increased risks of developing MM in persons who have a family history of certain diseases; however, the role of specific malignant and nonmalignant conditions among relatives in the etiology of MM remains unknown. In terms of genetic variation a number of studies suggest that gene mutations, as well as particular genetic polymorphisms, may be associated with risk of MM. Results have been inconsistent, and significant findings have not been replicated convincingly (Alexander et al., 2007). One observation noted that the risk of developing MM is approximately 3.7-fold higher for persons with a first-degree relative with the disease (Lynch & Sanger, 2001). Furthermore, clusters of two or more first-degree relatives, identical twins, and in four members spanning three generations in one family have been reported with an incidence of approximately three familial cases per 1000 patients with myeloma (Lynch et al., 2001, 2005, 2008; Camp, Werner and Cannon-Albright, 2008). Pathogenesis Multiple myeloma cells are the malignant counterparts of post-germinal center (GC) long-lived plasma cells, characterized by strong bone marrow dependence, somatic hypermutation (SHM) of immunoglobulin (Ig) genes, and isotype class switch resulting in the absence of IgM expression in all but 1 % of tumors (Kuehl & Bergsagel, 2002). However, MM cells differ from healthy plasma cells because they retain the potential for a low rate of proliferation. Multiple myeloma is preceded by a pre-malignant plasma cell tumor called monoclonal gammopathy of undetermined significance (MGUS) which is derived from GC B cells. Multistep genetic and microenvironmental changes lead to the transformation of these cells into a malignant neoplasm that progresses to smoldering myeloma and, finally, to symptomatic myeloma. It is thought that genetic abnormalities that occur in tumor plasma cells play a major role in the pathogenesis of myeloma. Based on chromosome content, MM is divided into two distinct genetic subtypes: Hyperdiploid myeloma which is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21, and lacks recurrent immunoglobulin gene translocations; and Non-hyperdiploid myeloma which is characterized by chromosome translocations t(4;14), t(14;16), t(14;20), t(6;14) and t(11;14). Both groups share the dysregulated expression of a cyclin D gene, either directly by juxtaposition to an immunoglobulin enhancer as a result of ectopic expression of a MAF family transcription factor, or indirectly by as yet unidentified mechanisms. Other genetic abnormalities associated with MM include rearrangements of MYC, activating mutations of NRAS, KRAS or BRAF, a promiscuous array of mutations that activate NFkB and deletions of 17p. Evidence seems to support the use of a risk-stratified approach in the treatment of patients with MM. Clinical Presentation, Diagnosis and Staging The diagnosis of MM is based on the presence of at least 10% clonal bone marrow plasma cells, and monoclonal protein in serum or urine. Multiple myeloma is classified as asymptomatic or symptomatic, depending on the absence or presence of myeloma-related organ or tissue dysfunction. The CRAB criteria is often used to describe the extent of the disease, and symptoms and signs includes hyperCalcemia, Renal insufficiency, Anemia, and Bone disease (Durie et al., 2003, 2006; Kyle and Rajkumar, 2009). Non-CRAB end-organ damage (e.g., hyperviscosity, recurrent bacterial infections, amyloidosis, peripheral neuropathy) are nonspecific and not diagnostic of MM. Most of the patient’s symptoms are due to damage from excess light chains production, as well as the infiltration of plasma cells into target organs. Weight loss, fatigue and generalized weakness are also characteristics of the disease. Neurologic complications include cord compression, peripheral neuropathy and CNS involvement. And due to a combination of immune dysfunction and physical factors, patients with MM are also prone to infection. The International Myeloma Working Group (IMWG), which emphasizes the importance of end organ damage, also has criteria which can be used in making the diagnosis. They suggest first a detailed medical history and physical examination. Diagnostic tools such as routine laboratory testing (complete blood count, chemical analysis, serum and urine protein electrophoresis with immunofixation, and quantification of monoclonal protein), and bone marrow examination (trephine biopsy plus aspirate for cytogenetic analysis or fluorescence in situ hybridization [FISH]) are required. Conventional radiography of the spine, skull, chest, pelvis, humeri, and femora can also be used to confirm clinical findings. Sometimes magnetic resonance imaging (MRI), as well as computed tomography (CT) and MRI are required to assess suspected cord compression if needed. Based on the occurrence of the disease in the population, the following risk stratifications had been noted by Rajkumar (2012): High risk disease — Approximately 15 percent of people with multiple myeloma have high risk disease based on cytogenetic testing (patients with translocation t (14;16)), translocation t (14;20) and deletion chromosome 17p). This is the aggressive form of multiple myeloma and may shorten survival; patients at high risk disease are treated with more aggressive therapy. Intermediate risk disease — Approximately 10 percent of people with multiple myeloma have intermediate risk disease based on cytogenetic testing (patients with translocation t (4;14)). With appropriate therapy, patients with this form of multiple myeloma can have outcomes similar to those of standard risk multiple myeloma. Standard risk disease — All patients with multiple myeloma who lack high or intermediate risk genetic abnormalities are considered to have standard risk multiple myeloma, and with appropriate therapy have an estimated median survival of 8 to 10 years. While survival has improved with the use of novel therapy, approximately 25% of patients have a median survival of 2 years or less (Biran, Jagannath, & Chari, 2013). Because the outcomes of patients with MM are highly variable, knowledge of tumor and host factors associated with prognosis are critical for understanding disease outcome, identifying risk groups, and optimizing patient treatment (Greipp et al., 2005). Previous staging systems have been used. For example, the Durie-Salmon Staging System, which is based on the risk factors on the amount of abnormal monoclonal immunoglobulin in the blood or urine, amount of calcium and hemoglobin in blood, and severity of bone damage based on x-rays (Durie & Salmon, 1975): Stage I - All of the following: - Hemoglobin value > 10 g/dL - Serum calcium value normal or ≤ 12 mg/dL - Bone x-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only - Low M-component production rate (IgG value < 5 g/dL; IgA value < 3 g/dL) - Bence Jones protein < 4 g/24 hr Stage II - Neither Stage I nor Stage III Stage III - One or more of the following: - Hemoglobin value < 8.5 g/dL - Serum calcium value > 12 mg/dL - Advanced lytic bone lesions (scale 3) - High M-component production rate - (IgG value > 7 g/dL; IgA value > 5 g/dL) - Bence Jones protein > 12 g/24 h Sub-classifications (either A or B) A: Relatively normal renal function (serum creatinine value < 2.0 mg/dL) B: Abnormal renal function (serum creatinine value = 2.0 mg/dL) However, this Durie-Salmon system did not include factors which were felt to be most important in prognosis. Because of the inadequacies of the Durie-Salmon system, another staging system has been developed. The International Staging System, which is the most recent, most reliantly used risk assessment system and identifies three risk groups on the basis of serum β2-microglobulin and albumin levels (Greipp et al., 2005): Stage I - Serum beta-2 microglobulin is less than 3.5 (mg/L) and the albumin level is 3.5 (g/dL) or greater Stage II - Neither stage I or III, meaning that either: The beta-2 microglobulin level is between 3.5 and 5.5 (with any albumin level), OR the albumin is below 3.5 while the beta-2 microglobulin is less than 3.5 Stage III - Serum beta-2 microglobulin is 5.5 or greater. Myeloma cell labeling as well as chromosomal changes detected by conventional cytogenetics and FISH (looking specifically for loss of a copy of chromosome 13 and translocation of material from chromosomes 4 and 14) can also be a part of a stratification system. These predictive models can have considerable influence on the choice of therapy which helps determine prognosis in patients with MM. In general, studies have confirmed that patients with higher stage levels and patients with chromosomal abnormalities have worse outcomes than those with normal karyotypes or stage I disease. Treatment The main options for treatment of MM include non-chemotherapy drugs that target the cancer cells, standard chemotherapy drugs, corticosteroids, and hematopoietic stem cell transplant (HSCT). Drugs such as thalidomide, lenalidomide, bortezomib, carfilzomib and pomalidomide have had limited success in the treatment of MM, both in newly diagnosed patients and in patients with advanced disease who have failed chemotherapy or transplantation. These agents are usually used in combination with dexamethasone, with each other, or with standard chemotherapy agents. HSCT has also been used in the treatment of MM. When discussing HSCT use in patients with MM there are basically two varieties: Those using one's own stem cells (autologous) or those transplantations that use cells from a close relative or matched unrelated donor (allogeneic). Most transplants performed in patients with MM are of the autologous in nature; although this is not curative, it has been shown to prolong life in selected patients. This form of transplantation can be done as initial therapy in newly diagnosed patients or at the time of relapse. In some selected patients more than one transplant (auto-auto) may be recommended to adequately control the disease. Allogeneic HSCT has also been performed on patients with MM. There are four different types of allogeneic transplants (Rajkumar 2014): Myeloablative allogeneic HSCT which requires hematopoietic cells from an HLA-matched donor. These cells are given after the patient receives high dose chemotherapy and total body radiation. This form of transplant has two advantages over autologous HSCT: the graft does not contain tumor cells, and the transplant can produce a graft-versus-myeloma effect. But due to the high toxicity associated with this treatment (overall mortality can be as high as 50 percent due to fungal infections, interstitial pneumonitis, and graft-versus-host disease), less than 5 to 10 percent of patients with MM are candidates for this approach. Syngeneic HSCT — this form of allogeneic transplant is performed on identical twins. Experience is limited due to the limited number of procedures performed and lack of studies. T Cell Depleted Allogeneic HSCT — the advantages of this form of transplant is that it decreases the incidence of GVHD and it reduces transplant mortality. But due to the high mortality rate T cell depleted transplants are not recommended outside of a clinical trial setting. Nonmyeloablative Allogeneic HSCT - this regimen uses less intensive chemotherapy or irradiation alone prior to the infusion of donor hematopoietic stem cells, and relies more on donor cellular immune effects and less on the cytotoxic effects of the regimen. Nonmyeloablative allogeneic HSCT and RIC HSCT are associated with lower rates of treatment-related toxicity and treatment-related mortality, but higher rates of relapse compared with rates previously seen with myeloablative allogeneic transplantation (Badros et al., 2001; Kroger et al., 2002; Crawley et al., 2007). Prospective trials investigating the use of nonmyeloablative HSCT have conflicting data regarding survival rates, but are consistent in their treatment-related mortality rates (11 to 18 percent at five years) and rates of extensive graft-versus-host disease (50 to 74 percent). Randomized trials of allogeneic HSCT have not been feasible for patients with myeloma, though Autologous followed by nonmyeloablative allogeneic HSCT in newly diagnosed myeloma have been tried resulting in mixed results. Approximately 25 percent of individuals who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease. Also, the efficacy of allogeneic HSCT compared with autologous HSCT has not been fully established. MYELOFIBROSIS Myleofibrosis is a stem cell-derived hematologic disorder. It is one of six types of chronic myeloproliferative neoplasm along with essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, and chronic eosinophilic leukemia. In most of these myeloproliferative neoplasms, an abnormal proliferation of stem cells results in the overproduction of red blood cells (e.g., PV), white blood cells (e.g., chronic neutrophilic or eosinophilic leukemia) or platelets (e.g., ET). Alternatively, in MF the abnormal proliferation is associated with cytopenia (Tefferi, 2014). Primary MF is defined as MF having arisen de novo . Secondary MF is defined as having arisen from ET or PV (Cervantes, 2014). The natural history of MF is highly variable (Alchalby & Kroger, 2014). Some patients may be initially asymptomatic. As the disease progresses, constitutional symptoms (e.g., fever, malaise, weight loss, night sweats) and cachexia occur along with abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly and extramedullary hematopoiesis, (Tefferi, 2014). These signs and symptoms typically occur and increase in a heterogeneous manner (Cervantes, 2014) and are frequently debilitating (Geyer & Mesa, 2014). MF may transform to AML, which has a median survival of 2.6 months and an overall survival at 12 months of 9% (Mesa et al., 2005). In the US the annual incidence of MF is 0.5 - 1.5 cases per 100,000 individuals. MF mostly affects elderly individuals (Cervantes, 2014) with a median age at diagnosis of 65 years (Cervantes, 1997). The pathogenesis of MF is unknown (Tefferi, 2011). Mutations in various genes (e.g., Janus kinase 2 [ JAK2 ]; calreticulin [ CALR ]) have been found and can be useful for prognosis and potentially treatment but these mutations are not specific to MF (Tefferi, 2014) and may not be present in every patient (Cervantes, 2014). The prognosis of MF was initially guided by the Lille score (a.k.a., the Dupriez score), which used hemoglobin and white blood cell counts to classify patients as “long-lived” (median survival of ten years) or “short-lived” (median survival of two years) (Dupriez, 1996). Patients were further grouped by risk, as shown in the table below: Lille risk group Number of risk factors Median survival (years) Low None 7 - 8 Intermediate 1 2.2 High 2 1 In the past decade the International Prognostic Scoring System (IPSS), which has been progressively updated to first the dynamic IPSS (DIPSS) and now the DIPSSplus as the understanding of the natural history and especially the impact of cytogenetics on the pathogenesis of MF has increased (Alchalby & Kroger, 2014) has gained prominence. The DIPSSplus prognostic score is based on eight risk factors (need for red blood cell transfusion, hemoglobin level, platelet count, leukocyte count, circulating blasts in the blood, constitutional symptoms, unfavorable cytogenetic profile and age). There are four risk categories based on the DIPSSplus score as show in the following table (Gangat et al., 2011): DIPSSplus risk category Number of risk factors Median survival (years) Low None 15.4 Intermediate-1 1 6.5 Intermediate-2 2 or 3 2.9 High 4 or more 1.3 Geyer and Mesa (2014) note that “MF treatment goals are based on assessment of both disease burden (symptoms, cytopenias, splenomegaly) and impact of disease on survival.” The authors further state that observation, medical therapies and alloSCT are the three therapeutic options for patients with MF. Observation is generally recommended for asymptomatic patients with a DIPSSplus score of low or intermediate-1 (Tefferi, 2014). Tefferi (2014) suggests, however, that a higher risk genetic profile in this specific patient population may be a reason to begin therapy instead. Geyer and Mesa (2014), on the other hand, state that it “remains unclear whether patients who are considered low risk by DIPSS but harbor high-risk molecular features should be managed differently (i.e., earlier choice for allo-SCT).” Conventional medical therapies, such as growth factors (e.g., erythropoietin, androgens, immunomodulatory drugs, interferon alfa, cytoreductive agents), blood transfusions, spleen irradiation and splenectomy, are generally recommended for patients with symptoms who have a DIPSSplus score of low or intermediate-1 (Tefferi, 2014). Of note, Alchalby and Kroger (2014) stated that “none of these approaches have been found to prolong survival.” In his 2014 review, Tefferi presented a similar opinion and stated that current drug therapy for primary MF “is not curative and has not been show to prolong survival; although there is controversy regarding the value of JAK inhibitors, in this regard, these drugs have not been shown to display disease-modifying activity, including reversal of bone marrow fibrosis or induction of complete or partial remissions.” The first FDA-approved JAK inhibitor is ruxolitinib; it is indicated for patients with intermediate- or high-risk MF (Alchalby & Kroger, 2014). The authors noted that ruxolitinib demonstrated an early and sustained reduction in splenomegaly, improvement of constitutional symptoms and a survival benefit during pre-market clinical trials. Tamari et al. (2015), however, stated that the post-market clinical experience “has not yielded as impressive results” due to the finding that about “50% of patients discontinue ruxolitinib therapy at 3 years due to loss of clinical benefit or adverse side effects.” Investigational drug therapy and alloSCT are recommended for patients with a DIPSSplus score of intermediate-2 or high (Tefferi, 2014). AlloSCT is considered to be “potentially curative but dangerous” for the treatment of MF (Tefferi, 2014). Similarly, Geyer and Mesa (2014) stated that alloSCT “is the only curative option for MF patients and is typically reserved for patients whose life expectancy is < 5 years.” The risks associated with alloSCT include graft failure, GVHD and transplantation-related drug treatment-associated toxicity (Geyer & Mesa 2014). SICKLE CELL DISEASE Sickle cell disease is a group of inherited red blood cell (RBC) disorders created by the presence of two abnormal hemoglobin genes. Hemoglobin, a protein in RBCs, carries oxygen throughout the body. The abnormal hemoglobin genes result in the formation of abnormal hemoglobin that causes the shape of the RBC to change from disc-like to crescent- or sickle-like. Sickle-shaped RBCs cannot carry oxygen, are less flexible than normal RBCs and can stick to blood vessel walls, which can slow or block blood flow (National Institutes of Health / National Heart, Lung and Blood Institute [NIH/NHLBI], 2015). The blockage of blood flow causes morbidity (pain and multi-organ dysfunction/failure). Multi-organ failure leads to premature death (Oringanje, Nemecek & Oniyangi, 2013). In all forms of SCD, at least one of the two abnormal hemoglobin genes causes the body to make the abnormal hemoglobin, called hemoglobin S. For a person with two hemoglobin S genes, the resultant hemoglobin is called hemoglobin SS and the disease is called sickle cell anemia. This is the most common and often most severe kind of SCD. Two other common forms of SCD are hemoglobin SC disease and hemoglobin Sβ thalassemia (NIH/NHLBI, 2015). Hemoglobin Sβ thalassemia is also associated with a severe kind of SCD (NIH/NHLBI, 2014). When an abnormal hemoglobin gene is inherited from only one parent, a person will have sickle cell trait. People with sickle cell trait are generally healthy (NIH/NHLBI, 2015). Sickle cell disease is a life-long illness that starts in infancy. Due to improved clinical management of the disease in children, currently more than 90% of children survive to adulthood (NIH/NHLBI, 2014). Compared to an average lifespan of 14 years for a person with SCD in 1973, currently the US life expectancy is 40 - 60 years; hence, today there is a greater prevalence of adults with SCD (NIH/NHLBI, 2015). In one recent study of adults with symptomatic SCD who were receiving conventional (i.e., non-alloSCT) therapies, the ten-year mortality rate was 45% (Steinberg et al., 2010). In the US, approximately 100,000 people have SCD. Most people with SCD are of African ancestry or identify themselves as black. About one in every 365 black children is born with SCD (NIH/NHLBI, 2015). There are also many people of Middle Eastern, Hispanic, southern European, Central American, and Asian Indian descent with SCD (NIH/NHLBI, 2014). The severity and clinical course of SCD varies widely from person to person and can change over time. Most of the signs and symptoms are related to complications of the disease that during a person’s lifetime can damage the spleen, brain, eyes, lungs, liver, heart, kidneys, joints, bones or skin. Vaso-occlusive crisis is the most common acute complication of SCD. It consists of recurrent sudden episodes of intense pain, which usually occur without warning. The management of vaso-occlusive crises is central to the care of patients with SCD. Other major acute complications of SCD include life-threatening bacterial infections, acute chest syndrome, stroke (including clinical stroke as well as silent stroke and thinking problems associated with silent brain injury), splenic sequestration with resultant severe anemia in addition to the chronic milder anemia associated with the disease, acute renal failure and mental health issues such as depression and anxiety. Chronic complications of SCD include chronic pain, renal impairment, pulmonary hypertension and retinal problems (NIH/NHLBI, 2014). Effective therapies exist to reduce symptoms, treat complications and prolong survival. Health maintenance measures to prevent complications such as immunizations and prophylactic use of penicillin (in children up to five years old and in any person who has had a splenectomy and/or past infection with pneumococcus) as well as regular medical care as needed contribute to improved well-being (NIH/NHLBI, 2015). Conventional treatment of SCD consists mainly of hydroxyurea and RBC transfusions as well as any therapies necessary to treat the numerous complications of the disease. Hydroxyurea and the long-term administration of RBC transfusions “are the only currently proven disease-modifying treatments for people with SCD. Both therapies are used in primary and secondary stroke prevention. Although neither has been shown to prevent all SCD-related organ damage, these treatment modalities can improve the quality of life for individuals with SCD” (NIH/NHLBI, 2014). Hydroxyurea has been shown to reduce or prevent several SCD complications (NIH/NHLBI, 2015). According to the NIH/NHLBI (2015), “studies of adults with hemoglobin SS or hemoglobin Sβ thalassemia showed that hydroxyurea reduced the number of episodes of pain crises and acute chest syndrome. It also improved anemia and decreased the need for transfusions and hospital admissions.” NIH/NHLBI (2015) also noted “studies in children with severe hemoglobin SS or Sβ thalassemia showed that hydroxyurea reduced the number of vaso-occlusive crises and hospitalizations. A study of very young children (between the ages of nine and 18 months) with hemoglobin SS or hemoglobin Sβ thalassemia also showed that hydroxyurea decreased the number of episodes of pain and dactylitis.” However, hydroxyurea can cause side effects such as leukocytopenia, thrombocytopenia and, rarely, worsening anemia that will prompt a temporary halt of administration of the medication and a resumption of administration at a lower dose (NIH/NHLBI, 2015). Since the RBCs in a blood transfusion have normal hemoglobin, acute and chronic RBC transfusions are used to treat and prevent certain SCD complications by lessening vaso-occlusion and improving oxygen delivery to the person’s tissues and organs. Common indications for acute RBC transfusions include severe anemia, acute stroke, acute chest crises and multi-organ failure. Regular administration of RBC transfusions is recommended for prevention of first stroke in children, for treatment of complications that do not improve with hydroxyurea or for people who experience too many side effects from hydroxyurea. Two significant complications of the routine administration of RBC transfusions include iron overload, which can severely impact heart and liver function and result in the need for chelation therapy, and alloimmunization, which can increase the risk of finding a matching unit of blood for future transfusions (NIH/NHLBI 2015). These conventional treatments ameliorate the disease and its complications thereby temporarily lessening the impact of SCD on the person but, importantly, do not cure SCD. According to the NIH/NHLBI (2014), “there is hope for a cure using hematopoietic stem cell transplantation (HSCT). NIH further stated: "Additional research regarding patient and donor selection and the specific transplantation procedure is required before this potentially curative therapy will become more widely available.” The goal of SCT is to eliminate the sickled RBCs (and the person’s stem cells that contain the genetic code for the abnormal hemoglobin) and replace them with normal stem cells that have the genetic code for the production of normal hemoglobin (Oringanje et al., 2013). In addition, NIH/NHLBI (2015) notes, “unfortunately, most people with SCD are either too old for a transplant or don’t have a relative who is a good enough genetic match for them to act as a donor. A well-matched donor is needed to have the best chance for a successful transplant.” Angelucci et al. (2014) stated that the indications for SCT for people with SCD are “less clearly defined because of the variability of the disease course.” The authors note that historically “the indication for HSCT in SCD was mainly based on SCD-associated morbidity: the sicker the child, the stronger the indication. With the reduction in TRM in recent years, and with the increasing knowledge of the severity of complications in untreated patients, the accepted indications for HSCT have become less restrictive.” Walters et al. (1996) suggested a list of indications for alloSCT for people with SCD: “Stroke or central nervous system event lasting longer than 24 h, acute chest syndrome with recurrent hospitalizations or previous exchange transfusions Recurrent vaso-occlusive pain (more than 2 episodes per year over several years) or recurrent priapism Impaired neuropsychological function with abnormal cerebral MRI scan Stage I or II sickle lung disease Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30 to 50% of the predicted normal value) Bilateral proliferative retinopathy with major visual impairment in at least one eye Osteonecrosis of multiple joints Red-cell alloimmunization during long-term transfusion therapy” King and Shenoy (2014) updated the Walters list of indications to account for the increased donor sources for stem cells: Table 1. Indications for HSCT in SCD Matched sibling donor (if available) Matched Unrelated Donor transplant Mismatched marrow donor, haploidentical donor, unrelated cord blood transplant Consider early,* prior to or at onset of SCD symptoms, with the highest priority given to patients with HbSS and HbSβ0 thalassemia Stroke Recurrent stroke despite adequate chronic transfusion therapy; progressive CNS changes Stroke Elevated TCD velocity Severe SCD symptoms and inability to tolerate supportive care resulting in symptom persistence/progression Elevated TCD velocity Recurrent acute chest syndrome despite supportive care Recurrent acute chest syndrome despite supportive care Recurrent severe VOE despite supportive care Recurrent severe VOE despite supportive care Red cell alloimmunization despite intervention + established indication for chronic transfusion therapy Red cell alloimmunization despite intervention + established indication for chronic transfusion therapy Pulmonary hypertension Pulmonary hypertension Recurrent priapism Recurrent priapism Sickle nephropathy Sickle nephropathy Bone and joint involvement Bone and joint involvement Sickle retinopathy For all genotypes, the morbidity of the disease is the driving factor in pursuing a HSCT. Preventative HSCT should be considered for children with higher-risk genotypes, HbSS, and HbSβ0. HSCT for adults with SCD is better tolerated with a low-intensity regimen, with the caveat of requiring prolonged immune suppression to maintain mixed-donor chimerism. AVN, avascular necrosis; TCD, transcranial Doppler; VOE, veno-occlusive episodes. *Especially in children with difficult access to adequate lifelong supportive medical care, we recommend reviewing statistics for OS, DFS, GR, and GVHD with families as they weigh these options. (King & Shenoy, 2014) NIH/NHLBI (2015) noted that currently “most SCD transplants are performed in children who have had complications such as strokes, acute chest crises, and recurring pain crises. These transplants usually use a matched donor. However, because only about 1 in 10 children with SCD has a matched donor without SCD in their families, the number of people with SCD who get transplants is low. HSCT is more risky in adults, and that is why most transplants are done in children.” In addition, “HSCT is successful in about 85 percent of children when the donor is related and HLA matched. Even with this high success rate, HSCT still has risks. Complications can include severe infections, seizures, and other clinical problems. About 5 percent of people have died. Sometimes transplanted cells attack the recipient’s organs (graft versus host disease). Medicines are given to prevent many of the complications, but they still can happen” (NIH/NHLBI, 2015). III. History of Medicare Coverage Section 110.8.1 of the Medicare National Coverage Determinations (NCD) Manual currently lists various clinical indications and conditions for which SCT is nationally covered or non-covered to date. MULTIPLE MYELOMA NCD 110.8.1 subsection A.1.b states: “Effective for services performed on or after May 24, 1996, allogeneic stem cell transplantation is not covered as treatment for multiple myeloma.” NCD 110.8.1 subsection A.2.a.ii states: “Effective October 1, 2000, single AuSCT is only covered for Durie-Salmon Stage II or III patients that fit the following requirements: - Newly diagnosed or responsive multiple myeloma. This includes those patients with previously untreated disease, those with at least a partial response to prior chemotherapy (defined as a 50% decrease either in measurable paraprotein [serum and/or urine] or in bone marrow infiltration, sustained for at least 1 month), and those in responsive relapse; and - Adequate cardiac, renal, pulmonary,and hepatic function.” NCD 110.8.1 subsection A.2.b states, in pertinent part, that: Insufficient data exist to establish definite conclusions regarding the efficacy of AuSCT for the following conditions: - Up to October 1, 2000, multiple myeloma; - Tandem transplantation (multiple rounds of AuSCT) for patients with multiple myeloma MYELOFIBROSIS and SICKLE CELL DISEASE CMS does not have a national policy that specifically addresses coverage of HSCT for MF or SCD. In the absence of a national coverag