Autologous Stem Cell Transplantation (AuSCT) for Multiple Myeloma (MM)

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The Centers for Medicare & Medicaid Services (CMS) is reconsidering one aspect of the Stem Cell Transplantation national coverage determination (NCD) at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03. Specifically, CMS is reconsidering section B.II.b of the NCD, which sets forth coverage criteria for autologous stem cell transplantation (AuSCT) for certain beneficiaries with multiple myeloma (MM). The focus of this reconsideration is to evaluate the evidence of prognostic assessment tools, particularly the International Staging System (ISS) and its revisions, in predicting outcomes in MM patients who have undergone AuSCT to determine if coverage criteria should be changed to reflect this evidence. We are proposing to expand the NCD to cover AuSCT for MM patients when the ISS or its revisions are used in the patient’s risk assessment. Specifically, we propose to cover single AuSCT for MM patients at Stage II or Stage III using the ISS and its revisions in patients who 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. See Appendix A for the proposed manual language, specifically Section B.II.b for the expanded nationally covered indications. CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act (the Act).

Decision Memo: July 30, 2026 Table of Contents Proposed Decision Clinical Review Background Epidemiology Clinical Presentation and Classification Management Prognostic Tool used to assess Staging of MM Food and Drug Administration Status Evidence Evidence Question(s) Technology Assessments Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) Clinical Literature Search Summary of Evidence Assessment of the Evidence Durie Salmon Staging System (DSSS) International Myeloma Working Group (IMWG) International Staging System (ISS) International Staging System-Revised (R-ISS) The Second Revised International Staging System (R2-ISS) Limitations Relevance and Generalizability to Medicare Beneficiaries Evidence from Systematic Reviews and Meta-Analyses Professional Society Recommendations and Guidelines Appropriate Use Criteria Public Comment CMS Coverage Analysis CMS Coverage Authority CMS Analysis and Rationale for Proposed Decision Evidence Question(s) – Answered Benefit Category History of Medicare Coverage Current National Coverage Request Timeline of NCA Milestones Appendices Appendix A: Proposed Medicare National Coverage Determinations Manual Language Abbreviations used throughout the Proposed Decision Memorandum for Autologous Stem Cell Transplant (AuSCT) for Multiple Myeloma (MM) ASCO – American Society of Clinical Oncology APBSCT-Autologous Peripheral Blood Stem Cell Transplant Allo-HSCT-Allogeneic Hematopoietic Stem Cell Transplant AuSCT-Autologous Stem Cell Transplant CA – Chromosomal Abnormalities CMS – Centers for Medicare & Medicaid Services CRAB-Hypercalcemia, Renal Disorders, Anemia, Bony Lesions DSSS-Durie Salmon Staging System eGFR-Estimated Glomerular Filtration Rate EBMT – European Bone Marrow Transplantation EHA – European Hematology Association EMN – European Myeloma Network ESMO – European Society for Medical Oncology FDA – Food & Drug Administration FFT-Fast and Frugal Tree HR-High Risk HRCA- High-Risk Chromosomal Abnormalities HSCT – Hematopoietic Stem Cell Transplant iFISH – Immunofluorescent in-situ hybridization IMWG – International Myeloma Working Group ISS-International Staging System LDH- Lactate Dehydrogenase MDE-Myeloma Defining Events MGUS-Monoclonal Gammopathy of Undetermined Significance ML-Machine Learning MM-Multiple Myeloma mSMART – Mayo Stratification of Myeloma and Risk-Adapted Therapy NCD – National Coverage Determination NDMM-Newly Diagnosed Multiple Myeloma OS – Overall survival PFS – Progression-free survival R-ISS-Revised International Staging System R2-ISS- Second Revised International Staging System ROC-Receiver Operating Characteristic SMM-Smoldering Multiple Myeloma SWOG – Southwest Oncology Group I. Proposed Decision The Centers for Medicare & Medicaid Services (CMS) is reconsidering one aspect of the Stem Cell Transplantation national coverage determination (NCD) at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03. Specifically, CMS is reconsidering section B.II.b of the NCD, which sets forth coverage criteria for autologous stem cell transplantation (AuSCT) for certain beneficiaries with multiple myeloma (MM). The focus of this reconsideration is to evaluate the evidence of prognostic assessment tools, particularly the International Staging System (ISS) and its revisions, in predicting outcomes in MM patients who have undergone AuSCT to determine if coverage criteria should be changed to reflect this evidence. We are proposing to expand the NCD to cover AuSCT for MM patients when the ISS or its revisions are used in the patient’s risk assessment. Specifically, we propose to cover single AuSCT for MM patients at Stage II or Stage III using the ISS and its revisions in patients who 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. See Appendix A for the proposed manual language, specifically Section B.II.b for the expanded nationally covered indications. CMS is seeking comments on our proposed decision pursuant to § 1862(l)(3)(B) of the Social Security Act (the Act). II. Clinical Review A. Background MM is a malignant disease belonging to a spectrum of hematological disorders known as plasma cell dyscrasias. In this condition, malignant plasma cells proliferate and accumulate in a patient's bone marrow, replacing healthy tissue and producing non-functional immunoglobulin monoclonal proteins. MM is genetically complex because of the high heterogeneity of tumor biology, its clinical features, treatment responses, and because outcomes are diverse (Kumar et al. 2018). MM encompasses a spectrum of clinical variants ranging from benign monoclonal gammopathy of undetermined significance (MGUS) and smoldering/indolent multiple myeloma (SMM) to more aggressive, disseminated forms of MM and plasma cell leukemia. Due to advances in therapy, the 5-year relative survival rate is approximately 70% (SEER 2021). 1. Epidemiology MM is a relatively uncommon cancer and accounts for approximately 1 - 2% of all new cancers and slightly more than 17% of hematologic malignancies (SEER 2021). It is more common in males than females, and more common among individuals of African American descent (Landgren et al. 2009). In the U.S. there are approximately 36,000 new cases of MM, and 12,000 deaths from MM annually, which represents 2% of all cancer deaths. MM is largely a disease of older adults. The median age at diagnosis is 65 to 74 years; only 10% and 2% of patients are younger than 50 and 40 years, respectively (Kyle et al. 2003). 2. Clinical Presentation and Classification Most patients with MM present with signs or symptoms related to kidney damage from immunoglobulin deposition, or the infiltration of plasma cells into the bone or other organs. The acronym "CRAB" is often used to describe manifestations of the disease: C alcium elevation; R enal insufficiency (kidney impairment); A nemia; and B one disease. Weight loss as well as generalized fatigue and weakness are also found in patients with MM. Most patients with this condition will have abnormal monoclonal (M) protein produced and secreted by the malignant plasma cells. MM types are classified by the abnormal immunoglobulin (M-protein) they produce—most commonly IgG (57%) or IgA (20%)—or by clinical behavior, including active (symptomatic), smoldering (asymptomatic- MGUS), and uncommon forms like light chain disease (15%). In rare instances, non-secretory myeloma (where cancerous plasma cells produce little to no detectable M-protein) can exist. There also might exist a solitary plasmacytoma, which is a single, isolated tumor of plasma cells, either in the bone or soft tissue (extramedullary), rather than widespread disease. It should be noted that SMM and MGUS are precursor conditions of MM with a 10% annual risk of progression (Bustoros, et al. 2020). Various prognostic models (e.g., Durie Salmon (DSSS); International Staging System (ISS)/International Staging System-REVISED (R-ISS)), exist for risk stratification of active disease; however, they are based on clinical features (e.g., physical findings, laboratory data, imaging studies). For that reason, these clinically based risk assessment tools are not appropriate for SMM and MGUS. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. In making the diagnosis of MM, the evaluation should include a thorough history and physical examination looking specifically at CRAB symptoms, as well as laboratory (blood and urine) studies, bone marrow studies, and imaging studies. 3. Management The primary treatment goal for patients with MM is to increase survival and quality of life by mitigating disease-related complications through suppression of malignancy over the long term (Cowan et al, 2022). That can be achieved by reducing malignant plasma cells in the bone marrow, and studies have demonstrated that the greater reductions in these malignant plasma cells correlates with more durable disease control (Lonial et al. 2014). The treatment of MM depends on the stage of the disease. Treatments can be differentiated into the following groupings: initial therapy for Newly Diagnosed Multiple Myeloma (NDMM), the treatment of relapsed and/or refractory disease, and for those patients that are transplant eligible-the use of hematopoietic stem cell transplantation (HSCT). Before initial therapy is initiated, an assessment is performed to distinguish between patients that are at standard-risk (low chance of progression to plasma cell leukemia), versus those of high-risk (high chance of progression to plasma cell leukemia). Several risk-stratification tools are available (See Section E). As part of the initial assessment, transplant eligibility must be determined. HSCT eligibility impacts the initial management of patients with MM regardless of whether they choose to proceed with HSCT as part of their initial management. AuSCT has been the standard for transplant-eligible MM patients. Patients who are not suitable for AuSCT are treated with 8 to 12 months of induction chemotherapy, which may consist of double or triple treatment regimens, followed by maintenance until progression or unacceptable toxicity. There is no single preferred induction regimen, and different experts use different regimens. The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has seen a sharp decline since the introduction of novel agents (e.g., proteasome inhibitors (PI), immunomodulating agents (IMIDs) etc.) (Puertas, et al. 2023). In recent years, more advanced treatments have been developed, which has resulted in longer survival. These include: Proteasome Inhibitors (e.g., bortezomib, ixazomib, and carfilzomib), Immunomodulatory agents (e.g., thalidomide, lenalidomide, and pomalidomide), Monoclonal antibodies directed against myeloma cell surface antigens (eg, daratumumab, elotuzumab, and isatuximab), Advanced immunotherapies (e.g., CAR-T: Idecabtagene vicleucel and ciltacabtagene autoleucel), Bispecific T-cell Engagers (BiTEs): (e.g., teclistamab, elranatamab), and Antibody-Drug Conjugates (ADCs): (e.g., belantamab mafodotin). As noted above, AuSCT in combination with certain therapeutic agents has been used in the treatment of MM. As noted by Rocchi- “Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (AuSCT) has established itself as a core treatment for newly diagnosed multiple myeloma (NDMM) patients in the past 30 years” (Rocchi et al. 2024). In transplant-eligible NDMM patients, HDM plus AuSCT remains the standard of care recommended by international guidelines such as those of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and European Bone Marrow Transplantation (EBMT) (Dimopoulos, et al. 2021; Mikhael et al. 2019; Snowden et al. 2022; Mohty et al. 2014). In the original NCD, CMS covered AuSCT for the treatment of MM in specified eligible beneficiaries. That decision was based on overwhelming evidence demonstrating its effectiveness (Rocchi et al. 2024; Mian et al. 2020; Lazana et al. 2022; Swan et al. 2022; Gagelmann et al. 2019; Garrido et al. 2023; Lin et al. 2023). AuSCT remains a key component of MM therapy in eligible patients and can be incorporated as part of the initial therapy or delayed until first relapse. The therapeutic path includes four phases: induction, HDM plus AuSCT, consolidation, and maintenance, a model associated with high response rates, prolonged progression-free (PFS), and overall (OS) survival (Bazarbachi, et al 2022; Goel et al. 2022; Perrot 2022). 4. Prognostic Tool used to assess Staging of MM The focus of this reconsideration is to determine if coverage criteria should be changed from the current staging tool DSSS to updated tools ISS and R-ISS, for predicting outcomes in MM patients who have undergone AuSCT. MM risk-stratification and staging systems are used to guide treatment decisions and to stratify patients enrolled in clinical trials and allow clinicians to better interpret data from such trials. They should be used only in patients with symptomatic, active MM; they should not be used in patients with SMM or MGUS since their value in such populations is not known. Risk stratification models specifically developed for those conditions should be utilized in those settings. For patients with MM, a number of factors are considered to predict outcomes including the underlying genetic abnormalities in the myeloma clone, a number of host factors (age, performance status, comorbidities), stage, and response to therapy. Risk stratification is important as high-risk patients may experience positive initial response to therapy but earlier development of drug resistance and useful to guide treatment strategies (Schmidt, 2022). Durie Salmon Staging System (DSSS) Historically, the DSSS (Durie et al. 1975) was used to assess tumor burden. It was first introduced in 1975, using commonly available clinical information such as laboratory data as well as histologic findings to assess tumor mass, which predicted myeloma cell tumor burden. The DSSS was widely adopted as the standard for prognostication in myeloma and, at the time of the publication of the NCD (2000), the DSSS was the most commonly used prognostic scheme in patients with newly diagnosed MM. For that reason, it was the only system listed. However, the DSSS has several limitations. Ooi and associates also noted that DSSS is predictive of clinical outcome after standard-dose chemotherapy but acknowledges that one of the limitations of the DSSS is the interobserver variability in the number of lytic lesions seen on a skeletal survey (Ooi et al. 2016). International Staging System (ISS) In the 1980s, serum beta2-microglobulin (Sβ2M) emerged as the single most powerful prognostic factor and was considered a simple reliable predictor of MM survival duration (Cassuto et al. 1978; Norfolk et al. 1979). Serum beta2-microglobulin (Sβ2M), along with serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. This combination provided the simplest, most powerful and reproducible three-stage classification. It did not include genomic features. In 2005, the International Myeloma Foundation (IMF) research division, the International Myeloma Working Group (IMWG), developed a new risk assessment tool, which was known as the ISS. The ISS was validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients < and ≥ 65 years of age; in patients with standard therapy or auto-transplantation; in comparison with the DSSS, as well as other prognostic assessment systems used in the management of MM. ISS is a good measure of tumor burden. At the time of its development, when assessing outcomes based on risk, patients with stage I disease had a median survival of 62 months, patients with stage II disease had a median survival of 45 months, and patients with stage III disease had a median survival of 29 months. Patients with stage III disease were considered at high risk. Though the ISS is based on the measurement of serum albumin and β2M levels, cutoff levels remained a matter of controversy because renal failure could elevate β2M levels even in patients with low tumor burden. International Staging System-Revised (R-ISS) The R-ISS was derived from the ISS classification. R-ISS uses ISS as a basis and adds to it lactate dehydrogenase (LDH) levels and immunofluorescent in-situ hybridization (iFISH) changes and the presence of multiple high-risk features, such as the combination of del(17p) and 1q+, confer additional risk (Walker et al. 2019). Neben and associates were also able to confirm that certain chromosomal abnormalities (CA) such as del(13q14), del(17p13), t(4;14),+1q21 were associated with adverse PFS and OS independently of the ISS classification (Neben et al. 2010). Moreau and associates reviewed data from three separate myeloma trials and found that patients with t(4;14) and/or del(17p) in addition to ISS stage III and/or high levels of LDH are at high risk of progression-related death despite modern treatment strategies (Moreau, et al 2014). Those findings demonstrate that the prognostic accuracy of the ISS could be enhanced through the incorporation of both biochemical and genetic parameters. The new stratification system proposed the R-ISS: R-ISS stage I, (ISS stage I, no high-risk CA [del(17p) and/ or t(4;14) and/or t(14;16)], and normal LDH); R-ISS stage III, (ISS stage III and high-risk CA or high LDH level); and R-ISS stage II, including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS stage I, 62% in the R-ISS stage II, and 40% in the R-ISS stage III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. The authors noted that the R-ISS was the exclusion of chromosome 1 abnormalities as a prognostic parameter, no interlaboratory standardization of iFISH analysis, and heterogeneous cutoff levels for LDH. According to Palumbo, R-ISS is the most widely recognized risk stratification tool for NDMM patients (Palumbo et al. 2015). It is clinically useful in predicting both OS and PFS in NDMM. As noted by Walker, though it incorporates important genomic markers including t(4;14), t(14;16), and del17p, it does not include 1q gain/amplification, an increasingly important prognostic marker, or mutational data from TP53 (Walker et al. 2019). R-ISS is a unified prognostic index that helps in clinical care as well as in comparison of clinical trial data (Palumbo et al. 2015). Dispenzieri also acknowledged that R-ISS is the most commonly used risk stratification system for patients with NDMM (Dispenzieri, et al. 2016). Both the ISS and DSSS systems assess the tumor burden, but neither ISS nor DSSS takes into consideration the biology of the disease, which determines the overall survival (OS) (Rajkumar et al. 2014; Greipp et al. 2005; Hari et al. 2009). R-ISS combines elements of tumor burden (ISS) and disease biology (Palumbo et al. 2015). It was developed based on a study of 11 international trials. The 5-year survival rates among the patients with stage I, II, and III R-ISS were 82%, 62%, and 40%, respectively (Rajkumar et al. 2016; Palumbo et al. 2015). Patients with stage III disease were considered at high risk. The major advantage of the R-ISS is that it more accurately identifies patients on the extremes of the risk stratification schema (Schmidt 2022). However, more than half of patients are now grouped into the R-ISS stage II classification, and outcomes of patients in this group remain highly variable. Also, the R-ISS includes only t(4;14), t(14;16), and del(17p) as high-risk cytogenetic abnormalities and does not include other genomic factors that have more recently been determined to be important prognostic biomarkers. Though there is a limitation in R-ISS (i.e., it classifies the majority of patients into stage II, and this group has a large degree heterogeneity in outcomes), it remains widely used in practice and in current clinical trials (Baysal et al 2025). According to Laubach, chromosomal analysis using metaphase cytogenetics and iFISH and the ISS stage is at present inclusive of the most important determinants of prognosis (Laubach et al., 2016). CA t(4;14), t(14;16), t(14;20), del17p, gain (1q), and del(1p) have been associated with high-risk disease, as has ISS stages II and III. Even though R-ISS has been established as a standard risk assessment tool, there were some studies that evaluated ISS along with elevated LDH, but the absence of CA (Lopes et. al, 2023). A consensus statement by the IMWG recommends using the combination of iFISH, LDH, and ISS stage (R-ISS) for risk stratification in NDMM (Sonneveld, et al. 2016). A study by Joseph and associates was able to demonstrate the validity of the R-ISS, but based on their study, they felt that R-ISS stage II could further be characterized into two distinct groups based on the presence or absence of high-risk cytogenetics (Joseph et al. 2022). They noted that R-ISS stage II with high-risk cytogenetics (HR-CTG) (HR-CTG is defined as t(4; 14), t(14; 16) or del 17p) portends both inferior PFS and increased risk of death when compared to R-ISS II without HR-CTG and behaved more similarly to R-ISS stage III disease. This finding helped lead to the development of the International Staging System-Revision Two (R2-ISS). Recently, researchers have found that 1q gain or amplification, which were not included in the R-ISS, proved to be independent poor prognostic factors in NDMM (Caltagirone et al. 2014). Also, in the R-ISS, high-risk CA were considered as present if at least one among del(17p), t(4;14), or t(14;16) was detected, whereas emerging data showed that having more than one high-risk CA predicted poorer outcomes (Shah et al. 2018). The European Myeloma Network (EMN), within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials and developed a model predicting PFS and OS. The model assigned risk features according to their OS impact, and patients were stratified into four risk groups: low (R2-ISS stage I), low-intermediate (R2-ISS stage II), intermediate-high (R2-ISS stage III) and high (R2-ISS stage IV). The model (R2-ISS) has been validated and shown to allow better stratification of patients with intermediate-risk NDMM. In support of R2-ISS, Mohan noted that the R2-ISS staging system was able to allocate patients who were previously assigned to R-ISS stage II into R2-ISS stages III and IV (Mohan et al. 2024). The authors note that while R2-ISS is an easy-to-implement and reliable prognostic tool, emerging prediction models, which integrate clinical, genomic, anatomical and treatment-related data, offer improved risk stratification, thereby proactively guiding treatment strategies (Maura et al. 2024). R2-ISS staging system has also been used as a risk assessment tool in the GMMG CONCEPT trial (Leypoldt et al. 2024). Several articles have been published comparing R2-ISS to R-ISS, including real world studies (Mohan et al. 2024; Richardson et al. 2024; Cani et al. 2025; Baysal et al. 2025; Cho et al. 2024). Table 1: R2-ISS Staging, Risk Groups, and Points R2-ISS Stage Risk Groups Points Stage I Low Risk 0 Stage II Low-Intermediate 0.5 - 1 Stage III Intermediate-High 1.5 - 2.5 Stage IV High 3 - 5 Over the course of time, several risk assessment models have been developed that evaluate outcomes in MM patients undergoing AuSCT (see table below). Some of these models were used as part of a clinical trial (e.g., Southwest Oncology Group (SWOG)) or in establishing criteria for diagnosis (IMWG/IMWG-14). These models have essentially been supplanted by newer models. Also, emerging systems are being developed (e.g. IRMMa, Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART)). These risk assessment tools are newer and are not in widespread use. And though they may be informative, more validation of them is needed. Table 2: Risk Assessment Models Staging System Components IMWG/IMWG-14 Serum features as well as radiologic imaging features such asskeletal radiography mSMART Serum as well as genomic features such as chromosomal anomalies and mutations MyPRS Genomic aberrations alone in the absence of serum features Glasgow Prognostic Score Inflammatory markers such as C-Reactive protein IRMMa AI-generated risk prognostic models for MM patients in settings where genomic tests cannot be performed due to geographical/economical constraints Modified Risk Staging (MRS) Age, albumin, β2-microglobulin (β2M), calcium, estimated glomerular filtration rate (eGFR) and hemoglobin Durie-Salmon PLUS (DS+) Included MRI and CT/PET results SWOG Included increased calcium level, renal dysfunction, anemia, and destructive bone lesions Cytogenic Prognostic Index Accounts for both high-risk and protective genetic factors CoMMpass Subgroups and phenotypes characterized by molecular profiling and clinical features EMN–HARMONY Machine learning (ML) risk stratification strategy for MM Individual Risk Model for Myeloma (IRMMa) Genomic individualized prediction model able to incorporate heterogeneous clinical and genomic information B. Food and Drug Administration Status There are several types of stem cell-based products that are FDA-approved for stem cell transplantation in the U.S. One type of product consists of blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood. These products are approved for limited use in patients with malignant and non-malignant disorders that affect the immune system and the body system that is involved in the production of blood (called the “hematopoietic” system). Another type of FDA-approved stem cell product is a significantly modified allogeneic cord blood product for accelerated engraftment in hematologic malignancies undergoing cord blood transplant. The third type of approved product is a bone marrow-derived mesenchymal stromal cell (MSC) that is used to treat steroid refractory acute graft versus host disease in young children, although MSC is not considered scientifically a stem cell-based product. These FDA-approved products are listed on the following FDA website: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products . III. Evidence This section provides a summary of the evidence considered during this review. The evidence presented in this proposed NCD includes the pertinent published clinical research on the use of ISS and its revisions as a prognostic tool for patients with MM. This proposed NCD does not address the long-standing policies on allo-HSCT or the existing coverage of AuSCT. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature can be found in the CMS National Coverage Analysis Evidence Review Guidance Document , published August 7, 2024. A. Evidence Question(s) The following question(s) guide our review and analysis of the evidence on the clinical utility of ISS and its revision for autologous hematopoietic stem cell transplant: For Medicare beneficiaries with MM who undergo AuSCT, is ISS/R-ISS an appropriate prognostic tool, as demonstrated by: relapse free mortality, progression-free survival, relapse, and overall survival? B. Technology Assessments CMS did not request an external technology assessment on this topic. C. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) A MEDCAC meeting was not convened on this topic. D. Clinical Literature Search We searched PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane for studies published between 2010 and 2025, using a combination of key words along with their synonyms, and Boolean operations to combine search terms. A systematic literature review focused on ISS/R-ISS as a prognostic assessment tool in MM patients who have undergone AuSCT was undertaken to address the evidence questions in Section III.A above. Literature searches were conducted in PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane with the following search terms: (1) “multiple myeloma;” OR (2) “autologous stem cell transplantation;” OR (3) “AuSCT;” OR (4) “prognostic assessment tools; OR (5) “Durie Salmon Staging System;” OR (6) “DSS;” OR (7) “International Scoring System;” OR (8) “ISS;” OR (9) “Revised International Scoring System;” OR (10) “R-ISS;” OR (11) “Revised Second International Scoring System;” OR (12) “R2-ISS.” The review included peer-reviewed English-language medical literature from January 1, 2010, to December 31, 2025. Of the references identified in the searches, 31 were deemed eligible for inclusion. Of the 31 studies included in this review, all the studies were retrospective reviews except for Kumar et al. 2025, which was a systematic review, and five studies that were clinical trials (Palumbo et al. 2015; Moreau et al. 2014; D’Agostino et al. 2022; Schavgoulidze et al. 2023; Richardson et al. 2024). In all studies, both PFS and OS were used as outcomes, though the Kumar et al. 2025, Pourmoussa et al. 2019, Chadva et al. 2019,Gopalakrishnan et al. 2019, Richardson et al 2024, and Scott et al. 2018 studies also included relapse, or relapse/refractory as an outcome. The study by Greipp used Tumor Burden, and Survival Duration as outcomes. Currently as written, the DSSS is the only prognostic staging system listed as a requirement in the NCD. But as we have noted above, the uses of the DSSS as a prognostication tool have been supplanted by other assessment tools. Several professional societies (e.g., American Society of Hematology) no longer use it as the standard of care in the management of patients with MM. It has been replaced by other more accurate tools. Below we will discuss the evidence supporting the use of prognostic assessment tools for MM patients undergoing AuSCT. We will first start with the DSSS since currently it is the only prognostic assessment tool listed in our NCD. We will then assess other prognostic tools used in this condition, and where available, will present direct comparisons between the risk assessment tools. Summary of Evidence Section II.A.4 includes a list of the prognostic assessment tools used in the studies reviewed. E. Assessment of the Evidence 1. Durie Salmon Staging System (DSSS) In searching the medical literature, there are few studies which have evaluated the use of DSSS for prognostic purposes. Using a cohort of 396 patients with MM who underwent AuSCT, Huang and associates analyzed the treatment efficacy to evaluate possible prognostic factors (Huang etal. 2019). Most patients were diagnosed with IgG-type myeloma (52.4%), followed by IgA-type (23.2%) and light-chain type (21.4%). The study revealed that patients with DSSS stage III disease accounted for 61.9% of the study cohort, while 23.7% had stage II and 14.4% had stage I disease. The median PFS and OS after AuSCT were 46.5 months and 70.4 months, respectively. DSSS III was found to be a poor prognostic factor that affected both PFS and OS with a duration of 35.9 months and 69.0 months, respectively, compared with the other two stages. It also revealed that patients with better treatment response before AuSCT had better PFS and OS compared with those who did not show a response. Avet-Loiseau notes that DSSS was predictive of clinical outcomes in the era of standard-dose chemotherapy but now has become a less precise predictor when high-dose therapies and novel agents are part of therapeutic management (Avet-Loiseau, et al. 2025). Studies comparing DSSS to other prognostic tools When viewing studies comparing DSSS to other staging systems (e.g., SWOG versus IMWG), the literature indicates that more advanced prognostic tools are better than DSSS at predicting outcomes in MM patients who undergo AuSCT. Kim and associates compared SWOG staging system, the ISS, and the DSSS to evaluate whether staging at the time of diagnosis could predict survival in 152 MM patients undergoing autologous peripheral blood stem cell transplantation (APBSCT) (Kim et al. 2006). Each of the three staging systems had their own classification: DSSS and ISS had three levels, while SWOG had four levels. The study revealed that PFS and OS from the day of diagnosis were statistically significant using the SWOG staging system and ISS but was not statistically significant using the DSSS. PFS from day of transplant was not predicted by SWOG, DSSS, or ISS, (not statistically significant), but OS from day of transplant could be predicted by the SWOG staging system and ISS (statistically significant). Using the DSSS, OS was not found to be statistically significant. The findings indicated that PFS and OS in patients undergoing AuSCT can be predicted by stages assessed by the SWOG and ISS systems, but not by the DSSS. Kastritis and associates performed a study comparing DSSS, ISS, and R-ISS as a prognostic tool in 475 MM patients who have undergone AuSCT (Kastritis et al. 2017). Patients were grouped by disease severity and categorized in the three staging systems: DSSS stages IA, IB, IIA, IIB, IIIA, IIIB; ISS-I, II, III; R-ISS I, II, and III. The median follow-up of the entire cohort was 40 months; 57% of the patients have progressed or died and 63% remained alive. The median PFS was 27 months and estimated median OS was 63 months. Analysis of the data indicated that the R-ISS provided significant prognostic information when compared to the other staging systems. The median PFS for patients rated as R-ISS stage I, R-ISS stage II and R-ISS stage III were 34, 28 and 17 months, respectively. According to the R-ISS, the probability of OS at 3 years was 83%, 69% and 45% and that at 5 years was 77%, 53% and 19% for patients rated as R-ISS stage I, R-ISS stage II and R-ISS stage 3, respectively. Kumar and associates performed a systematic review of the medical literature to rank the importance of prognostic factors for relapse/refractory in MM patients (Kumar et al. 2025). After reviewing 125 clinical studies (which included 130 records), their assessment revealed that cytogenetic risk, age, refractory status, disease stage, performance status, and extramedullary disease/plasmacytoma were the most important factors in determining PFS and OS. Looking specifically at disease stage, ISS and R-ISS were found to be important in determining PFS and OS. DSSS was not found to be an important prognostic factor in relapse/refractory in MM patients. Real world studies evaluating DSSS as a risk assessment tool There have also been real world studies evaluating the use of DSSS as a risk assessment tool (see section below on Real World studies for further explanation). In a real world study, Shang and associates performed an assessment to evaluate staging systems for MM (Shang et al. 2022). The study included 859 MM patients at two institutions. Laboratory findings, imaging examinations and staging system from medical records were used. Receiver operating characteristic (ROC) curves were used as the objective measure in the study (ROC indicates how well the model separates populations based on staging). The study revealed that OS of eligible patients was 61.0 months. R-ISS had a larger ROC curve area (0.603) than both the ISS (0.573) and the DSSS (0.567). In the group receiving immunomodulatory agents-based regimens, the median OS was 92.0 months in R-ISS stage I, 63.0 months in R-ISS stage II and 18.0 months in R-ISS stage III (which was superior compared to staging using ISS or DSSS). In the group receiving proteasome inhibitors (PI)-based regimens, the median OS was 102.0 months in R-ISS stage I, 63.0 months in R-ISS stage II and 22.0 months in R-ISS stage III (which again was superior compared to staging using ISS or DSSS). Multivariate analyses performed on patients in the R-ISS stage II category, which accounted for 69.9% of all patients in the study, revealed that age >65 years, HGB < 100 g/L, elevated LDH, and CA were independent predictors of worse prognosis. The authors concluded that because of its prognostic ability, the R-ISS was a more valuable staging system in the real world of the novel drug era than DSSS. Though most of the real world studies that compared the DSSS to ISS showed that that latter was more accurate in assessing outcomes in patients with MM, the study by Hari and associates had mixed results (Hari et al. 2009). When comparing the two staging systems in 729 patients who have undergone AuSCT, it found that the median OS for stages I, II, III by DSSS and ISS were 82, 68, 50 and 64, 68, 45 months, respectively, but the concordance between the two staging systems was only 36%. The relative risks of PFS and OS were significantly different for stages I vs II and II vs III for DSSS, but only for stages II vs III for ISS. Though both systems were predictive of PFS and OS, the DSSS was superior to ISS in formal statistical comparison using Brier score. However, neither system was strongly predictive of outcomes. 2. International Myeloma Working Group (IMWG) Scott and associates performed a study comparing the use of the IMWG 2014 staging system, the ISS, and the R-ISS as prognostic assessment tools (Scott et al. 2018). The goal of the study was to identify MM patients treated with AuSCT within 18 months of diagnosis and to compare outcomes based on staging systems. The study involved 628 patients with MM who had received an AuSCT and who were part of the CIBMTR® (Center for International Blood and Marrow Transplant Research®) research collaboration. Each of the three prognostic assessment tools had staging: ISS stages I, II, and III; R-ISS stages I, II, and III; IMWG-2014 level Low, Standard, and High, and the study reported the separation between the 3 stages within each staging system for relapse/progression, PFS and OS. The authors used separation score (SEP) because they felt that it represented greater outcome discrimination between patient groups (the higher the SEP, the more useful the staging system). Results of the study revealed that separation between stage I, II and III for ISS was 1.40 for relapse/progression, 1.42 for PFS and 1.58 for OS. The highest separation for each outcome was seen with R-ISS followed by ISS for relapse/progression and PFS. R-ISS had the highest separation followed by IMWG-2014 for OS. The analysis revealed that the R-ISS showed the greatest discrimination between stages compared to ISS and IMWG 2014 indicating that R-ISS provides the greatest differentiation between groups among the three staging systems. Currently, there are few additional studies in the medical literature addressing DSSS, SWOG, and IMWG 2014 as prognostic assessment tools in patients with MM, and risk models that are based on molecular subgroups and structural mutations are being validated. For that reason, the remainder of this NCD will address ISS and R-ISS as well as its derivatives as a prognostic assessment tool. 3. International Staging System (ISS) In 2005, Greipp and associates conducted a study to develop a simple, reliable staging system for MM that could be applied internationally for patient classification and stratification (Greipp et al. 2005). Using clinical and laboratory data from 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia, they evaluated prognostic factors that would independently predict tumor burden and survival duration. They found that serum beta2-microglobulin, serum albumin, platelet count, serum creatinine, and age were powerful predictors of survival, and each factor was then used in a model. This led to the genesis of the ISS, which created stages of risk (stage I, stage II, and stage III). The ISS has been validated and favorably compared to the DSSS (Tandon et al 2017). And as seen above, several studies have been conducted which have shown that ISS and R-ISS are superior to DSSS as a prognostic tool for risk assessment in patients with MM (Kim et al 2006; Kastritis et al. 2017;Kumar et al. 2025). Pourmoussa and associates conducted a study toidentify factors that predict early relapse in patients with MM who receive autologous hematopoietic peripheral stem cell (Pourmoussa et al. 2019). They found that factors associated with inferior PFS were: disease status—less than complete response at the time of AuSCT, no use of maintenance therapy after AuSCT, ISS stage III, and high Freiburg Comorbidity Index. They also found that disease status less than complete response, ISS stage III, higher Freiburg Comorbidity Index, no use of maintenance therapy, and male sex were the most predictive factors for early relapse (< 18 months). In confirming the importance of the ISS staging system as a predictive risk factor influencing post–AuSCT outcomes in MM patients, Hsu followed a cohort of 150 MM patients to determine PFS and OS (Hsu et al. 2024). The study revealed that AuSCT in patients age ≥ 65 and the presence of extramedullary disease had a negative impact on PFS, while among the factors that had a positive effect on OS was ISS stage III status. Though not a covered indication in this NCD, ISS has also been assessed in MM patients for autologous re-transplantation. Sellner and associates evaluated the role of salvage AuSCT in a cohort of 200 patients with MM (Sellner et al. 2013). The study revealed that factors associated with improved PFS and OS after salvage AuSCT included an initial PFS of >18 months after upfront AuSCT, bortezomib-containing or lenalidomide-containing therapies for reinduction, response to reinduction, and an ISS stage of I status before salvage AuSCT. Further analysis revealed that the median OS decreased from 58.5 months in the low-risk group to 33.9 months and 13.5 months in the intermediate-risk and high-risk groups, respectively, but regarding PFS, the prognostic stratification according to response time and ISS stage was found to be of only marginal significance. Other staging systems have been explored using ISS as its basis along with certain other laboratory factors. Maltezas and associates explored using ISS along with serum free light chain ratio (sFLCR) and LDH (Maltezas et al. 2013). Xu and associates also explored using ISS in combination with the ratio of light chains (Xu et al. 2013). Though these studies are informative, more fruitful studies involving the use of ISS along with genetic factors have provided more actionable information. 4. International Staging System-Revised (R-ISS) As noted above, the R-ISS includes ISS as well as iFISH. Numerous studies have been conducted that explore the combination of ISS with cytogenetics and have demonstrated improved accuracy in predicting outcomes in post AuSCT MM patients (D'Agostino et al. 2022; Richardson et al. 2024; Scott et al. 2018; Bila et al. 2017). Some published articles have even used what has been described as real world studies that demonstrate that R-ISS is superior compared to other risk assessment tools in patients with MM (Brieghel et al. 2025; Zepeda et al. 2016; Shang et al. 2022; Rahman et al. 2023). Most of these studies were retrospective in nature. When evaluating the effectiveness of various risk assessment tools, many studies have confirmed that the use of R-ISS is an even better prognostic tool for assessing MM patients who have undergone AuSCT than ISS alone (Schavgoulidze, et al 2023; Udupa et al. 2020; Gopalakrishnan et al. 2019; Chavda et al. 2019;Byun et al., 2019; Calle et al. 2018; Bila et al. 2017;Shang et al. 2022; Palumbo et al. 2015; Inamoto, et. al, 2009; Cowan et al. 2022). A consensus statement by the IMWG recommends using the combination of iFISH, LDH, and ISS stage for risk stratification in NDMM (Sonneveld, et al. 2016). And as noted by Bonello, R-ISS is the gold standard for risk stratification in NDMM, and iFISH analysis is routinely performed and represents a strong baseline prognostic predictor (Bonello et al. 2022). In a recent publication in the JAMA, the authors list R-ISS as the only stratification tool used to assess risk in MM patients (Cowan et al. 2022). They note that genetic analysis of the malignant plasma cell can be performed using iFISH, thereby identifying genetic factors to risk stratify patients. But the authors also note limitations as to iFISH analysis, including the variability of diagnostic thresholds between different laboratories, and lack of standardization of iFISH panels used for MM (Saxe et al. 2019). iFISH analysis is a component of R-ISS but is not a component of ISS. R-ISS Studies based on Clinical Trials Some of the studies used to validate the R-ISS were based on data obtained from clinical trials. Two studies in this assessment that used clinical trial data were performed by Palumbo and Moreau. Palumbo and associates developed a model that combined the ISS with CA detected by interphase iFISH, and serum LDH (Palumbo et al. 2015). Clinical and laboratory data from 4,445 AuSCT patients with NDMM enrolled in 11 international trials was pooled together; 3,060 patients had complete data. From this number the authors created R-ISS stage groups consistent with current definition (see R-ISS staging definition above). Based on this definition, 81 patients were R-ISS stage I; 295 were stage III; 1894 were stage II. After a median follow-up of 46 months, the 5-year OS rate was 82% in R-ISS stage I, 62% in the R-ISS stage II, and 40% in the R-ISS stage III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. These numbers were superior compared to ISS staging. Moreau and associates confirmed the validity of R-ISS as a prognostic assessment tool in MM patients undergoing AuSCT using data from multiple clinical trials (Moreau et al. 2014). Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial were used to construct the prognostic index, while the index was validated using data from: the Gruppo Italiano Malattie Ematologiche dell’ Adulto (GIMEMA) 26866138-MMY-3006 trial (N 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)–GEMMENOS65 trial, and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) –65/German-Speaking Myeloma Multicenter Group (GMMG) –HD4 trial. Study results revealed that risk of early MM progression–related death was related to three independent prognosticvariables: higher than normal LDH levels, ISS stage III, and adverse cytogenetics [t(4;14) and/or del(17p)]. Using these three variables the authors were able to create a prognostic classification composed of four scores (0 to 3). Patients with ascore of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS-stage III, and/or high LDH,had a very poor prognosis. When applied to thepopulation of patients who had received bortezomib-based induction therapy in the four trials,the prognostic classification was also able to segregate patients into four categories, with a verypoor prognosis attributed to patients with a score of 3. But not all clinical trial studies that compared R-ISS to ISS showed that the former was a better risk predictive tool. Schavgoulidze and associates conducted a study to explore the heterogeneity of outcomes among R-ISS stage II patients assessing the impact of ISS staging, CAs, and LDH level in this subgroup (Schavgoulidze et al. 2023). Using data from three clinical trials that enrolled 1,343 transplant-eligible MM patients (NCT00430365, NCT01191060, and NCT02197221), it revealed that patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I and patients in R-ISS stage II but with ISS stage III had a better OS than patients in R-ISS stage III. However, among patients classified in R-ISS II, ISS stage and CAs (del[17p] and t[4;14]) were still relevant prognostic factors for death. R-ISS stage II was further divided into three subgroups: ISS stage I with standard-risk CAs, ISS II or III with standard-risk CAs, and patients with HR CAs. In this scenario, median OS times (112 months and 71 months) respectively, was not reached. The authors concluded that stratification of patients in the R-ISS stage II group could be improved upon by taking into account CAs and ISS. This could have led to a further refinement of the R-ISS (see R2-ISS below). Other studies evaluating R-ISS Using data from 474 patients who underwent AuSCT at University College London Hospital, UK, Chadva and associates conducted a study to determine factors influencing outcomes of relapse (Chadva et al. 2019). PFS, disease progression, post-relapse survival (PRS) was measured from date of progression and OS from date of AuSCT, and time to event endpoints were used as outcomes. Predictive accuracy of risk model systems was estimated using area under the survival curve of Cox models. Of the total number of patients involved in the study, 269 had relapsed at a median of 20 months post-AuSCT. Of this number who relapsed, the median PRS was 40 months, and OS was 67 months. The study demonstrated that higher ISS scores (stage II and III), in combination with the presence of adverse cytogenetics (t(4;14), t(14;16), t(14;20), del(17p), 1q gain or 1p loss) as demonstrated by iFISH, were associated with shorter PRS and OS. Byun and associates developed an adaptive risk stratification model in Asian MM patients undergoing AuSCT (Byun et al. 2019). The study involved 161 patients who were not only staged based on ISS classification, but also by genetic abnormalities as detected by iFISH. Patients were divided into three groups according to risk stratification: 1) low-risk, patients without del(17p13) nor t(14;16) or t(4;14) and ISS I/II; 2) high-risk, patients with t(4;14), regardless of ISS stage; and 3) intermediate-risk, all remaining patients in the study that do not fall into the low or high-risk group. PFS was the outcome sought. The study revealed that the median PFS for the low-risk group was 18 months versus 13 months for the intermediate group versus 10 months for the high-risk group. The authors felt that the addition of genetic abnormalities as detected by iFISH improved the efficiency of ISS. Calle and associates validated the R-ISS prognostic assessment tool using a population of 134 MM patients who had undergone AuSCT at the Mayo Clinic in Arizona and the University Hos