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

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).

July 30, 2026

Table of Contents

1. Proposed Decision
2. Clinical Review
   1. Background
      1. Epidemiology
      2. Clinical Presentation and Classification
      3. Management
      4. Prognostic Tool used to assess Staging of MM
   2. Food and Drug Administration Status
3. Evidence
   1. Evidence Question(s)
   2. Technology Assessments
   3. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)
   4. Clinical Literature Search
      Summary of Evidence
   5. Assessment of the Evidence
      1. Durie Salmon Staging System (DSSS)
      2. International Myeloma Working Group (IMWG)
      3. International Staging System (ISS)
      4. International Staging System-Revised (R-ISS)
      5. The Second Revised International Staging System (R2-ISS)
      6. Limitations
      7. Relevance and Generalizability to Medicare Beneficiaries
      8. Evidence from Systematic Reviews and Meta-Analyses
   6. Professional Society Recommendations and Guidelines
   7. Appropriate Use Criteria
   8. Public Comment
4. CMS Coverage Analysis
   1. CMS Coverage Authority
   2. CMS Analysis and Rationale for Proposed Decision
      1. Evidence Question(s) – Answered
   3. Benefit Category
5. History of Medicare Coverage
   1. Current National Coverage Request
   2. Timeline of NCA Milestones
6. Appendices
   1. 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

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).

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).

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: Calcium elevation; Renal insufficiency (kidney impairment); Anemia; and Bone 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.

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).

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

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

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.

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?

CMS did not request an external technology assessment on this topic.

A MEDCAC meeting was not convened on this topic.

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.

Section II.A.4 includes a list of the prognostic assessment tools used in the studies reviewed.

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.

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.

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.

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 Hospital of Salamanca in Spain (Calle et al. 2018). Based on ISS staging criteria, 62 (46%) patients had stage I, 38 (28%) stage II, and the remaining 34 (25%) stage III disease at the time of diagnosis. In addition, there were 39 patients (29%) with high-risk CA: 18 patients (14%) with del17p; 17 patients (13%) with t(4;14); and 7 (5%) with t(14;16). Seventeen patients (13%) had high LDH levels. When reclassification was performed using R-ISS criteria, 44 patients (33%) had stage I, 75 (56%) had stage II, and 15 (11%) had stage III. Thus, 18 patients who were previously categorized as having low risk (ISS stage I) and 15 patients as high risk (ISS stage III) were reclassified as intermediate risk (R-ISS stage II), according to the R-ISS. After a median follow-up of 60 months, R-ISS assessed at diagnosis was an independent predictor for OS after AuSCT, with median OS not reached, 111 and 37 months for R-ISS stages I, II and III, respectively. The authors found that patients belonging to R-ISS stage II and those having high risk chromosomal abnormalities (HRCAs) had a significant shorter median OS than those with R-ISS II without CA: 70 vs. 111 months, respectively.

Gopalakrishnan and associates examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on post-relapse survival after an early relapse (Gopalakrishnan et al. 2019). Using the Center for International Blood and Marrow Transplant Research database, the authors identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (n= 628). Outcomes explored included relapse/progression, PFS and OS, using R-ISS group as a predictor. Among early relapsers, post-relapse survival was tested to identify factors affecting post-relapse OS. The cumulative incidence of early relapse was 23%, 39% and 50% for R-ISS stage I, stage II and stage III, respectively. Shorter PFS and OS were seen with higher stages of R-ISS, and R-ISS was independently predictive for inferior post-relapse OS among early relapsers. Other predictors of poor post-relapse OS was the presence of ≥3 comorbidities and the use of ≥2 induction chemotherapy lines.

International studies evaluating R-ISS as a risk assessment tool.
R-ISS as a prognostic tool has been replicated in more diverse populations other than those found in the U.S. Udupa and associates studied the prognostic stratification by R-ISS compared to ISS among an Indian population (Udupa et al. 2020). Records of 117 NDMM were analyzed for high-risk cytogenetic abnormalities by using iFISH and were staged according to R-ISS. Analysis of the data revealed that of the 117 patients, 42% were staged ISS-stage III, whereas 32% were staged R-ISS stage III. High risk cytogenetics was observed in 19 patients (17%) staged as either ISS-stage III, ISS stage II, or as ISS stage I, and some patients exhibited high risk cytogenetics had more than one high risk cytogenetic abnormality. This was the first Indian study where the R-ISS system was used to stage the disease and found that patients with R-ISS stage III were significantly higher in the Indian population compared to studies done in other parts of the world.

Inamoto and associates used cytogenetics and ISS to evaluate 60 consecutive Japanese MM patients who had AuSCT and salvage therapy with thalidomide at four institutions to determine factors associated with prognosis (Inamoto et al. 2009). Of the total patients, 0% had DSSS stage IA, 16% had DSSS stage IIA, 4% had IIB, 52% had IIIA, and 28% had IIIB. Of that same group 12 % were ISS stage I, 20% were ISS stage II, and 68% were ISS stage III. Cytogenetic analyses detected metaphase abnormalities in nine of 51 patients and interphase abnormalities in six of 35 patients (17p13 deletion, t(4;14) and t(14;16)). After a median follow-up of 3.4 years, the study revealed that OS and event-free survival (EFS) at three years were significantly worse in high-risk patients despite the higher complete response (CR) plus very good partial response (VGPR) rates among high-risk patients.

And, although cytogenetic abnormalities had much more impact on the outcome than ISS stage III, ISS stage III was associated with a trend for worse OS and a significantly worse survival after relapse among patients without cytogenetic abnormalities. Also, survival at one year after progression was significantly worse in high-risk patients despite chemotherapy. The EFS among patients with the only ISS stage III as a risk factor was similar to that among standard-risk patients. The OS among patients with the only ISS stage III as a risk factor showed a trend for a worse survival than that among standard-risk patients. The authors concluded that the combinations of cytogenetics and ISS could readily predict prognosis.

Zeng and associates conducted a study to identify the subgroup of MM patients who could benefit most from AuSCT as a consolidation therapy after novel agent inductions (Zeng et al. 2015). Different risk stratifications were based on ISS staging and R-ISS staging systems. In the study, 67 consecutive Chinese MM patients received AuSCT after bortezomib and/or thalidomide-based induction was conducted. High risk was defined as ISS stage II/III and t(4; 14)/17p13 del (R-ISS); intermediate risk was defined as ISS stage III with no adverse iFISH or ISS I and t(4; 14)/17p13 del; and low risk was defined as ISS stage I/II with no adverse iFISH. Of the 67 patients, 17 high-risk, 24 intermediate-risk, and 26 low-risk patients were enrolled, based on iFISH and ISS stage. In the meantime, another 67 risk-response depth-, and age-matched patients who had not received AuSCT were chosen as controls. The study revealed that, in the high-risk subgroup (R-ISS), PFS and OS were both significantly prolonged after AuSCT, while, in the intermediate-risk subgroup, neither PFS nor OS was prolonged significantly after AuSCT, and in the low-risk subgroup, only PFS was extended significantly after AuSCT. Analysis indicated that AuSCT and risk stratification based on R-ISS were independent prognostic factors for OS.

Real world studies of R-ISS
The ISS and R-ISS staging systems were developed using data from patients enrolled in clinical trials. Some may consider these trials to be too rigid and controlled and not be truly reflective of what actually happens in medical encounters. When considering a medical intervention, there are many factors at hand that cannot be collected or controlled for within the sterile environment of an experiment. Additional clinical evidence about the usage and potential benefits or risks of an intervention must be ascertained in order to make an informed decision. In a real-world setting, uncontrolled, diverse clinical practice may provide information that experimental clinical studies lack. For that reason, to make studies more applicable to real world situations, real world medical studies are being performed. In this section, we will discuss real-world studies involving the use of R-ISS as risk assessment tool in MM patients undergoing AuSCT. There have been numerous studies described as real world examples which have demonstrated that R-ISS staging systems can be used to assess risk in MM patients undergoing AuSCT (Grant et al. 2023; Bonello et al. 2022; Chen et al. 2023; Abe et al. 2019; Sun et al. 2025; Morè, et al. 2025; Kim et al. 2022).

To assess the effect of R-ISS in real world patients, Zepeda and associates conducted a study to confirm the role of R-ISS in an unselected non-clinical trial (Zepeda et al. 2016). In the study a comparison was made between the ISS and R-ISS staging systems to determine which was more useful in assessing risk. A total of 381 consecutive patients at Tom Baker Cancer Center were identified using ISS stages I, II, and III, then reclassified based on the R-ISS staging system. The analysis revealed that R-ISS stage I exhibited a median OS and PFS of not reached and 38.9 months, compared with 77.9 and 26.9 months and 29.9 and 15.3 months for R-ISS stage II and III, respectively. These findings correlated well with those seen in the ISS staging system. Conducting a multivariate analysis revealed that age > 65 years, ISS stage III, abnormal LDH and HRCA by iFISH [t(4:14), deletion 17p, and t(14;16)] were independent prognostic factors for OS and PFS, while ß₂-microglobulin ≥ 5.5 mg/L, C-reactive protein > 20 mg/L, and creatinine > 200 mmol/L were not. The authors felt that LDH, HRCA, when combined with ISS (all components of R-ISS) was a very robust prognosticator for MM patients undergoing AuSCT.

Rahman and associates conducted a real-world assessment of the treatment patterns and outcomes of patients with MM, across different risk stratification criteria (Rahman et al. 2023). ISS, R-ISS, and CA were used as staging classifications. Two groups of patients were used to evaluate: treatment patterns (cohort 1; n = 1979) and survival outcomes (cohort 2; n = 1382). In both cohorts, approximately 18%, 41%, and 37% of patients were high-risk according to the R-ISS, ISS, and high-risk CA criteria, respectively. In cohort 2, the median modified PFS decreased with each increasing risk stage (23.5, 12.1, and 8.8 months in R-ISS stage I, II, and III, respectively, and 16.0, 12.7, and 10.4 months in ISS stage I, stage II, and stage III, respectively. Similar results were seen in the 2-year OS. The authors felt that R-ISS had greater discriminatory power than ISS or HRCA alone.

In another real world study, Sun and associates were able to demonstrate that by incorporating a bone marrow plasma cell percentage (BMPC%) ≥ 50% into the R-ISS staging for patients with NDMM, it could further enhance R-ISS’s predictive power, especially within the R-ISS stage II patient population (Sun et al. 2025). This study involved 208 patients who were diagnosed with NDMM and had received standardized treatment. PFS and OS were used as outcomes. Though the findings of this study do support the use of R-ISS as a prognostic tool, it may not be applicable to all populations of MM because a total of 169 patients (82.4%) did not undergo AuSCT.

R-ISS as a risk assessment tool in MM patient's ineligible for AuSCT
Several studies have shown that R-ISS is an effective risk assessment tool even in MM patients who are ineligible for AuSCT. Ozaki and associates were able to demonstrate that R-ISS was superior to ISS in prognostication of both transplant-eligible and transplant-ineligible patients (Ozaki et al., 2019). The study involved a group of 718 Japanese patients with MM—some were transplanted, while others were non-transplanted. The distribution of patients according to response was similar between the ISS and R-ISS staging. As expected, transplant patients had better outcomes than non-transplant patients. The authors also found that the R-ISS discriminated the difference in OS between the stages more distinctly than the ISS. They also noted that differences in OS were clarified by both R-ISS and ISS in non-transplanted patients, but the ISS failed to distinguish the difference between the stages in transplanted patients. Even in non-transplant patients, R-ISS was able to differentiate stage I ineligible transplant patients, who had a better prognosis, from ineligible transplant patients with stage II and III disease, who had the worst prognosis.

Bila and associates compared R-ISS to ISS analyzing 102 transplant-ineligible MM patients who were treated with thalidomide-based combinations (Bila et al. 2017). Though the study revealed that both ISS and the R-ISS influenced the EFS and OS, the ISS staging system was unable to discriminate patients in ISS stages I and II regarding OS, while R-ISS was able to differentiate risk categories regarding OS and it also provided an improved discriminative power compared to the ISS. Multivariate analysis revealed that R-ISS was shown to be the most important parameter influencing OS.

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).

According to Avet-Loiseau and associates, while the ISS is a practical, easy-to-use, and expedient tool for routine clinical use, it does not capture features that track the underlying biology of MM (Avet-Loiseau et al. 2025). The authors also note that although cytogenetic risk features were added to the ISS to develop the R-ISS, its stages/risk categories are not reported consistently across trials. For that reason, alternative stratification systems were sought. The R2-ISS is an attempt to improve upon the ISS and R-ISS.

The genesis of R2-ISS is as follows: Based on data collected from CIBMTR database, Scott and associates found that the majority of NDMM patients fall into the R-ISS Intermediate risk group (62%) (Scott et al. 2018). Because these patients have heterogeneous outcomes, the EMN developed this staging system to allow for better risk stratification of patients in this risk group (D’Agostino et al. 2022). The R2-ISS incorporates the ISS stage, LDH, and HRCA e.g., del(17)p, t(4;14), or t(14;16)) as detected by iFISH analysis.

Recently, numerous studies in the literature have shown the effectiveness of R2-ISS as opposed to R-ISS as a prognostic tool in MM patients who have received AuSCT (Abdallah et al. 2022; Alzahrani et al. 2024; Chu et al. 2024; Katodritou et al. 2025;D’Agostino et al. 2022; Guo et al. 2023;Kastritis et al. 2017; Mizuguchi, et al. 2023). Also, there are some articles that discuss the real world application of R2-ISS (Tan et al. 2023; Yan et al. 2023;Brieghel et al. 2025). Guidelines have also included R2-ISS. The EHA–EMN Evidence-Based Guidelines used for diagnosis, treatment and follow-up of patients with MM, also incorporates the use of R2-ISS based on four prognostic markers, combining serum biomarkers and CA. The basis of using R2-ISS in the guideline was based on the seminal study by D’Agostino, M. et al. 2022. There have also been some clinical trials that have included the use of R2-ISS as a risk assessment tool (Richardson et al. 2024).

Abdallah and associates used the records of 2556 Mayo Clinic patients with MM to assess a risk model that included R-ISS as well as additional iFISH abnormalities not included in the R-ISS (Abdallah et al. 2022). They used data from 1327 patients to develop a risk stratification model and validated this in 502 patients enrolled in the MMRF CoMMpass study. Multivariate analysis revealed that five factors: (high-risk IgH translocations; 1q gain/amplification; chromosome17 abnormalities; ISS III; and elevated LDH) were independently associated with decreased OS. Among 1327 evaluable patients, OS was 11.0, 7.0, and 4.5 years in patients with 0 (stage I), 1 (stage II), and ≥2 (stage III) high-risk factors, respectively. The authors demonstrated that this 5-factor, 3-tier system R2-ISS was easier to implement and improved upon the current R-ISS.

Alzahrani and associates also built upon R2-ISS as a prognostic tool (Alzahrani et al. 2024). In their assessment of 1291 MM patients, the distribution of R2-ISS stages was: (10%) stage I, (36%) stage II, (44%) stage III, and (10%) stage IV. At the median follow-up period of 42.2 months, the median PFS was 73.0, 65.2, 44.0, and 24.8 months and the median OS was 130.8, 128.5, 94.2, and 61.4 months for patients with R2-ISS stages I, II, III, and IV, respectively. Multivariable analysis for PFS, using R2-ISS stage I as reference, R2-ISS stages III and IV were associated with significantly inferior PFS. Also, using R2-ISS stage I as reference, only R2-ISS stage IV was associated with significantly inferior OS.

D’Agostino and associates tested a model using data from EMN, which included patients with NDMM enrolled in 16 clinical trials (D’Agostino et al. 2022). They wanted to determine the top features predicting PFS and OS using testing and validation data. Risk factors were determined according to their OS impact (R-ISS stage III, R-ISS stage-II, del(17p), high LDH levels, t(4;14), and 1q1). R-ISS stage II had the largest number of patients. Patients were then stratified into four risk groups according to the R2-ISS staging: low, low-intermediate, intermediate-high, and high. When assessing PFS and OS in R-ISS stage II patients according to the new R2-ISS score, results revealed that R-ISS stage II patients in the training and validation set were statistically different, confirming that R-ISS stage II patients represented a very heterogeneous population in terms of survival that could be discriminated through the R2-ISS.

Guo and associates validated R2-ISS investigating a total of 860 patients with MM who received an upfront AuSCT (Guo et al. 2023). ISS, R-ISS, and R2-ISS staging systems were used as prognostic tools. Analysis revealed that all three ISS staging systems exhibited robust discrimination in terms of both PFS and OS. The ISS system effectively stratified patients into three risk groups, whereas the R-ISS system accurately identified patients at extremely high or low risk. The R2-ISS system further refined risk stratification by dividing patients into four more balanced risk groups. The study further revealed that low-risk R2-ISS stages (I and II) distinguished patients with OS > 10 years, and high-risk R2-ISS stages (III and IV) distinguished patients with OS < 3 years.

Katodritou and associates also confirmed R2-ISS as a prognostic marker of early progressive disease (EPD) in patients with MM (Katodritou et al. 2025). Of the 1436 NDMM in the study, 23.3% had EPD. This population presented most commonly with advanced stage (ISS stage III, R-ISS stage III, and R2-ISS stage III/IV). Multivariate analysis further revealed that R2-ISS, AuSCT, and Daratumumab-based therapies (DBT) were independent prognosticators for EPD.

Real World studies using R2-ISS
Tan and associates published a real world study that used R2-ISS as a risk assessment tool in MM patients in Australian and New Zealand population (Tan et al. 2023), just as Yan and associates used R2-ISS in a real world study conducted in China evaluating MM patients (Yan et al. 2023). In both studies the authors were able to demonstrate that R2-ISS provided more discriminatory information which enabled them to identify groups with diverse prognosis resulting in prediction of survival outcomes.

Brieghel and associates wanted to create an improved real-world international staging system (RW-ISS) MM based on R2-ISS (Brieghel et al. 2025). The authors felt that R2-ISS could only be fully validated in elderly transplant ineligible patients as stratification according to R2-ISS in younger patients was unclear- regardless of transplant eligibility. The study included 2,929 Danish patients with MM and complete R2-ISS data. Included in the model was information about age >70 years, performance status (PS), t(14;16), ISS stage III, ISS stage II, high LDH levels, and del(17p). The authors found that patients with RW-ISS stage I (38.2%), stage II (19.8%), stage III (27.1%), and stage IV (15.0%) demonstrated a median OS of 9.5, 5.5, 3.4, and 1.1 years, respectively, and the C-index was superior for RW-ISS as compared to both R2-ISS and R-ISS (0.708 vs 0.604 vs 0.595, respectively). The authors felt that this real world model was in part externally validated, but based on their finding, suggested that RW-ISS should be reserved for elderly patients enrolled in clinical trials.

A Real World Clinical Trial study using R2-ISS as a Risk Assessment tool
R2-ISS as a prognostic tool has also been used in clinical trials. Using the ICARIA-MM and IKEMA clinical trial study, Richardson and associates validated the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and showed that R2-ISS as a prognostic scoring system could be applied to patients with relapsed/refractory MM (Richardson et al. 2024).

Beyond R2-ISS
As we have described in the evidence section of this document, some studies in the literature that assess risk in MM patients have progressed beyond using R2-ISS as a staging system. Some of these new prognostic tools rely on the addition of new components to the R2-ISS/R-ISS model (adding SKY92 GEP to R-ISS) (Baysal et al. 2025); adding circulating plasma cells (CPC) to R2-ISS (Chu et al. 2024); while others have developed new models based on a different mechanism. As we noted before, the mSMART system, the MASS, and the MPSS, all use the ISS stage III, elevated LDH levels, and HRCA. One of the newer models that is not based on ISS or R-ISS staging is the Unique Molecular Assay (UMA) panel. It uses a targeted DNA-sequencing approach designed to capture critical genomic aberrations in MM (Poletti et al. 2025). It is the first MM sequencing panel validated against traditional methods like iFISH and SNP arrays. Another newer staging model used for MM patients is the Fast and Frugal Tree (FFT) technique (Goswami et al. 2019). It was developed because the authors felt that neither the DSSS nor the ISS system were sufficient to discriminate between high and low risk MM patients. Finally, new models based on ML have also been developed (Orgueira et al 2025). Though these new risk assessment tools may provide some risk assessment information on MM patients undergoing AuSCT, additional information on their effect on outcomes, as well as further validation, is needed.

The major limitation of using ISS and its revisions is the fact that risk assessment tools are evolving based on new discoveries and are prone to modification. MM is a heterogenous disease with biological complexity. Though the tumor burden (staging) component may be straight forward, the biology (cytogenetic abnormalities) is complex. In the future there may be other tools other than the current ISS and its revisions that may more accurately reflect risk assessment outcomes. As we have noted in this document, there have been a number of risk assessment tools that have been used in the past, and for the most part, are no longer being used. We mentioned DSSS, which was the first risk assessment tool for MM patients undergoing AuSCT. At one time it was the standard. But since then, it has been replaced. Currently DSSS is only being used in clinical trials and research. Other risk assessment tools have also largely been supplanted (e.g. SWOG, IMWG-14). ISS was the standard, but now R-ISS is the standard risk assessment tool, and some studies have shown that R2-ISS is an even better risk assessment tool.

In this proposed decision memorandum, we mention possible candidates for future coverage, including models based on Molecular Subgroups, Structural Mutations, as well as models based on ML. One way to allow for further expansion of coverage of these new risk assessment tools is by leaving discretion to the Medicare Administrative Contractors (MACs) to cover claims involving these tools. Based on the medical literature, if there is sufficient evidence that a new risk assessment tool appropriately identified a beneficiary for whom AuSCT is reasonable and necessary, we propose leaving MACs discretion to cover the AuSCT service. 

As noted in the background section of this document, the median age of diagnosis for MM is 65 to 74 years, which is squarely within the Medicare population. And within this demographic group, there are approximately 36,000 new cases, and 12,000 deaths from MM annually, representing 2% of all cancer deaths. Novel therapeutic agents, drug combinations, as well as AuSCT, has made it possible to improve survival outcomes. But despite these therapeutic advances, outcomes remain highly variable. This disparity highlights the importance of risk stratification at the time of diagnosis for prognostication and patient selection.

Based on the age of the cohort in the studies found in the evidence section of this document, they primarily included patients who were Medicare eligible. They suffered with multiple co-morbidities that are commonly found in this age group, as well as various stages of MM. These studies were able to demonstrate that risk stratification, based on clinical features, as well as prognostic tools such as ISS, LDH levels, and CA can result in improved outcomes in MM patients undergoing AuSCT. This is especially true in the large group of patients with intermediate-risk NDMM. We feel confident that using risk stratification when assessing MM patients results in improved health outcomes (PFS and OS). This is based on the fact that multiple research designs (e.g., retrospective reviews, systematic review, and clinical trials) have confirmed this finding. Also of importance, real world studies have duplicated clinical trial findings that risk stratification improves outcomes in MM patients undergoing AuSCT. Because of the diversity of studies included in this assessment, CMS feels that risk-stratification as part of the management of MM patients undergoing AuSCT has both relevance as well as generalizability to the Medicare population.

There were no meta-analyses in the medical literature on the use of ISS or its revisions in MM patients undergoing AuSCT, but there was one systematic review article. This systematic review was conducted by Kumar and associates and involved 125 clinical studies (Kumar et al. 2025). It revealed that both ISS and R-ISS were found to be important in determining PFS and OS in MM patients undergoing AuSCT.

The American Society of Transplantation and Cellular Therapy’s (ASTCT) Committee on Practice Guidelines formulated consensus clinical practice recommendations regarding the role, timing, and sequencing of autologous and other stem cell transplantation. In this update, ASTCT mentions the use of ISS but does not mention DSSS. (Dhakal et al., 2022)

In their 2021 clinical practice guidelines, the European Hematology Association (EHA) and ESMO recommend using the R-ISS for staging (Dimopoulos et al., 2021).

In their 2025 clinical practice guidelines, EHA and ESMO recommend using the R2-ISS for staging. EHA-EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with MM (Dimopoulos et al., 2025).

The National Comprehensive Cancer Network cites the ISS, the R-ISS and the R2-ISS as the only guidelines for staging and treatment as of May 2026 (Kumar et al., 2026).

ASCO and CCO Joint Clinical Practice states that while the DSSS was previously used and the most widely accepted, “more recently, the International Staging System (ISS) and the Revised-ISS (R-ISS) have been more commonly used to define disease stage” (Mikhael et al., 2019).

American Society of Hematology-as published in an ASH publication-“The earliest staging system for MM, the Durie-Salmon (DS), associated disease and symptom burden with prognosis; however, it has been largely replaced by the International Staging System (ISS), which is easier to compute and better identifies patients with the poorest prognosis” (Fiala et al., 2015).

There are no relevant, published appropriate use criteria.

Because CMS opened this NCD analysis with a proposed decision memorandum, there will be one 30-day public comment period which commences with the posting of this proposed decision memorandum.  Public comments that cite published clinical evidence give CMS useful information.  Public comments that contain information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.

IV. CMS Coverage Analysis

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§ 1869(f)(1)(B) of the Act). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B and must not be otherwise excluded from coverage. Moreover, with limited exceptions, items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§ 1862(a)(1)(A) of the Act).

This section includes CMS’ analysis of the evidence related to the use of ISS and its revisions as a risk assessment tool in MM patients who are undergoing AuSCT. The evidence in Sections III.D-E indicates that there is benefit for MM patients undergoing AuSCT when using ISS and its revisions as a risk assessment tool in defined clinical study conditions.

As further discussed below in the analysis, we are proposing to include coverage of AuSCT for MM when ISS and its revisions are used. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that the specific assessment questions raised in a National Coverage Analysis (NCA) can be answered conclusively. When conducting NCAs for an item or service under the reasonable and necessary statute, CMS generally makes three kinds of assessments: (1) The quality of relevant individual studies; (2) What conclusions can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential harms and benefits; and (3) The generalizability of findings from relevant studies to the Medicare beneficiary population. (See CMS’ Evidence Review Guidance Document).

Our initial literature search and review of the evidence on the use of ISS and its revisions as a risk assessment tool in Medicare beneficiaries with MM undergoing AuSCT were guided by the following research question. The answer to this question informs the overarching question of whether ISS and its revisions meet the reasonable and necessary standard under § 1862(a)(1)(A) of the Act.

For Medicare beneficiaries with MM who undergo AuSCT, is ISS/R-ISS or its revisions a more appropriate prognostic tool, as demonstrated by:

• relapse free mortality,

• progression-free survival,

• relapse, and

• overall survival?

Yes – Based on the studies included in this assessment, ISS stages II and III, R-ISS and its revisions are a more accurate prognostic assessment tool compared to DSSS when assessing MM patients undergoing AuSCT. At the time the NCD was written, DSSS was the most common risk assessment tool used for that purpose. DSSS was considered the standard of care (Durie et al. 1975). For that reason, it was listed as part of our inclusion criteria. Since then, other prognostic assessment tools have been introduced and have supplanted DSSS, though DSSS is still sometimes used in clinical research and clinical trials.

Today in the medical literature, there are few studies evaluating DSSS for prognostic purposes. But as part of our review, we were able to find five studies thatcompared DSSS to other assessment tools (Kim et al 2006; Kastritis et al. 2017; Kumar et al. 2025; Shang et al 2022; Hari et al 2009). For the most part, each of the studies demonstrated that all of the other risk assessment tools used in the comparison (SWOG, ISS, R-ISS) provided more useful information about risk of outcomes of MM patients undergoing AuSCT than did DSSS, though there were no studies found that directly compared IMWG-14 to DSSS staging. When comparing the different staging systems, MM patients achieved better outcomes (PFS, OS, and relapse/refractory) when using SWOG, ISS, or R-ISS as a risk assessment tool, than when using DSSS. Even the study conducted by Shang, which was a real world study, revealed that when using ROC curves, which were used as the object measure to indicate how well the model separates populations based on staging, DSSS’s performance was inferior to both ISS and R-ISS.

When comparing prognostic accuracy, the only study that failed to show a difference between DSSS and ISS was the one that was conducted by Hari and associates. Because of the low degree of concordance between the two staging systems, and the fact that neither system was strongly predictive of outcomes, it set the stage for an alternative staging system to DSSS and ISS, such as R-ISS, which was later developed.

In all, these findings are consistent with current strategies employed in the management of MM patients. And as mentioned before, DSSS risk assessment tools are no longer being used, except in research and clinical trials.

For all practical purposes, SWOG and IMWG-14 are also no longer being used as staging systems. Currently in the medical literature there is little evidence of its use. SWOG’s purpose primarily was to conduct research and perform clinical trials for the purpose of understanding and treating patients with MM. Using its findings as a staging tool was not its emphasis. The same can also be said about IMWG-14. This staging system uses myeloma defining events (MDEs) which could include MRI imaging. When combined with CRAB, it confirms a diagnosis of active MM. IMWG-14 has been used in patients with SMM, and MGUS, which are not considered forms of active MM. The ISS and its revisions are used for active myeloma. Other staging systems based on molecular subgroups, structural mutations, or ML models are not considered appropriate at this time due to the need for further validation. That leaves only ISS, R-ISS, and its revisions as alternatives for the purpose of staging MM patients undergoing AuSCT.

In looking at individual studies included in this assessment, Scott, using data from CIBMTR® (Center for International Blood and Marrow Transplant Research®) research collaboration, found that by using SEP as a measure to compare staging systems, the R-ISS demonstrated the highest separation for relapse/progression, PFS and OS, more so than compared to IMWG 2014 or even the ISS. This indicated that R-ISS provided the greatest differentiation between groups among the three staging systems. This information can help physicians by allowing them to compare the discrimination between outcomes by each staging system. This study also addressed most of the outcome parameters mentioned in our research question.

In our assessment, we wanted to explore the use of risk assessment tools for MM patients undergoing AuSCT in multiple settings, including both clinical trials as well as real world settings. Studies conducted by Palumbo and Moreau used a combination of clinical trials to show that R-ISS was a useful risk assessment tool in MM.  Schavgoulidze also used clinical trials in his study, but due to mixed results, he felt that the stratification of patients in the R-ISS stage II group could be improved upon. This led to the further development of the R2-ISS, which Richardson ultimately used in a clinical trial.

There were no clinical trials that included DSSS as a staging system. This again demonstrates that DSSS has diminished importance as a staging system in MM patients undergoing AuSCT. There was only one real world study that involved using DSSS as a risk assessment tool (Shang et al. 2022) but its performance was inferior to both ISS and R-ISS.

Studies conducted by Zepeda, Rahman, and Sun, used real world data. They revealed that using R-ISS as a staging system provided MM patients undergoing AuSCT the best outcomes when considering PFS and OS. Richardson, as part of a clinical trial, also used real world data and showed that using R2-ISS as staging system helped in determining relapse/refractory rates. We found no real world studies involving SWOG, IMWG-14, or ISS as a risk assessment tool in MM patients undergoing AuSCT. As we have noted before, clinical trials are conducted in a controlled environment, and results may not be replicated in non-experimental settings. In this assessment we have shown that using R-ISS and R2-ISS have been found useful in real world settings using real world data.

Using ISS or R-ISS as a risk assessment tool has played numerous roles in patients with MM. First, as to transplantations, the focus of the NCD is on prognostic assessment tools that can be used in the management of MM patients undergoing AuSCT. Though not discussed here, sources of stem cells used in AuSCT include bone marrow as well as peripheral blood. ISS as a staging system has been shown to be a helpful risk assessment tool in MM patients who use peripheral blood as a source for their AuSCT. Though our NCD does not cover autologous re-transplantation, ISS stage I status before salvage AuSCT was associated with improved PFS and OS after salvage AuSCT in autologous re-transplantation. Finally, in reference to transplantation, the R-ISS staging system was found to be an effective risk assessment tool even in patients who are not eligible for AuSCT.

The ISS has also served a role in comorbidity determination. Stage III, in conjunction with other factors and higher Freiburg Comorbidity Index scores, are the most important predictive factors associated with early relapse and inferior PFS in MM patients undergoing AuSCT. Also, a comorbidity index developed by Englehardt (a revised Myeloma Comorbidity Index (R-MCI)) included ISS stage II and III. This index was generally shown to be comparable to non-MM specific comorbidity scores.

The R2-ISS has been incorporated in the EHA–EMN Evidence-Based Guidelines, which is used for the treatment of patients with SMM and MM. R-ISS, R2-ISS has also been incorporated in other guidelines and is recommended by medical professional organizations (see Section III.F Professional Society Recommendations and Guidelines).

Studies included in this NCD reveal diverse populations. Studies involving Chinese, Taiwanese, Indian, Spanish, and Japanese ethnic groups, as well as U.S. populations were included in this assessment. Also, patients from Germany, Korea, the U.K., Canada and Denmark were included in these studies that involved risk assessment based on staging system. Though these groups were ethnically diverse, results of the studies are consistent across all demographic groups of patients with MM undergoing AuSCT.

Returning to our research question, we mentioned a number of outcomes, which we felt were important (e.g., relapse, overall survival). All of the studies that were a part of this assessment included information on PFS and OS. Both ISS, R-ISS, and its revisions demonstrated superior outcomes when compared to using DSSS as a risk assessment tool. Some studies provided additional information on other outcomes mentioned in the research question. The study conducted by Pourmoussa evaluated relapses using the ISS, the Gopalakrishnan study evaluated relapses using R-ISS, Kumar evaluated relapse using both ISS and R-ISS as staging systems, Chadva reported on post-relapse survival using R-ISS, Scott evaluated relapse/progression using R-ISS, while Richardson used R2-ISS in relapse patients. All of these studies showed favorable outcomes based on their staging system.

In summary, though there are new risk assessments models being proposed for the management of MM patients undergoing AuSCT (e.g., MASS, mSMART, UMA, FFT), they are early in their development and await validation. There is sufficient evidence to demonstrate that stage II or stage III ISS, R-ISS, and its revisions appropriately identified a beneficiary for whom AuSCT is reasonable and necessary as a risk assessment tool in MM patients.

For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories, such as those outlined in §1812 (Scope of Part A), §1832 (Scope of Part B), or §1861(s) (Definition of Medical and Other Health Services) of the Act.

AuSCT qualifies as:

• Inpatient Hospital Services
• Outpatient Hospital Services Incident to a Physicians’ Service
• Incident to Physicians’ Services

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

V. History of Medicare Coverage

This is a reconsideration of NCD (110.23) Stem Cell Transplantation (Formerly 110.8.1). This request was externally initiated. CMS received a complete, formal request to open an NCA on the topic of using ISS and its revisions from The American Society of Hematology (ASH), the Association of Cancer Care Centers, Corewell Health, the International Myeloma Foundation, the Medical University of South Carolina, and the Hollings Cancer Center. The request letter is available at https://www.cms.gov/files/document/id323.pdf.

B. Timeline of NCA Milestones

VI. Appendices

110.23 – Stem Cell Transplantation (Formerly 110.8.1) (Various Effective Dates Below)

A. General

Stem cell transplantation is a process in which stem cells are harvested from either a patient’s (autologous) or donor’s (allogeneic) bone marrow or peripheral blood for intravenous infusion. Autologous stem cell transplantation (AuSCT) is a technique for restoring stem cells using the patient's own previously stored cells. AuSCT must be used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure in which a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion. Allogeneic HSCT may be used to restore function in recipients having an inherited or acquired deficiency or defect. Hematopoietic stem cells are multi-potent stem cells that give rise to all the blood cell types; these stem cells form blood and immune cells. A hematopoietic stem cell is a cell isolated from blood or bone marrow that can renew itself, differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosis - a process by which cells that are unneeded or detrimental will self-destruct.

The Centers for Medicare & Medicaid Services (CMS) is clarifying that bone marrow and peripheral blood stem cell transplantation is a process which includes mobilization, harvesting, and transplant of bone marrow or peripheral blood stem cells and the administration of high dose chemotherapy or radiotherapy prior to the actual transplant. When bone marrow or peripheral blood stem cell transplantation is covered, all necessary steps are included in coverage. When bone marrow or peripheral blood stem cell transplantation is non-covered, none of the steps are covered.

B. Nationally Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

MDS refers to a group of diverse blood disorders in which the bone marrow does not produce enough healthy, functioning blood cells. These disorders are varied with regard to clinical characteristics, cytologic and pathologic features, and cytogenetics. The abnormal production of blood cells in the bone marrow leads to low blood cell counts, referred to as cytopenias, which are a hallmark feature of MDS along with a dysplastic and hypercellular-appearing bone marrow.

II. Autologous Stem Cell Transplantation (AuSCT)

C. Nationally Non-Covered Indications

I. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Effective for claims with dates of service on or after May 24, 1996, through January 26, 2016, allogeneic HSCT is not covered as treatment for multiple myeloma.

II. Autologous Stem Cell Transplantation (AuSCT)

Insufficient data exist to establish definite conclusions regarding the efficacy of AuSCT for the following conditions:

In these cases, AuSCT is not considered reasonable and necessary within the meaning of §l862(a)(1)(A) of the Act and is not covered under Medicare.

D. Other

Coverage of all other indications for stem cell transplantation not otherwise specified above as covered or non-covered will be made by local Medicare Administrative Contractors under section 1862(a)(1)(A).

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