Medical policy: Hematopoietic Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and Poems Syndrome

Policy number: MP 9.044

Effective date: 5/1/2026

Policy

Multiple myeloma

A single or second (salvage) autologous hematopoietic stem-cell transplantation may be considered medically necessary to treat multiple myeloma.

Tandem autologous hematopoietic cell transplantation may be considered medically necessary to treat multiple myeloma in individuals who fail to achieve at least a near-complete or very good partial response after the first transplant in the tandem sequence. (For definitions of near-complete response and very good partial response, see Policy Guidelines.)

Tandem transplantation with an initial round of autologous hematopoietic cell transplantation followed by a non-marrow-ablative conditioning regimen and allogeneic hematopoietic stem-cell transplantation (i.e., reduced-intensity conditioning transplant) may be considered medically necessary to treat newly diagnosed multiple myeloma individuals.

Allogeneic hematopoietic cell transplantation, myeloablative or nonmyeloablative, as upfront therapy of newly diagnosed multiple myeloma or as salvage therapy, is considered investigational. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

POEMS syndrome

Autologous hematopoietic cell transplantation may be considered medically necessary to treat disseminated POEMS syndrome. (See Policy Guidelines.)

Allogeneic and tandem hematopoietic cell transplantation are considered investigational to treat POEMS syndrome. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure for these indications.

Policy guidelines

The International Working Group on Myeloma has updated the European Group for Blood and Marrow Transplant (EBMT) criteria to describe a complete response to multiple myeloma therapy. The criteria include negative immunofixation on the serum and urine; disappearance of soft tissue plasmacytomas; and 5% or fewer plasma cells in bone marrow aspiration.

Individuals with disseminated POEMS syndrome may have diffuse sclerotic lesions or disseminated bone marrow involvement.

Cross-references

• MP 9.046 Hematopoietic Cell Transplantation for Waldenstrom Macroglobulinemia

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO – Refer to FEP medical policy manual.

Description/background

Multiple myeloma

Multiple myeloma (MM) is a systemic malignancy of plasma cells that represents approximately 10% of all hematologic cancers. It is treatable but rarely curable. At diagnosis, most patients have generalized disease, and the selection of treatment is influenced by patient age, general health, prior therapy, and the presence of disease complications.

The disease is staged by estimating tumor mass, based on various clinical parameters such as hemoglobin, serum calcium, number of lytic bone lesions, and the presence or absence of renal failure. MM usually evolves from an asymptomatic premalignant stage (termed monoclonal gammopathy of undetermined significance). Treatment is usually reserved for patients with symptomatic disease (usually progressive myeloma), whereas asymptomatic patients are observed because there is little evidence that early treatment of asymptomatic MM prolongs survival compared with therapy delivered at the time of symptoms or end-organ damage.

In some patients, an intermediate asymptomatic stage but more advanced premalignant stage is recognized and referred to as smoldering MM. The overall risk of disease progression from smoldering to symptomatic MM is approximately 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% for the next 10 years.

POEMS syndrome

POEMS syndrome (also known as osteosclerotic myeloma, Crow-Fukase syndrome, or Takatsuki syndrome) is a rare, paraneoplastic disorder secondary to a plasma cell dyscrasia. This complex, multiorgan disease was first described in 1938, but the acronym POEMS was coined in 1980, reflecting hallmark characteristics of the syndrome: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes.

No single test establishes the presence of POEMS syndrome. Its pathogenesis is undefined, although some evidence has suggested it is mediated by an imbalance of proinflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α); vascular endothelial growth factor may also be involved. However, specific criteria have been established, and the syndrome may entail other findings in the constellation of signs and symptoms, as shown in Table 1. Both major criteria and at least one of the minor criteria are necessary for diagnosis.

The prevalence of POEMS syndrome is unclear. A national survey in Japan showed a prevalence of about 0.3 per 100,000. Other large series had been described in the United States, France, China, and India. In general, patients with POEMS have superior overall survival compared with that of MM (nearly 14 years in a large series). However, given the rarity of POEMS, there is a paucity of RCT evidence for POEMS therapies. Numerous approaches have been tried, including ionizing radiation, plasmapheresis, intravenous immunoglobulin, interferon-α, corticosteroids, alkylating agents, tamoxifen, trans-retinoic acid, and high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HCT) support. Optimal treatment involves eliminating the plasma cell clone (e.g., by surgical excision or local radiotherapy for an isolated plasmacytoma) or systemic chemotherapy in patients with disseminated disease (e.g., medullary disease or multiple plasmacytomas). Given the underlying plasma cell dyscrasia of POEMS syndrome, newer approaches to MM, including bortezomib, lenalidomide, and thalidomide, have also been investigated.

Hematopoietic cell transplantation

HCT is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone marrow–toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood is discussed in detail in MP 9.001 Placental/Umbilical Cord Blood as a Source of Stem Cells.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allo-HCT compatibility between donor and patient is a critical factor for achieving a good outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome six. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (except umbilical cord blood).

Conditioning for HCT

Conventional conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect of this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells.

While the slower graft-versus-malignancy effect is considered to be the potential curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by cytotoxic drugs. Subsequent to graft infusion and allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiotherapy to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-intensity conditioning allo-HCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less-intense regimens of cytotoxic drugs or radiotherapy that are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops.

Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full donor chimerism. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative as opposed to fully myeloablative (traditional) regimens.

MM treatment overview

In the prechemotherapy era, the median survival for a patient diagnosed with MM was approximately 7 months. After the introduction of chemotherapy (e.g., the alkylating agent melphalan in the 1960s), prognosis improved with a median survival of 24 to 30 months and a 10-year survival of 3%.

In a large group of patients with newly diagnosed MM, there was no difference in overall survival reported during a 24-year period from 1971-1994, with a trend toward improvement during 1995-2000, and a statistically significant benefit in overall survival during 2001-2006. These data suggested that autologous HCT was responsible for the trends during 1994-2000, while novel agents have contributed to the improvement since 2001.

The introduction of novel agents and better prognostic indicators has been the major advances in the treatment of this disease. Novel agents such as the proteasome inhibitors (e.g., bortezomib), the monoclonal antibody daratumumab, and the immunomodulatory derivatives thalidomide and lenalidomide first showed efficacy in relapsed and refractory myeloma and now have been integrated into first-line regimens. With the introduction of these newer treatments, it is now expected that most patients with MM will respond to initial therapy, and only a small minority will have refractory disease.

Regulatory status

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Rationale

Summary of evidence

Newly diagnosed MM

For individuals who have newly diagnosed MM who receive autologous HCT as initial treatment, the evidence includes several prospective, randomized controlled trials (RCTs) that compared conventional chemotherapy with high-dose chemotherapy plus autologous HCT to standard chemotherapy regimens or regimens containing newer MM agents. Relevant outcomes include overall survival and treatment-related morbidity.

In general, the evidence has suggested overall survival rates improved with autologous HCT compared with conventional chemotherapy in this setting. Limitations of the published evidence include patient heterogeneity, variability in treatment protocols, short follow-up periods, inconsistency in reporting important health outcomes, and inconsistency in reporting or collecting outcomes. Recent RCTs comparing high-dose chemotherapy plus autologous HCT to regimens that include novel MM agents have also shown that high-dose chemotherapy plus autologous HCT improves progression-free survival. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Relapsed or refractory MM

For individuals who have relapsed MM after failing an autologous HCT who receive autologous HCT, the evidence includes RCTs, retrospective studies, and reviews summarizing recent studies on second autologous HCT in relapsed myeloma. Relevant outcomes are OS and treatment-related morbidity. Despite some limitations of the published evidence, including patient sample heterogeneity, variability in treatment protocols, and short follow-up periods, available trial evidence has suggested OS rates are improved with autologous HCT compared with conventional chemotherapy or continuous lenalidomide plus dexamethasone in this setting. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have refractory multiple myeloma after failing a first HCT who receive tandem autologous HCT, the evidence includes systematic reviews and a retrospective study. Relevant outcomes are OS and treatment-related morbidity. The evidence has shown tandem autologous HCT improves OS rates in this setting. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

POEMS syndrome

For individuals who have POEMS syndrome who receive HCT, the evidence includes case reports and series. Relevant outcomes include overall survival and treatment-related morbidity. No RCTs of HCT of any type have been performed in patients with POEMS syndrome of any severity, nor is it likely such studies will be performed because of the rarity of this condition. Available case reports and series are subject to selection bias and are heterogeneous concerning treatment approaches and peri-transplant support. However, for patients with disseminated POEMS syndrome, a chain of evidence and contextual factors related to the disease and MM would suggest improvement in health outcomes with autologous HCT. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Definitions

N/A

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the members’ benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Investigational; therefore, not covered

Allogeneic hematopoietic cell transplantation for newly diagnosed multiple myeloma or as salvage therapy; and allogeneic and tandem hematopoietic cell transplantation for POEMS syndrome.

Covered when medically necessary

Autologous hematopoietic cell transplantation to treat multiple myeloma and POEMS syndrome.

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