Hematopoietic Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and POEMS Syndrome

POLICY NUMBER

A.8.01.17

DESCRIPTION

Multiple myeloma is a systemic malignancy of plasma cells that represents approximately 10% of all hematologic cancers. POEMS syndrome, characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes, is a rare, paraneoplastic disorder secondary to a plasma cell dyscrasia. Plasma cell dyscrasias are treatable but rarely curable. In some cases, autologous or allogeneic hematopoietic cell transplantation (HCT) is considered as therapy.

Multiple Myeloma

Multiple myeloma is a systemic malignancy of plasma cells that represents approximately 18% of all hematologic cancers in the United States. 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. Multiple myeloma 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 multiple myeloma prolongs survival compared with therapy delivered at the time of symptoms or end-organ damage. In some patients, an intermediate asymptomatic but more advanced premalignant stage is recognized and referred to as smoldering multiple myeloma. The overall risk of disease progression from smoldering to symptomatic multiple myeloma is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% for the next 10 years.

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin abnormalities (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 imbalance of proinflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor 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 the table. Both mandatory major criteria, at least one of the other major criteria, and at least one of the minor criteria are necessary for diagnosis.

Criteria and Associations for POEMS Syndrome

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 multiple myeloma (nearly 14 years in a large series). However, given the rarity of POEMS, there is a paucity of randomized controlled trial evidence for POEMS therapies. Numerous approaches have been tried, included ionizing radiation, plasmapheresis, intravenous immunoglobulin, interferon alfa, corticosteroids, alkylating agents, tamoxifen, trans-retinoic acid, and high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT) support. Optimal treatment involves eliminating the plasma cell clone (eg, by surgical excision or local radiotherapy for an isolated plasmacytoma) or systemic chemotherapy in patients with disseminated disease (eg, medullary disease or multiple plasmacytomas). Given the underlying plasma cell dyscrasia of POEMS syndrome, newer approaches to multiple myeloma, including bortezomib, lenalidomide, and thalidomide, have also been investigated.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune 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 from 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 transplantation is discussed in detail in the Placental and Umbilical Cord Blood as a Source of Stem Cells medical policy.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allo-HCT, immunologic compatibility between donor and patient is a critical factor for achieving a successful 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 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional ConditioningThe 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 cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the 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 the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Subsequent to graft infusion in 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 potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone 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 Allogeneic Hematopoietic Cell TransplantationReduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of 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. For the purposes of this Policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be non-myeloablative.

Multiple Myeloma Treatment Overview

In the prechemotherapy era, the median survival for a patient diagnosed with multiple myeloma was approximately 7 months. After the introduction of chemotherapy (eg, 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 multiple myeloma, there was no difference in overall survival reported during a 24-year period from 1971 to 1994, with a trend toward improvement during 1995 to 2000, and a statistically significant benefit in overall survival during 2001 to 2006. These data suggested that autologous HCT was responsible for the trends from 1994 to 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 (eg, 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 novel treatments, it is now expected that most patients with multiple myeloma will respond to initial therapy, and only a small minority will have refractory disease.

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.

POLICY

No benefits will be provided for a covered transplant procedure unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.

Multiple Myeloma

A single or second (salvage) autologous hematopoietic 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 individuals with newly diagnosed multiple myeloma.

Allogeneic hematopoietic cell transplantation, myeloablative or nonmyeloablative, as initial therapy of newly diagnosed multiple myeloma or as salvage therapy, is considered investigational.

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.

POLICY EXCEPTIONS

For Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage. For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

8/1998: Approved by Medical Policy Advisory Committee (MPAC).

2/11/2002: Investigational definition added.

5/8/2002: Type of Service and Place of Service deleted.

3/18/2003: HCPCS G0266, G0267 added covered codes, CPT code 38242 added non-covered codes.

1/27/2004: Policy reviewed, policy title "Tandem High Dose Chemoradiotherapy with Autologous Stem Cell Support for Multiple Myeloma" renamed "Single or Tandem Courses of High-Dose Chemotherapy plus Hematopoietic Stem-Cell Support to Treat Multiple Myeloma", Description, Policy, and Policy Guidelines sections aligned with BCBSA policy # 8.01.17, See "High-Dose Chemotherapy with Hematopoietic Stem-Cell Support for Malignancies" medical policy for dates of service prior to 1-27-2004.

3/25/2004: Reviewed by MPAC, "Tandem high-dose chemotherapy with autologous stem-cell support is considered investigational to treat multiple myeloma." changed to "Tandem high-dose chemoradiotherapy with autologous stem-cell support may be considered medically necessary to treat newly diagnosed or responsive multiple myeloma.", "An initial course of high-dose chemotherapy with autologous stem-cell support followed by non marrow-ablative chemotherapy and allogeneic stem-cell support (i.e. "mini transplant") is considered investigational to treat multiple myeloma" added.

7/19/2004: Code Reference section updated.

11/18/2004: Reviewed by MPAC, “An initial course of high-dose chemotherapy with autologous stem-cell support followed by non marrow-ablative chemotherapy and allogeneic stem-cell support (i.e. “mini transplant”) is considered investigational to treat multiple myeloma.” Changed to medically necessary.

7/11/2005: Code Reference section updated, CPT code 38204, 86812, 86813, 86816, 86817, 86821, 86822 moved from covered codes to non-covered codes, CPT code 38230 added covered codes, HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added covered codes, HCPCS J9000-J9999 statement added to HCPCS and all separately listed codes deleted.

10/21/2005: Code reference section updated, ICD9 code 41.01, 41.09 added to the covered table, 41.02, 41.03 added to the non-covered table, ICD9 procedure code 41.04, 99.79 description revised.

03/17/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy.

12/20/2007: Coding updated per 2008 CPT/HCPCS revisions.

9/11/2008: Annual ICD-9 updates applied.

04/27/2010: Policy title changed from “Single or Tandem Courses of High Dose Chemotherapy plus Hematopoietic Stem Cell Support to Treat Multiple Myeloma” to “Hematopoietic Stem-Cell Transplantation for Multiple Myeloma.” Changed “Stem-Cell Support” to “Stem-Cell Transplantation” throughout policy. Policy description updated regarding prevalence of disease and treatment approaches. Added the prior authorization requirement to the policy statement. Policy statement updated regarding situations when autologous SCT may be indicated for patients with primary progressive myeloma, and statement regarding allogeneic HSCT being investigational as initial or salvage therapy was reworded. FEP and State and School Employees verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826 to the non-covered table. Deleted CPT codes 96400, 96414, 96520, 96530, and 96545 from the code section as these codes were deleted on 12/31/2005. Deleted HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, and G0362 from the code section as these codes were deleted on 12/31/2005. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007. Updated policy source section.

06/21/2011: Added "in the tandem sequence" to the medically necessary tandem autologous-autologous policy statement.

05/09/2012: Policy reviewed; no changes.

10/30/2013: Policy title changed from "Hematopoietic Stem Cell Transplantation for Multiple Myeloma" to "Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and POEMS Syndrome." Updated policy description regarding POEMS Syndrome and added the following policy statements: Autologous hematopoietic stem-cell transplantation may be considered medically necessary to treat disseminated POEMS syndrome. Allogeneic and tandem hematopoietic stem-cell transplantation are considered investigational to treat POEMS syndrome.

10/23/2014: Policy reviewed; description updated. Policy statement unchanged. Policy guidelines updated to add the EBMT criteria to describe a complete response to MM therapy.

08/27/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38242; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.

12/11/2015: Policy description updated regarding multiple myeloma. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

05/25/2016: Policy number A.8.01.17 added.

09/30/2016: Code Reference section updated to add the following new ICD-10 procedure codes: 30230G2, 30233G2, 30240G2, 30243G2, 30230G3, 30233G3, 30240G3, 30243G3, 30230G4, 30233G4, 30240G4, 30243G4, 30230Y2, 30233Y2, 30240Y2, 30243Y2, 30230Y3, 30233Y3, 30240Y3, 30243Y3, 30230Y4, 30233Y4, 30240Y4, and 30243Y4.

02/16/2017: Policy updated to change "hematopoietic stem-cell transplantation" to "hematopoietic cell transplantation" throughout policy. Policy description updated regarding FDA regulations. Policy statements unchanged.

12/21/2017: Code Reference section updated to add new 2018 CPT code 38222. Revised descriptions for CPT codes 38220 and 38221 effective 01/01/2018. Removed deleted ICD-10 procedure codes 30230G1, 30233G1, 30240G1, 30243G1, 30230Y1, 30233Y1, 30240Y1, 30243Y1 and ICD-9 procedure codes 41.02, 41.03, 41.05, and 41.08.

02/12/2018: Policy description updated regarding treatment of multiple myeloma. Policy statements unchanged.

03/08/2019: Policy reviewed. Policy statements unchanged. Code Reference section updated to remove deleted HCPCS code G0364 and CPT code 86822.

09/27/2019: Code Reference section updated to add new ICD-10 procedure codes 30230U2, 30233U2, 30240U2, 30243U2, 30230U3, 30233U3, 30240U3, 30243U3, 30230U4, 30233U4, 30240U4, and 30243U4, effective 10/01/2019.

02/19/2020: Policy description updated. Investigational statement for multiple myeloma updated to change "upfront therapy" to "initial therapy."

03/04/2021: Policy description updated regarding criteria and associations for POEMS syndrome. Added information regarding multiple myeloma treatments. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/22/2021: Code Reference section updated to make note of deleted ICD-10 procedure codes.

02/16/2022: Policy description updated. Policy statements unchanged.

02/22/2023: Policy description updated regarding multiple myeloma and criteria and associations for POEMS syndrome. Policy statements and Policy Guidelines updated to change "patients" to "individuals." Code Reference section updated to remove deleted ICD-10 procedure codes 30230G0, 30240G0, 30230Y0, 30240Y0, 30230G2, 30240G2, 30230G3, 30240G3, 30230G4, 30240G4, 30230U2, 30240U2, 30230U3, 30240U3, 30230U4, 30240U4, 30230Y2, 30240Y2, 30230Y3, 30240Y3, 30230Y4, and 30240Y4.

02/22/2024: Policy reviewed; no changes.

10/01/2024: Code Reference section updated to add new ICD-10 diagnosis code C81.7A.

03/28/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 8.01.17

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.