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

Policy Number: MP-415

Latest Review Date: February 2022

Category: Surgery                                                                   

POLICY:

Multiple Myeloma

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

Tandem autologous hematopoietic cell transplantation may be considered medically necessary to treat multiple myeloma in patients who fail to achieve at least a near-complete or very good partial response after the first transplant in the tandem sequence.

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 patients.

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.

Allogeneic and tandem hematopoietic stem-cell transplantation are considered investigational to treat POEMS syndrome.

POLICY GUIDELINES:

The International Working Group on Myeloma has updated the European Group for Blood and Marrow Transplant criteria to describe a complete response to multiple myeloma therapy.

The criteria includes:

  • Negative immunofixation on the serum and urine;
  • Disappearance of soft tissue plasmacytomas; AND
  • 5% or fewer plasma cells in bone marrow aspiration.

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

Tandem transplantation is defined as a HCT technique where the preplanned intent for therapy involves two sequential HCTs. The “tandem” implies a very short preplanned interval between the two transplants, as well as the therapeutic intent to do two transplants from the outset of therapy. These may be autologous followed by a second autologous (auto-auto) transplantation, autologous followed by allogeneic (auto-allo) transplantation, or autologous followed by RIC-allogeneic (auto–RIC-allo) transplantation.

Salvage transplantation is defined as a hematologic cell transplantation (HCT), either autologous, allogeneic, or RIC (Reduced Intensity Conditioning)-allogeneic. It is used as a second-line therapy after failure of primary therapy of any type. Salvage transplantation is sometimes referred to as a “rescue” transplant. It implies that the original therapy has failed. A salvage second HCT is often an autologous HCT if the prior therapy is chemotherapy. If the prior therapy is a failed autologous transplant a salvage second HCT would more likely be an allogeneic HCT or an RIC-allogeneic HCT. Typically, a salvage transplantation is done after enough time has elapsed to identify that the primary therapy has failed, so the interval between the two transplants would be longer.

**NOTE: FOR POEM, refer to Policy 537 Peroral Endoscopic Myotomy (POEM) for Treatment of Esophageal Achalasia

DESCRIPTION OF PROCEDURE OR SERVICE:

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.

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 a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, 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 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 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 or failure caused by 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 Transplantation

RIC refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than 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. RIC 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.

MM Treatment Overview

In the pre-chemotherapy 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 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 inhibitor bortezomib 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 MM will respond to initial therapy, and only a small minority will have refractory disease.

KEY POINTS:

This policy has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 17, 2021.

Summary of Evidence

Newly Diagnosed Multiple Myeloma

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 high-dose chemotherapy plus autologous HCT to standard chemotherapy regimens or regimens containing newer MM agents. Relevant outcomes are overall survival (OS) and treatment-related morbidity. In general, the evidence has suggested OS rates are 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.

For individuals who have newly diagnosed MM who receive tandem autologous HCT, the evidence includes several RCTs. Relevant outcomes are OS and treatment-related morbidity. Compared with single autologous HCT, RCTs have generally found that tandem autologous HCT improve s OS and recurrence-free survival in newly diagnosed MM. Two recent RCTs found conflicting results on the benefit of tandem autologous HCT versus single autologous HCT; however, the study that found no additional benefit with tandem autologous HCT had a higher rate of non-adherence to the second planned HCT. Differences in initial therapy regimens between trials may also have led to conflicting results. Several RCTs compared reduced-intensity conditioning allogeneic HCT (allo-HCT) following a first autologous HCT with single or tandem autologous transplants. The RCTs were based on genetic randomization (i.e., patients with a human leukocyte antigen-identical sibling were offered reduced-intensity conditioning allo-HCT following autologous HCT, whereas other patients underwent either one or two autologous transplants). Although the body of evidence has shown inconsistencies regarding OS and disease-free survival rates, some studies have shown a survival benefit with tandem autologous HCT followed by reduced-intensity conditioning allo-HCT, although at the cost of higher transplant-related mortality compared with conventional treatments. Factors across studies that may account for differing trial results include different study designs, nonuniform preparative regimens, different patient characteristics (including risk stratification), and criteria for advancing to a second transplant. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have newly diagnosed MM who receive allo-HCT as initial or salvage treatment, the evidence includes nonrandomized studies. Relevant outcomes are OS and treatment-related morbidity. Studies have reported on patients with both myeloablative conditioning and reduced-intensity conditioning. Limitations of the published evidence include patient sample heterogeneity, variability in treatment protocols, short follow-up periods, inconsistency in reporting important health outcomes, and inconsistency in reporting or collecting outcomes. Nonmyeloablative allo-HCT as first-line therapy is associated with lower transplant-related mortality but a greater risk of relapse; convincing evidence is lacking that allo-HCT improves survival better than autologous HCT. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Relapsed or Refractory Multiple Myeloma

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 a 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, the 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 retrospective cohort studies, case reports, and case series. Relevant outcomes are OS 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 peritransplant 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 an improvement in the net health outcome.

Practice Guidelines and Position Statements

American Society for Blood and Marrow Transplantation

In 2015, the American Society for Blood and Marrow Transplantation (ASBMT) published evidence-based guidelines for the use of HCT in patients with MM. These guidelines are generally consistent with the conclusions of this evidence review based on published literature through December 31, 2014. ASBMT recognizes that much of the RCT evidence summarized in the 2015 guidelines comes from trials that predate the advent of novel triple therapy induction regimens. Furthermore, advances in supportive care and earlier disease detection has increasingly influenced decision-making and allows individual tailoring of therapy. ASBMT guidelines do not address POEMS or other plasma cell dyscrasias besides MM.

In 2015, ASBMT, and three other groups published joint guidelines based on an expert consensus conference. These guidelines contained the following recommendations for HCT as salvage therapy:

“…autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as bridging strategy to allogeneic HCT; (4) The role of post salvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, -modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short remission (less than 18 months remissions) after primary therapy (and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM [multiple myeloma] relapsing after primary therapy comparing to ‘best non-HCT’ therapy.

Regarding allogeneic HCT…: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or with high-risk features (i.e., cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of post allogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role of salvage allogeneic HCT in patients with MM relapsing after primary therapy.”

International Myeloma Working Group

The conclusions and recommendations of the consensus statement on the current status of allogeneic stem cell transplantation for MM are as follows: Myeloablative allogeneic HCT may cure a minority of patients, but is associated with a high transplant-related mortality (TRM), but could be evaluated in well-designed prospective clinical trials. Nonmyeloablative allogeneic HCT as first-line therapy is associated with lower TRM but a greater risk of relapse and convincing evidence is lacking that allogeneic HCT improves survival as compared to autologous HCT.

National Comprehensive Cancer Network (NCCN)

Autologous HCT

The National Comprehensive Cancer Network (NCCN) guidelines (v.3.2022) consider autologous HCT a category 2A recommendation as follow-up to induction therapy for newly diagnosed MM and as a category 1 recommendation for relapsed or progressive disease if the patient is considered a transplant candidate. For relapsed or progressive disease, the guideline also says, “allogeneic stem cell transplant in multiple myeloma should only be used in the setting of a clinical trial. Current data do not support mini-allografting alone.”

Tandem Autologous-Autologous Transplant

The NCCN (v.3.2022) recommends collecting enough stem cells for two transplants in younger patients if tandem transplant or salvage transplant would be considered. A tandem transplant with or without maintenance therapy can be considered for all patients who are candidates for HCT and is an option for patients who do not achieve at least a very good partial response after the first autologous HCT and those with high-risk features.

Allogeneic Transplant

The NCCN  states the following for allo-HCT: "Allogeneic HCT includes either myeloablative or nonmyeloablative (i.e., "mini" transplant) transplants. Allogeneic HCT has been investigated as an alternative to autologous HCT to avoid the contamination of reinfused autologous tumor cells, but also to take advantage of the beneficial graft-versus-tumor effect associated with allogeneic transplants. However, lack of a suitable donor and increased morbidity has limited this approach, particularly for the typical older MM population”. The guidelines also note that allo-HCT should be done in the context of a clinical trial when possible.

POEMS Syndrome

The NCCN (v.3.2022) guidelines recommend autologous HCT in patients with POEMS syndrome who are eligible as sole therapy or as consolidation therapy after induction therapy.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY  WORDS:

Multiple Myeloma, Myeloablative Chemotherapy, Tandem Transplant, Single Transplant, hematopoietic cell transplantation, HCT, autologous, allogeneic, reduced intensity conditioning, RIC, POEMS Syndrome**

APPROVED BY GOVERNING BODIES:

The U.S. Food and Drug Administration regulate human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT codes:

38204

Management of recipient hematopoietic cell donor search and cell acquisition

38205

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic

38206

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous

38208

Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing, per donor

38209

; thawing of previously frozen harvest, with washing, per donor

38210

; specific cell depletion with harvest, T-cell depletion

38211

; tumor-cell depletion

38212 

; red blood cell removal

38213

; platelet depletion

 

38214  

; plasma (volume) depletion

 

38215

; cell concentration in plasma, mononuclear or buffy coat layer

38220

Diagnostic bone marrow; aspiration(s)

38221

Diagnostic bone marrow; biopsy(ies),

38222

Diagnostic bone marrow; biopsy(ies) and aspiration(s) (Effective 01/01/2018)

38230

Bone marrow harvesting for transplantation; allogeneic

38232

Bone marrow harvesting for transplantation; autologous

38240

Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic

38241

Bone marrow or blood-derived peripheral stem-cell transplantation; autologous

38242

Management/transplant preparation/infusion of hematopoietic progenitor cells code range

   HCPCS:

S2140

Cord blood harvesting for transplantation, allogeneic

S2142

Cord blood-derived stem-cell transplantation, allogeneic

S2150

Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre and post-transplant care in the global definition

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  55. Garderet L, Cook G, Auner HW, et al. Treatment options for relapse after autograft in multiple myeloma - report from an EBMT educational meeting. Leuk Lymphoma. Apr 2017; 58(4):797-808.
  56. Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. Dec 2015; 16(16):1617-1629.
  57. Giralt S, Costa L, Schriber J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.  Biol Blood Marrow Transplant. Mar 2014; 20 (3):295-308.
  58. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group consensus conference on salvage hematopoietic cell transplantation in patients with relapsed multiple myeloma. Biol Blood Marrow Transplant. Dec 2015; 21(12):2039-2051.
  59. Giralt S, Koehne G. Allogeneic hematopoietic stem cell transplantation for multiple myeloma: what place, if any? Curr Hemotol Malig Rep. Dec 2013; 8(4):284-290.
  60. Goldschmidt H, Baertsch MA, Schlenzka J, et al. Salvage autologous transplant and lenalidomide maintenance vs.lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE. Leukemia. Jul 21 2020.
  61. Goldschmidt H, Cremer FW, Hegenbart U, et al. Comparison of 3 high-dose regimens with autologous peripheral blood stem cell transplantation for multiple myeloma: A single center experience in 261 patients. Proc VII Int Multiple Myeloma Workshop 1999. Abstract 117a.
  62. Hahn T, Wingard JR, Anderson KC, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: An evidence-based review. Biol Blood Marrow Transplant. Jan 2003; 9(1):4-37.
  63. Harousseau JL. The allogeneic dilemma. Bone Marrow Transplant. Dec 2007; 40(12):1123-1128.
  64. Ikeda T, Mori K, Kawamura K, et al. Comparison between autologous and allogeneic stem cell transplantation as salvage therapy for multiple myeloma relapsing/progressing after autologous stem cell transplantation. Hematol Oncol. Dec 2019; 37(5): 586-594.
  65. Jang IY, Yoon DH, Kim S, et al. Advanced POEMS syndrome treated with high-dose melphalan followed by autologous blood stem cell transplantation: a single-center experience.  Blood Res. Mar 2014; 49(1):42-48.
  66. Koreth J, Cutler CS, Djulbegovic B, et al.  High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma:  A systematic review and meta-analysis of randomized controlled trials.  Biol Blood Marrow Transplant 2007; 13(2):183-196.
  67. Krishnan A, Pasquini MC, Logan B et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12(13):1195-1203.
  68. Kumar, S, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016; 17(8): e328–e346.
  69. Kumar A, Loughran T, Alsina M, et al.  Management of multiple myeloma:  A systematic review and critical appraisal of published studies.  Lancet Oncol 2003; 4(5):293-304.
  70. Kuwabara S, Dispenzieri A, Arimura K et al. Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. Cochrane Database Syst Rev 2012; 6:CD006828.
  71. Kyle RA and Rajkumar SV.  Multiple myeloma.  Blood 2008; 111(6):2962-2972.
  72. Kyle RA.  High-dose therapy in multiple myeloma and primary amyloidosis: an overview.  Semin Oncol 1999; 26(1):74-83.
  73. Lahuerta JJ, Martinez-Lopez J, Grande C, et al.  Conditioning regimens in autologous stem cell transplantation for multiple myeloma: A comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma.  Br J Haematol 2000; 109(1):138-147.
  74. Larocca A, Palumbo A. Evolving paradigms in the treatment of newly diagnosed multiple myeloma. J Natl Compr Canc Netw 2011; 9(10):1186-1196.
  75. Lokhorst H, Einsele H, Vesole D et al. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol. Oct 10 2010; 28(29):4521-4530.
  76. Lokhorst H, Mutis I. Allogeneic transplantation and immune interventions in multiple myeloma. In: Green T, Salles G, Boregaard N, eds. Hematology Education: the education program for the annual congress of the European Hematology Association 2008; 2:106-114.
  77. Maffini E, Storer BE, Sandmaier BM, et al. Long-term follow-up of tandem autologous-allogeneic hematopoietic cell transplantation for multiple myeloma. Haematologica. Sep 27 2018.
  78. Maloney DG, Molina AJ, Sahebi F, et al.  Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.  Blood 2003; 102(9): 3447-3454.
  79. Marini C, Maia T, Bergantim R, et al. Real-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma. Ann. Hematol., 2018 Oct 29; 98(2).
  80. McCarthy PL, Holstein SA. Role of stem cell transplant and maintenance therapy in plasma cell disorders. Hematology Am Soc Hematol Educ Program. Dec 2 2016; 2016(1):504-511.
  81. Mian H, Mian OS, Rochwerg B, et al. Autologous stem cell transplant in older patients (age65) with newly diagnosed multiple myeloma: A systematic review and meta-analysis. J Geriatr Oncol. Jan 2020; 11(1): 93-99.
  82. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol.May 10 2019; 37(14): 1228-1263.
  83. Michaelis LC, Saad A, Zhong X, et al. Salvage second hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant. May 2013; 19(5):760-766.
  84. Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. Apr 2013; 88(4):360-376.
  85. Moreau P, Garban F, Attal M et al. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. Nov 1 2008; 112(9):3914-3915.
  86. Moreau P, Garban F, Facon T, et al.  Preliminary results of the IFM9903 and IFM9904 protocols comparing autologous followed by mini-allogeneic transplantation and double autologous transplant in high-risk de novo multiple myeloma.  Blood 2003; 102(11):43a. Abstract 138.
  87. Moreau P, Facon T, Attal M, et al.  Comparison of 200 mg/m (2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma:  Final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial.  Blood 2002; 99(3):731-735.
  88. Nasu S, Misawa S, Sekiguchi Y et al. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry. May 2012; 83(5):476-479.
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POLICY HISTORY:

Medical Policy Group, February 2010 (2)

Medical Policy Administration Committee, February 2010

Available for comment February 23-April 8, 2010

Medical Policy Group, December 2011; Updated CPT codes for 2012: 38208, 38209 and added codes 38230 & 38232

Medical Policy Panel, April 2012

Medical Policy Group, February 2013(3): Updated Description, Key Points, and References; no change in policy statement

Medical Policy Panel, August 2013

Medical Policy Group, August 2013(3):  Updated Title, Description, Policy Statement, Key Points and References; no change in Multiple Myeloma policy statement; policy statements regarding POEMS syndrome added

Available for comment August 15 through September 28, 2013

Medical Policy Group, January 2014 (1): 2014 Coding Update: added current codes Q2049 and Q2050 to coding section; new codes are included in the chemotherapy drug code range

Medical Policy Panel, August 2014

Medical Policy Group, August 2014 (3): 2014 Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Panel, August 2015

Medical Policy Group, October 2015 (2): 2015 Updates to Description, Key Points, Approved by Governing Bodies, and Reference, no change to policy statement.

Medical Policy Panel, January 2017

Medical Policy Group, March 2017 (7): 2017 Updates to Title, Key Points and References. Policy statement reworded for clarification. Removed verbiage from 2013. No change in intent.

Medical Policy Group, December 2017. Annual Coding Update 2018. Added new CPT code 38222 effective 1/1/18 to the Current Coding section. Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Panel, January 2018

Medical Policy Group, February 2018 (7): 2018 Updates to Description, Key Points, & References. No change in policy statement.

Medical Policy Panel, January 2019

Medical Policy Group, March 2019 (3): 2019 Updates to Key Points, Practice Guidelines and Position Statements, References and Key Words: added: hematopoietic cell transplantation, HCT, autologous, reduced intensity conditioning, RIC and allogeneic. No changes to policy statement or intent.

Medical Policy Panel, January 2020

Medical Policy Group, February 2020 (3): 2020 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. Minor change to policy statement by removing “upfront” and adding initial to policy statement. Added Policy Guidelines section. No changes to policy intent.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. Policy statement updated to remove “not medically necessary, “no other changes to policy statement or intent.

Medical Policy Panel, January 2022

Medical Policy Group, February 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.