Coverage Policy Manual
Policy #: 2007013
Category: Medicine
Initiated: July 2007
Last Review: June 2018
  HDC & Autologous Stem Cell Support Followed by Nonmyeloablative Allogeneic Stem Cell Transplant for Multiple Myeloma

High-Dose Chemotherapy
High-dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the abbreviation HDC when applicable. The most significant adverse effect of HDC is marrow ablation. Thus, HDC is followed by infusion of hematopoietic stem cells to repopulate the bone marrow.
Typically, 1 course is given of HDC followed by stem-cell support (SCS). Two or more planned courses of HDC/SCS are referred to as “tandem” transplantation. Tandem transplants are typically administered at intervals of 2–6 months irrespective of the patient’s remission status but contingent on recovery from prior toxicity. Potential donors and sources of stem cells are described below.
Donor Types
Autologous - Autologous hematopoietic stem cells are harvested from patients prior to myeloablative therapy.
Syngeneic - Syngeneic hematopoietic stem cells are harvested from an identical twin. Their use is limited by the rarity of identical twins.
Allogeneic - Allogeneic hematopoietic stem cells are those harvested from a donor, after verifying the donor and recipient are well matched with respect to human leukocyte antigens (HLA). Allogeneic cells provide 2 theoretical advantages: the lack of tumor contamination associated with autologous stem cells, and the possibility of a beneficial graft-versus-tumor effect. Their disadvantage is the risk of graft-versus-host disease (GVHD), which increases with greater HLA disparity and recipient age.
Stem-Cell Sources
Hematopoietic stem cells can be collected from either the bone marrow or the peripheral blood of patients or donors. Stem cells may be harvested from the peripheral blood using a pheresis procedure. To increase the number of stem cells in the peripheral circulation (termed mobilization), patients providing autologous blood stem cells are pretreated with a course of chemotherapy or hematopoietic growth factors, or both. Donors providing allogeneic blood stem cells are mobilized with growth factors only.
The following discussion does not distinguish between stem cells collected from the peripheral blood or marrow, and refers to either as SCS. Therefore, HDC/AuSCS refers to high-dose chemotherapy with autologous stem-cell support, while AlloSCS refers to allogeneic stem-cell support. However, note that hematopoiesis, as measured by neutrophil and platelet counts, recovers more rapidly after blood stem cells than after bone marrow stem cells. On the other hand, chronic GVHD after AlloSCS is more frequent with blood than with marrow stem cells.
Blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Although cord blood is an allogeneic source, these stem cells are antigenically naïve and apparently are associated with a lower incidence of GVHD.
Multiple Myeloma
Multiple myeloma is a systemic malignancy of relatively well-differentiated plasma cells. Management of myeloma is generally related to tumor mass at diagnosis or at the time treatment is initiated. Patients with a high tumor mass undergo systemic cytotoxic therapy, typically intermittent melphalan/prednisone (MP) or other combination therapy such as VAD (vincristine, doxorubicin, and dexamethasone) or VMCP (vincristine, melphalan, cyclophosphamide, and prednisone). However, multiple myeloma rarely is cured with standard-dose chemotherapy, prompting interest in high-dose chemotherapy with either autologous or allogeneic SCS. There has also been interest in tandem HDC/SCS to further reduce the relapse rate seen after a single course of HDC/SCS.
This policy addresses only high dose chemotherapy with autologous stem cell support followed by nonmyeloablative allogeneic stem cell transplant for multiple myeloma.  For coverage of HDC & autologous stem &/or progenitor cell support for the treatment of multiple myeloma see Coverage Policy 2000009, HDC & Autologous Stem &/or Progenitor Cell  Support-Multiple Myeloma.

Tandem transplants for patients 65 years of age or less, with an HLA-identical sibling donor and in otherwise reasonably good health, with an initial AuSCS followed by non-marrow-ablative chemotherapy and allogeneic stem-cell support (i.e., “mini-transplant) may be covered to treat newly diagnosed or responsive multiple myeloma.  
For purposes of this policy the term responsive is defined as a tumor showing either a complete or partial remission.  Partial remission is defined as at least a 50% reduction in tumor burden, typically measured in terms of serum levels of beta-2 microglobin or monoclonal immunoglobulins, both considered tumor markers for multiple myeloma.  
Refractory or resistant is defined as a tumor response of less than 50%.
Allogenic hematopoietic cell transplantation as initial treatment for newly diagnosed multiple myeloma does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, allogenic hematopoietic cell transplantation as initial treatment for newly diagnosed multiple myeloma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Research continues on many aspects of treatment for multiple myeloma, such as chemotherapy regimens and stem-cell transplantation.  The web site,, lists 305 studies relating to multiple myeloma currently recruiting patients.  This policy may change as additional results, especially with longer follow-up, are released.  The decision to cover an autograft followed by an allograft in younger, newly diagnosed patients, was based primarily on a recent study (Bruno, 2007) using “genetic randomization”, i.e., 80 patients with an HLA-identical sibling were allowed to choose allografts or autografts for the second transplant (58 completed and auto/allograft sequence) and 82 without an HLA-identical sibling were assigned to tandem autografts (46 completed the double autograft sequence).  The transplantation was preceded by chemotherapy with VAD.  The validity of the “genetic randomization” is open to question, but the results among those completing tandem transplantation showed a higher complete response rate at the completion of the second transplant for the autograft/allograft group (55%) than for the autograft/autograft group (26%; p=0.004).  Analyzing the group with HLA-identical siblings versus those without, in a pseudo intention-to-treat analysis, event-free survival and overall survival were significantly longer in the group with HLA-identical siblings.  However, it is difficult to gauge the impact of the different percentages in each group who actually complete treatment.  The treatment-related mortality rate at 2 years was 2% in the double autograft group and 10% in the auto/allograft group; 32% of the latter group has extensive, chronic graft-versus-host disease.
2013 Update
A literature review was conducted using the MEDLINE database through May 2013. There was no new literature identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
In 2011, Krishnan and colleagues conducted a Phase 3 trial comparing tandem autologous-autologous HSCT (auto-auto group) versus tandem autologous-RIC allogeneic HSCT (auto-allo group) in patients from 37 transplant centers in the U.S., who between 2003 and 2007, had received an autologous HSCT (n=710) (Krishnan, 2011).  Of these patients, 625 had standard-risk disease, and 156 of 189 patients (83%) in the auto-allo group and 366 of 436 (84%) in the auto-auto group received a second transplant. Patients were eligible if they were younger than 70 years of age and had completed at least 3 cycles of systemic therapy for myeloma within the past 10 months. Patients were assigned to receive a second autologous or allogeneic HSCT based on the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent random assignment to observation (n=219) or maintenance therapy with thalidomide plus dexamethasone (n=217). Kaplan-Meier estimates of 3-year PFS were 43% (95% CI: 36-51) in the auto-allo group and 46% (42-51) in the auto-auto group (p=0.67). OS also did not differ at 3 years (77% [95%CI 72-84] versus 80% [77-84]; p=0.19). Grade 3-5 adverse events between the two groups were 46% and 42%, respectively. The authors concluded that non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk myeloma.
The final results of 2 completed prospective Phase III trials comparing double autologous with single autologous followed by RIC-allogeneic transplant are awaited (Lokhorst, 2008; Bjorkstrans, 2008). Interim results of the study by the HOVON Group at 36 months of follow-up found no significant difference between the groups that received autologous/RIC-allogeneic transplants or tandem autologous transplants in EFS (median 34 months and 28 months, respectively) or OS (80% and 75%, respectively) at 36 months (Lokhorst, 2008).  An interim analysis of a European Group for Blood and Marrow Transplant (EBMT) study was recently presented with somewhat different inclusion criteria. (36) Previously untreated patients received vincristine, doxorubicin, dexamethasone (VAD) or VAD-like induction treatment, and had a response status of at least stable disease (i.e., complete or partial remission or stable disease) at the time of autologous transplantation, which was also the time point for study inclusion. Patients with an HLA-identical sibling proceeded to RIC-allogeneic transplantation, while those without a matched sibling received no further treatment or a second autologous stem-cell transplant (if treated within a tandem program). A total of 356 patients were included, with a median follow-up of 3.5 years. Of these, 108 patients were allocated to the RIC-allogeneic transplant group and 248 to the autologous transplant group. Of the patients allocated to the allogeneic group, 98 received an RIC-allogeneic transplant. As of now, there is no significant difference in PFS or OS between the double autologous and autologous/RIC-allogeneic transplant recipients. However, the follow-up is too short for firm conclusions to be drawn and the study is still ongoing.
In summary, The results of trials comparing tandem autologous-reduced-intensity conditioning (RIC) allogeneic HSCT to tandem autologous-autologous have shown conflicting results (Garban, 2006; Moreau, 2008; Bruno, 2007; Rosinol, 2008), although most studies have not shown a survival benefit with tandem autologous-RIC allogeneic, and have shown higher transplant-related mortality. Factors across studies that may account for differing trial results include different study designs, non-uniform preparative regimens, different patient characteristics (including risk stratification) and criteria for advancing to a second transplant. The future of the use of tandem autologous-RIC allogeneic in treating myeloma will depend on additional trials with longer follow-up data.
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
The EBMT reported an analysis of 413 MM patients who received a related or unrelated RIC allogeneic HSCT for the treatment of relapse or disease progression after a prior autologous HSCT (Au7ner, 2013). Median age at RIC allogeneic HSCT was 54 years, and 45% of patients had undergone two or more prior autologous transplants. The median OS and PFS from the time of allogeneic transplantation for the entire population were about 25 and 10 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was about 22%. In a multivariate analysis, cytomegalovirus (CMV) seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior autologous transplants was associated with better OS, and shorter time from the first autologous HSCT to the RIC allogeneic HSCT was associated with lower NRM. These results suggest patient and donor CMV seronegativity represent key prognostic factors for outcome after RIC allogeneic HSCT for MM that relapses or progresses following one or more autologous transplants.
At 96 months in the EBMT trial, progression-free survival (PFS) and overall survival (OS) were 22% and 49% versus 12% (P = .027) and 36% (P = .030) with autologous/RIC-allogeneic and autologous HSCT, respectively (Gahrton. 2013).  The corresponding relapse/progression rate (RL) was 60% versus 82% (P = .0002). Nonrelapse mortality at 36 months was 13% versus 3% (P = .0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and 47% versus 5% (P = .026), and 31% (P = .154) (Gahrton. 2013).  Long-term outcome in patients with multiple myeloma was better with autologous/RIC-allogeneic HSCT as compared with autologous only and the autologous/RIC-allogeneic approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation.
The role of allogeneic HSCT remains controversial, in particular because of conflicting data from cooperative group trials, but also because of improvement in outcomes that have been observed with proteasome inhibitors, new immune modulatory agents, and the use of post-transplant maintenance therapy. These issues have recently been reviewed and summarized (Giralt, 2014; Giralt, 2013).
POEMS Syndrome
A second recent series included 9 advanced POEMS syndrome patients, who had an Eastern Cooperative Oncology Group performance status score of 3 or 4, and were treated with high-dose melphalan therapy followed by autologous stem cell transplantation from 2004 to 2011 (Jang, 2014). Eight patients achieved an initial hematologic response, 4 of whom had complete responses. At a median follow-up of 44 months (range, 8-94 months), 7 patients were alive, with 3-year overall survival rate of 78%. There were no hematologic relapses in the survivors. One patient died of disease progression; the other died of pneumonia despite a hematologic response 3 months after autologous stem cell transplantation. All survivors achieved improvement in general performance status and in clinical response. The responses observed in these patients with advanced POEMS suggest it is a valid treatment option for such cases.
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Randomized Controlled Trials
One randomized controlled trial (RCT) was identified that compared autologous HCT to standard chemotherapy plus lenalidomide, a newer agent for treatment of MM (Gay, 2015). The study was an open-label RCT from 59 centers in Europe and Australia that used a 2×2 factorial design to compare 4 groups (1) standard consolidation therapy plus HCT, followed by maintenance with lenalidomide alone, (2) standard consolidation therapy plus HCT, followed by maintenance with lenalidomide and prednisone, (3) consolidation with chemotherapy plus lenalidomide, followed by maintenance with lenalidomide alone, and (4) consolidation with chemotherapy plus lenalidomide, followed by maintenance with lenalidomide plus prednisone. The primary outcome was progression-free survival (PFS). Mean follow-up at the time of publication was 52 months. Median PFS was superior for the HCT group (43.3 months; 95% confidence interval [CI], 33.2 to 52.2 months) compared to chemotherapy plus lenalidomide (28.6 months; 95% CI, 20.6 to 36.7 months; p<0.0001). The rate of grade 3 or 4 adverse events was higher for the HCT group than for chemotherapy (hematologic events, 84% vs 26%; gastrointestinal complications, 20% vs 5%; infections, 19% vs 5%).
Final survival data for the BSBMT/UKMF Myeloma Xtrial (NCT00747877) and EudraCT (2006-005890-24) (Cook, 2014) were reported in 2016 (Cook, 2016). The HCT group had superior median OS compared to the chemotherapy group (67 months [95% CI, 55 months to not estimable] vs 52 months [95% CI, 42 to 60 months; p<0.001). Time to disease progression continued to favor the HCT group at the longer follow-up (19 months [95% CI, 16 to 26 months vs 11 months [95% CI, 9 to 12 months; p=0.02). There were no further adverse events related to the HCT procedure reported during longer follow-up. The cumulative incidence of second malignancies was 5.2% (95% CI, 2.1% to 8.2%).
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
In 2017, Schneidawind et al retrospectively analyzed data from 41 myeloma patients who were treated with allogeneic stem cell transplantation for relapsed or refractory disease between 2001 and 2015 (Schneidawind, 2017). Among various immunosuppression regimens, anti-thymocyte globulin was given to 35 (85%) of the patients; conditioning regimens were myeloablative in 15 patients, reduced-intensity myeloablative in 18 patients, and nonmyeloablative in 8 patients. In univariate analysis, EFS was significantly lower for the 18 patients who received a tandem autologous HCT prior to the allo-HCT than for the 23 patients who received either a single autologous HCT or no transplant before the current treatment (6% vs 24%, respectively; hazard ratio, 0.48; 95% CI, 0.23 to 0.98; p=0.04). At the latest follow-up, a total of 25 patients had died, 14 (56%) of whom died of relapse or refractory disease. Salvage regimens (thalidomide, lenalidomide, pomalidomide, bortezomib, or a combination) were given to 20 patients, who showed significantly improved OS rates at 1 year (79%) and 3 years (68%), compared with the rest of the cohort (1-year OS=29%, p=0.001; 3-year OS=14%, p=0.004).
In 2017, EBMT reported on potential treatments for myeloma patients whose disease has relapsed following autologous stem cell transplantation; the included systematic review was primarily descriptive (Gardaret, 2017). Among the treatments suggested were immunomodulatory drugs (ie, thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (ie, bortezomib, carfilzomib, ixazomib), monoclonal antibodies, and autologous HCT or allo-HCT. Reviewers noted that most of the studies of stem cell transplantation are retrospective analyses of case series or data drawn from databases; to confirm the apparent benefits of transplantation over chemotherapy alone, reviewers suggested that more prospective studies are needed for both types of procedure following relapse.

38241Hematopoietic progenitor cell (HPC); autologous transplantation

References: Auner HW, Szydlo R, van Biezen A, et al.(2013) Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. Nov 2013;48(11):1395-1400. PMID 23708704

Bjorkstrand B, Iacobelli S, Hegenbart U et al.(2008) Autologous stem cell transplantation (ASCT) versus ASCT followed by reduced-intensity conditioning allogeneic SCT with identical sibling donor in previously untreated multiple myeloma: preliminary analysis of a prospective controlled trial by the EBMT. Bone Marrow Transplant 2008; 41:S38.

Bruno B, Rotta M, et al.(2007) A comparison of allografting with autografting for newly diagnosed myeloma. NEJM, 2007; 356:1110-20.

Cook G, Williams C, Brown JM, et al.(2014) High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. Jul 2014;15(8):874-885. PMID 24948586

Dunavin NC, Wei L, Elder P, et al.(2013) Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma. Leuk Lymphoma. Aug 2013;54(8):1658-1664. PMID 23194056

Gahrton G, Iacobelli S, Bjorkstrand B, et al.(2013) Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMTNMAM2000 study. Blood. Jun 20 2013;121(25):5055-5063. PMID 23482933

Garban F, Attal M, Michallet M et al.(2006) Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04) trial in high-risk de novo multiple myeloma. Blood 2006; 107(9):3474-80.

Garderet L, Cook G, Auner HW, et al.(2017) Treatment options for relapse after autograft in multiple myeloma - report from an EBMT educational meeting. Leuk Lymphoma. Apr 2017;58(4):797-808. PMID 27650125

Gay F, Oliva S, Petrucci MT, et al.(2015) 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. PMID 26596670

Giralt S, Costa L, Schriber J, et al.(2014) Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. Mar 2014;20(3):295- 308. PMID 24141007

Giralt S, Garderet L, Durie B, et al.(2015) 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. PMID 26428082

Giralt S, Koehne G.(2013) Allogeneic hematopoietic stem cell transplantation for multiple myeloma: what place, if any? Curr Hematol Malig Rep. Dec 2013;8(4):284-290. PMID 24146203

Jang IY, Yoon DH, Kim S, et al.(2014) 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. PMID 24724066

Lokhorst H, Mutis I.(2008) 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; 2:106-14.

McCarthy PL, Holstein SA.(2016) 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. PMID 27913522

Michaelis LC, Saad A, Zhong X, et al.(2013) Salvage second hematopoietic cell transplantation in myeloma. . Biol Blood Marrow Transplant. May 2013;19(5):760-766. PMID 23298856

Moreau P, Garban F, Attal M et al.(2008) 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 2008; 112(9):3914-5.

Rosinol L, Perez-Simon JA, Sureda A et al.(2008) A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112(9):3591-3.

Schneidawind C, Duerr-Stoerzer S, Faul C, et al.(2017) Follow-up of patients with refractory or relapsed multiple myeloma after allogeneic hematopoietic cell transplantation. Clin Transplant. Jul 2017;31(7). PMID 28470884

Ziogas DC, Terpos E, Dimopoulos MA.(2017) When to recommend a second autograft in patients with relapsed myeloma? Leuk Lymphoma. Apr 2017;58(4):781-787. PMID 27894207

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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