Pending Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma (MM) and POEMS Syndrome

Number:SUR703.030

Effective Date:04-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Multiple Myeloma

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

Tandem autologous HSCT may be considered medically necessary to treat MM in patients who fail to achieve at least a near-complete or very good partial response after the first transplant in the tandem sequence. (See NOTE 1 on “complete response and very good partial response to MM therapy.”)

NOTE 1: The criteria for “complete response and very good partial response to MM therapy” include negative immunofixation on the serum and urine; disappearance of soft tissue plasmacytomas; and 5% or fewer plasma cells in bone marrow aspiration.

Tandem transplantation with an initial round of autologous HSCT followed by a non-marrow-ablative conditioning regimen and allogeneic HSCT (i.e., reduced-intensity conditioning [RIC] transplant) may be considered medically necessary to treat newly diagnosed MM patients.

Autologous HSCT is considered experimental, investigational and/or unproven for patients with refractory MM, including those with primary resistant disease or in a resistant relapse.

Allogeneic HSCT is considered experimental, investigational and/or unproven to treat patients:

As an initial therapy for newly diagnosed and untreated MM; OR

After a failed course or as salvage therapy of autologous hematopoietic stem-cell transplantation; OR

For treatment of refractory MM, including those with primary resistant disease or in a resistant relapse.

Tandem allogeneic HSCT is considered experimental, investigational and/or unproven for the treatment of newly diagnosed, responsive or refractory MM.

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, and Skin changes) Syndrome

Autologous HSCT may be considered medically necessary to treat disseminated POEMS syndrome, including patients having diffuse sclerotic lesions or disseminated bone marrow involvement.

Allogeneic and tandem HSCTs are considered experimental, investigational and/or unproven to treat POEMS syndrome.

NOTE 2: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

Hematopoietic Stem-Cell Transplantation (HSCT)

HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Plasma Cell Dyscrasias

Plasma cell dyscrasias are treatable but rarely curable. In some cases, HSCT is considered as a therapy. Multiple myeloma (MM) 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.

Multiple Myeloma (MM)

MM is treatable but rarely curable. At the time of 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. (1-3)

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. (1) 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. (1, 2) In some patients, an intermediate asymptomatic but more advanced premalignant stage is recognized and referred to as smoldering MM. (3) The overall risk of disease progression from smoldering to symptomatic MM 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. (1, 2)

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. (4, 5) This complex, multiorgan disease was first described in 1938, but the acronym POEMS was coined in 1980, reflecting hallmark characteristics of the syndrome. (6) 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. (5, 7) 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 1 of the minor criteria are necessary for diagnosis. (7)

Table 1: Criteria and Associations

Major Criteria

Minor Criteria

Known Associations

Possible Associations

Polyneuropathy

 

Sclerotic bone lesions

Clubbing

Pulmonary hypertension

Monoclonal plasma-proliferative disorder

 

Castleman disease

Weight loss

Restrictive lung disease

Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy)

Thrombocytosis

Thrombotic diatheses

Edema (edema, pleural effusion, ascites)

Polycythemia

Arthralgias

Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)

Hyperhidrosis

Cardiomyopathy (systolic dysfunction)

Skin changes (hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails)

 

Fever

Papilledema

Low vitamin B12 values

Diarrhea

The prevalence of POEMS syndrome is unclear. A national survey in Japan showed a prevalence of about 0.3 per 100,000. (8) Other large series have been described in the United States (5, 7, 9) and in India. (10) In general, patients with POEMS have a superior overall survival (OS) compared with that of MM, nearly 14 years in a large series from Mayo Clinic. (7) However, given the rarity of POEMS, no randomized controlled trials (RCTs) of therapies have been reported. (11) Numerous approaches have included ionizing radiation, plasmapheresis, intravenous immunoglobulin, interferon-α, corticosteroids, alkylating agents, azathioprine, tamoxifen, trans-retinoic acid, and high-dose chemotherapy (HDC) with autologous HSCT support. (5, 7) 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, such as medullary disease or multiple plasmacytomas. Given the underlying plasma cell dyscrasia of POEMS, newer approaches to MM, including bortezomib, lenalidomide, and thalidomide, are also under investigation. (5, 12).

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (65) Hematopoietic stem-cells are included in these regulations.

Rationale:

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell transplant (HSCT) (i.e., blood or marrow) is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, bone marrow, or umbilical cord blood stem-cells.

The earliest versions of this evidence review were based on two 1996 (61, 62) and two 1998 (63, 64) Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments. Since 1999, the treatment of multiple myeloma (MM) has changed radically.

The literature search of the MedLine database for this evidence review was updated through January 2017. No new evidence was identified that would support a change in any of the review conclusions on MM. New information on POEMS syndrome was added to the review in 2016. The following is a summary of the key literature to date.

Multiple Myeloma (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 (OS) reported during a 24-year period from 1971-1994, with a trend toward improvement during 1995-2000, and a statistically significant benefit in OS during 2001-2006. (2) These data suggested that autologous stem-cell transplantation (SCT) was responsible for the trends during 1994-2000, while novel agents have contributed to the improvement since 2001. (2)

The introduction of novel agents and better prognostic indicators has been the major advances in the treatment of this disease. (13, 14) 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. (13-15) 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. (16)

Newly Diagnosed MM

Risk-Adapted Therapy

The approach to the treatment of newly diagnosed MM (symptomatic) is dictated by eligibility for autologous HSCT and risk-stratification. (17) Risk stratification, using fluorescent in situ hybridization and conventional karyotyping, divides patients into standard- or high-risk categories.

High-risk patients, which comprise approximately 25% of patients with MM, are defined by any of the following cytogenetic findings: 17p deletion, t(4;14), t(14;16), t(14;20), deletion 13 or hypodiploidy. (17) Standard-risk patients are those with hyperdiploidy, t(11;14) or t(6;14).

Standard-risk patients are typically treated with non-alkylator-based therapy such as lenalidomide plus low-dose dexamethasone followed by autologous HSCT; however, if the patient is tolerating the induction regimen well, an alternative strategy is to continue the initial therapy after hematopoietic stem-cell collection, reserving the transplant for first relapse. High-risk patients are generally treated with a bortezomib-based induction followed by autologous HSCT and then bortezomib-based maintenance. (17)

Recent reviews highlight the treatment of newly diagnosed myeloma, (18) relapsed, and refractory myeloma. (19) A review of the literature highlights advances in the use of autologous and allogeneic HSCT. (20)

Single Autologous HSCT versus Standard Chemotherapy

Randomized Controlled Trials (RCTs)

One RCT was identified that compared autologous HSCT to standard chemotherapy plus lenalidomide, a newer agent for treatment of MM. (21) 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 HSCT, followed by maintenance with lenalidomide alone;

2. Standard consolidation therapy plus HSCT, 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 HSCT 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 HSCT group than for chemotherapy (hematologic events, 84% versus 26%; gastrointestinal complications, 20% versus 5%; infections, 19% versus 5%).

Based on several prospective, randomized trials comparing conventional chemotherapy to high-dose therapy plus autologous HSCT for patients with MM, autologous HSCT has become the treatment of choice in patients younger than 65 years of age.

Data from 7 randomized studies are available. (22-28) In all but 1 study (Barlogie et al.), (24) the complete response (CR) rate was superior in the HDC with autologous HSCT arm. The Barlogie study published final results from the phase 3-S9321 trial, which was initiated in 1993 and randomized 516 patients with MM to receive standard therapy or myeloablative conditioning with melphalan 140 mg/m2 plus total body irradiation followed by autologous HSCT. (24) These trialists reported virtually no difference in outcomes, including response rates, PFS, and OS. In 5 of the 7 studies, the superior CR rate translated into a significant increase in PFS. However, in the 2 studies that did not show an improved PFS with autologous HSCT, randomization was not performed at diagnosis but only after induction treatment, possibly introducing selection bias. (22) Three of the 7 studies showed superior OS in the autologous HSCT group. (23, 26, 28)

The Intergroupe Francophone du Myélome (IFM) showed the superiority of HDC plus autologous HSCT compared with conventional chemotherapy in a randomized trial of 200 patients younger than 65 years of age. (23) The group that underwent autologous HSCT had significantly improved response rates, event-free survival (EFS), and OS. Seven years later, the British Medical Research Council published similar results. (26)

Systematic Reviews

A meta-analysis of 2411 patients enrolled in RCTs compared standard-dose chemotherapy to myeloablative chemotherapy plus single autologous HSCT. (29) The meta-analysis concluded that myeloablative therapy with autologous HSCT increased the likelihood of PFS (hazard ratio [HR] of progression, 0.75; 95% CI, 0.59 to 0.96) but not OS (HR of death, 0.92; 95% CI, 0.74 to 1.13); in this group, the odds ratio for treatment-related mortality (TRM) was 3.01 (95% CI, 1.64 to 5.50). However, the effects of myeloablative chemotherapy and autologous HSCT may have been diluted by the fact that up to 55% of patients in the standard chemotherapy group received myeloablative chemotherapy with autologous HSCT as salvage therapy when MM progressed. This could account for the lack of a significant difference in OS between the 2 groups.

These randomized trials of autologous HSCT following induction therapy were designed and implemented before the availability of thalidomide, lenalidomide, and bortezomib. Introduction of these agents has dramatically changed the treatment paradigm of MM. Ongoing trials incorporating these newer agents into induction regimens are ongoing. Preliminary results have shown CRs in a substantial proportion of these patients, raising questions about what role autologous HSCT will continue to play. However, it will require further follow-up to determine if these newer induction regimens will translate into improved survival. (30)

Tandem HSCT

A tandem transplant involves an autologous transplant followed by a preplanned second transplant, either another autologous or a RIC-allogeneic transplant. A tandem transplant differs from a second salvage transplant in that a tandem transplant involves prospective planning for a second transplant at the time the first transplant is being planned.

Tandem Autologous HSCT

The first randomized trial of tandem autologous transplants (IFM-94) was published in December 2003 by Attal et al. (31) This trial randomized patients with newly diagnosed myeloma to single or tandem autologous transplants. Outcomes were analyzed by intention to treat (ITT) at 75-month follow-up. Among those randomized to single transplants (n=199), 148 relapsed: 33 were salvaged with a second autotransplant, 13 received no salvage, and the remainder received conventional chemotherapy plus thalidomide. Among those randomized to tandem autotransplants (n=200), 129 patients experienced disease relapse: 34 received salvage therapy with another (third) transplant, 12 received no salvage, and the remainder received conventional chemotherapy plus thalidomide. Seven years after diagnosis, patients randomized to tandem transplants had higher probabilities than those randomized to single transplants for EFS (20% versus 10%, respectively; p=0.03), relapse-free survival (RFS; 23% versus 13%, respectively; p<0.01), and OS (42% versus 21%, respectively; p=0.010). TRM was 6% and 4% after tandem and single transplants, respectively (p=0.40). Second transplants extended survival only for those who failed to achieve a CR or without a very good partial response after 1 transplant (OS at 7 years, 43% versus 11%, respectively; p<0.001).

An accompanying editorial by Stadtmauer raised concerns that these results might be specific to the regimens used for myeloablative therapy in IFM-94. (32) Patients in the single transplant arm received melphalan 140 mg/m2 plus total body irradiation (TBI), while those in the tandem arm received the same dose without TBI for the initial transplant and with TBI for the second transplant. The editorial cited the IFM-95 study as evidence, suggesting melphalan 140 mg/m2 plus TBI may be less effective and more toxic than myeloablative therapy than melphalan 200 mg/m2 and no TBI. Based on this, the author hypothesized that increased survival in the IFM-94 tandem arm may have resulted from greater cumulative exposure to melphalan (280 mg/m2 versus 140 mg/m2).

The Bologna 96 clinical study, compared single and double autologous HSCT (N=321). (33) Patients undergoing tandem autologous HSCT were more likely than those with a single autologous HSCT to attain at least a near CR (47% versus 33%, respectively; p=0.008), to prolong RFS (median, 42-months versus 24-months, respectively; p<0.001), and extend EFS (median, 35-months versus 23-months, respectively; p=0.001). There was no significant difference between the groups in TRM (3%-4%). There was a trend for improved OS among patients in the double transplant group (7-year rate, 60%) compared with the single transplant group (7-year rate, 47%; p=0.10). Conversely, among patients achieving CR or near CR after 1 transplant, EFS and OS did not differ significantly according to transplant(s) received by study randomization. A subgroup analysis of outcomes of patients assigned to the 2 treatment arms was evaluated by response and showed that the benefit of a second transplant was particularly evident in patients who failed to achieve at least near CR after the first autologous transplant.

Tandem Autologous-RIC-allogeneic HSCT

Several trials have compared RIC-allogeneic HSCT following a first autologous HSCT with autologous transplants, single or in tandem. These studies were based on “genetic randomization,” i.e., patients with a human leukocyte antigen (HLA)-identical sibling were offered an RIC-allogeneic HSCT following the autologous HSCT, whereas the other patients underwent either 1 or 2 autologous transplants.

The first published study by Garban et al. included high-risk patients. (34) Sixty-five patients were in the autologous followed by RIC-allogeneic group and 219 in the autologous/autologous group. Based on the ITT analysis, there was better median EFS and OS in the autologous/autologous group (35 months versus 31.7 months, p=NS; 47.2 months versus 35 months, p=0.07, respectively). If results for only those patients who actually received the autologous followed by RIC-allogeneic (n=46) or tandem autologous transplants (n=166) were analyzed, the superior OS was again seen in the tandem autologous group (median, 47.2-months versus 35-months; p=0.07). Updated results from this population were reported in 2008 by Moreau et al. (35) Comparing the results of the 166 patients who completed the whole tandem autologous HSCT protocol to the 46 patients who underwent the entire autologous followed by RIC-allogeneic program, no difference was seen regarding EFS (median, 25-months versus 21-months, respectively; p=0.88), with a trend toward superior OS in favor of double autologous HSCT (median OS, 57-months versus 41-months, respectively; p=0.08), due to longer survival after relapse in the tandem autologous transplant arm.

A study by Bruno et al. included 80 patients with an HLA-identical sibling and who were allowed to choose allografts or autografts for the second transplant (58 completed an autograft or allograft sequence) and 82 without an HLA-identical sibling who were assigned to tandem autografts (46 completed the double autograft sequence). (36) Results among those completing tandem transplantation showed a higher CR rate after the second transplant for the autograft/allograft group (55%) than for the autograft/autograft group (26%; p=0.004). EFS and OS were superior for patients who underwent autologous allogeneic transplantation (35-months versus 29-months; p=0.02; 80-months versus 54-months; p=0.01, respectively). Analyzing the group with HLA-identical siblings versus those without, in a pseudo ITT analysis, EFS and OS were significantly longer in the group with HLA-identical siblings. The TRM rate at 2 years was 2% in the double autograft group and 10% in the autograft/allograft group; 32% of the latter group had extensive, chronic graft-verus-host disease (GVHD).

Rosinol et al. reported the results of a prospective study of 110 patients with MM who failed to achieve at least near CR after a first autologous HSCT and were scheduled to receive a second autologous transplant (n=85) or an RIC-allogeneic transplant (n=25), depending on the availability of an HLA-identical sibling donor. (37) The autologous followed by RIC-allogeneic group had a higher CR rate (40% versus 11%, respectively; p=0.001) and a trend toward a longer PFS (median, 31-months versus not reached, respectively; p=0.08). There were no statistical differences in EFS or OS between groups. The autologous followed by RIC-allogeneic group experienced a higher TRM rate (16% versus 5%, respectively; p=0.07) and a 66% chance of chronic GVHD.

Although results differed between the Garban and the Moreau studies (34, 35) and the Bruno and the Rosinol studies, (36, 37) these differences may have been due to study designs. The Moreau study focused on patients with high-risk disease and involved a conditioning regimen before the RIC-allogeneic transplant that may have eliminated some of the graft-versus-myeloma effect. Other contributing factors may have been nonuniform preparative regimens, different patient characteristics, and criteria for advancing to a second transplant (i.e., only patients who failed to achieve a CR or near CR after the first autologous transplant underwent a second), and a small population in the allogeneic group in the Moreau study. The authors suggested that the subgroup of high-risk patients with de novo MM may have had equivalent or superior results with a tandem autologous/autologous transplant versus a tandem autologous followed by RIC-allogeneic transplant and that, in patients with standard-risk and/or chemosensitive MM, RIC-allograft may be an option.

Interim results of 2 prospective phase 3 trials that compared double autologous with single autologous followed by RIC-allogeneic transplant have been published. (38, 39) The HOVON Group study at 36-month follow-up found no significant differences between groups that received autologous followed by RIC-allogeneic transplants or tandem autologous transplants in EFS (median, 34-months and 28-months, respectively) or in OS (80% and 75%, respectively). (38)

An interim analysis of a European Group for Blood and Marrow Transplant (EBMT) study presented somewhat different inclusion criteria. (39) Previously untreated patients received vincristine, doxorubicin, and 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 patients allocated to the allogeneic group, 98 received an RIC-allogeneic transplant. At interim reporting, no significant differences in PFS or OS were noted between the double autologous and autologous followed by allogeneic transplant recipients.

At 96 months in the EBMT trial, PFS and OS were 22% and 49% versus 12% (p=0.027) and 36% (p=0.030) with autologous followed by RIC-allogeneic and -autologous HSCT, respectively. (40) The corresponding relapse/progression rate was 60% versus 82% (p<0.001). Non relapse mortality at 36 months was 13% versus 3% (p<0.001). In patients with the del(13) abnormality, corresponding PFS and OS were 21% and 47% versus 5% (p=0.026), and 31% (p=0.154), respectively. (40) Long-term outcome in patients with MM was better with autologous followed by RIC-allogeneic HSCT than with autologous only, and the autologous followed by RIC-allogeneic approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation.

Krishnan et al. conducted a phase 3 trial comparing tandem autologous-autologous HSCT group versus tandem autologous followed by RIC-allogeneic HSCT group in patients from 37 transplant centers in the U.S., who, between 2003 and 2007, had received an autologous HSCT (n=710). (41) Of these patients, 625 had standard-risk disease, and 156 (83%) of 189 patients in the autologous-allogeneic group and 366 (84%) of 436 in the autologous-autologous group received a second transplant. Patients were eligible for transplantation 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 autologous-autologous group subsequently underwent random assignment to observation (n=219) or to maintenance therapy with thalidomide plus dexamethasone (n=217). Kaplan-Meier estimates of 3-year PFS were 43% (95% CI, 36% to 51%) in the autologous-allogeneic group and 46% (42% to 51%) in the autologous-autologous group (p=0.67). OS also did not differ at 3 years (77% [95%, CI, 72% to 84%] versus 80% [CI, 77% to 84%]; p=0.19). Grade 3, 4, or 5 morbidity between the 2 groups was 46% and 42%, respectively. The data suggested nonmyeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk myeloma.

Allogeneic HSCT

Although myeloablative allogeneic HSCT may be the only curative treatment in MM (due to its graft-versus-myeloma effect), its use has been restricted to younger patients. Even with the limited indications, the toxic death rate related to infections and GVHD is high, and this strategy has been almost completely abandoned. (42)

In an approach to reduce NRM associated with allogeneic HSCT, nonmyeloablative conditioning or RIC methods have been investigated. Most studies are phase 2, with no comparison with other treatment modalities. One retrospective study compared myeloablative and nonmyeloablative conditioning. (43) This study, conducted by EBMT, found that TRM was significantly reduced with RIC but, because of a higher relapse or progression rate, there was no significant improvement in OS.

When RIC-allogeneic transplant alone is used in patients with a high tumor burden or with chemotherapy-resistant disease, the immunologic effect of the graft is not sufficient to preclude relapses. (44) Therefore, RIC-allogeneic transplantation is currently used after tumor mass reduction with HDC and autologous HSCT. (42)

The role of allogeneic HSCT remains controversial, in particular because of conflicting data from cooperative group trials, but also because of improvement in outcomes observed with proteasome inhibitors, new immune modulatory agents, and the use of post-transplant maintenance therapy. These issues have recently been reviewed and summarized. (45, 46)

Section Summary: Newly Diagnosed MM

RCT evidence has demonstrated a survival benefit for autologous HSCT compared to alternative treatments. There is also RCT evidence for improved survival for tandem HSCT, when done using an autologous first transplant followed by a RIC-allogeneic transplant. The evidence for allogeneic HSCT is insufficient to make conclusions.

Relapsed or Refractory MM

Salvage HSCT

Despite improved survival rates with autologous HSCT versus conventional chemotherapy, nearly all patients will relapse and require salvage therapy. Therapeutic options for patients with relapsed MM after a prior autologous HSCT include novel biologic agents (e.g., thalidomide, lenalidomide, bortezomib, as single agents, or in combination with dexamethasone, and in combination with cytotoxic agents or with each other), traditional chemotherapy, or a second HSCT. (47)

The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, open-label, phase 3 study involving 51 centers across the United Kingdom, with enrollment occurring between April 2008 and November 2012. (48) Inclusion criteria were patients ages at least 18 years with MM who needed treatment for first progressive or relapsed disease at least 18 months after a previous autologous HSCT U.S. trial (NCT00747877) and EudraCT (European Union Drug Regulating Authorities Clinical Trials [2006-005890-24]). Before randomization, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilization and harvesting, if applicable. Eligible patients were randomly assigned (1:1) to receive high-dose melphalan 200 mg/m2 plus salvage autologous HSCT or oral cyclophosphamide 400 mg/m2/wk for 12 weeks. The primary end point was time to disease progression, analyzed by ITT. A total of 297 patients were enrolled, of whom 293 received PAD reinduction therapy. Among the latter, 174 patients with sufficient harvest of peripheral blood stem-cells were randomly allocated to undergo salvage HSCT (n=89) or receive cyclophosphamide (n=85). After a median follow-up of 31-months, median time to progression was significantly longer in the salvage HSCT group (19 months; 95% CI, 16 to 25) than in the cyclophosphamide group (11 months; 95% CI, 9 to 12 months; HR=0.36; 95% CI, 0.25 to 0.53; p<0.001). Frequently reported (>10% of patients) grade 3 or 4 morbidity with PAD induction, salvage HSCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD and 63 [76%] of 83 patients in the salvage HSCT group versus 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, 60 [72%] versus 4 [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none versus none, respectively).

Final survival data for the trial were reported in 2016. (49) The HSCT group had superior median OS compared to the chemotherapy group (67 months [95% CI, 55-months to not estimable] versus 52-months [95% CI, 42- to 60-months; p<0.001). Time to disease progression continued to favor the HSCT group at the longer follow-up (19-months [95% CI, 16- to 2-months versus 11-months [95% CI, 9- to 12-months; p=0.02).

There were no further adverse events related to the HSCT procedure reported during longer follow-up. The cumulative incidence of second malignancies was 5.2% (95% CI, 2.1% to 8.2%).

Repeat Autologous HSCT for Relapse After Initial Autologous HSCT

An evidence-based systematic review sponsored by the American Society for Blood and Marrow Transplantation (ASBMT) summarized data from 4 relevant clinical series. (50) Investigators reported that some myeloma patients who relapsed after a first autotransplant achieved durable complete or partial remissions after a second autotransplant as salvage therapy. Factors that apparently increased the likelihood of durable remissions and extended survival included a chemosensitive relapse, younger age, a long disease-free or progression-free interval since the initial autotransplant, and fewer chemotherapy regimens before the initial autotransplant. Thus, clinical judgment plays an important role in selecting patients for this treatment with a reasonable likelihood that potential benefits may exceed harms.

Olin et al. reported their experience with 41 patients with MM who received a second salvage autologous HSCT for relapsed disease. (47) Median time between transplants was 37-months (range, 3- to 91-months). Overall response rate in assessable patients was 55%. TRM was 7%. Median follow-up time was 15-months, with median PFS of 8.5-months and median OS 20.7-months. In a multivariate analysis of OS, the number of prior lines of therapy (≥5) and time to progression after initial transplant were the strongest predictors of OS.

Allogeneic HSCT for Relapse after Initial Autologous HSCT

Qazilbash et al. reported their experience with salvage autologous or allogeneic transplantation after a failed first autologous transplant. (51) Fourteen patients (median age, 52 years) received a second autologous transplant, and 26 patients (median age, 51 years) underwent a RIC-allogeneic transplant. Median interval between first and second transplant was 25- and 17-months for the autologous and allogeneic groups, respectively. After a median follow-up of 18-months (range, 2- to 69-months) for the autologous group, median PFS was 6.8-months and OS was 29-months, respectively. After a median follow-up of 30-months (range, 13- to 66-months) for the allogeneic group, median PFS was 7.3-months and OS was 13-months. On univariate analysis, in the allogeneic group, an interval of greater than 1-year between the first and salvage transplants predicted a significantly better OS (p=0.02). None of the prognostic factors evaluated for the allogeneic group had a significant impact on survival in the autologous group (which included age, cytogenetics, type of donor, and chronic GVHD, among others).

European Group for Blood and Marrow Transplant (EBMT) analyzed 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. (52) Median age at RIC-allogeneic HSCT was 54-years, and 45% of patients had undergone 2 or more prior autologous transplants. Median OS and PFS from the time of allogeneic transplantation for the entire population were about 25-months 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 sex mismatch was associated with better PFS; fewer than 2 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 suggested patient and donor CMV seronegativity represent key prognostic factors for outcome after RIC-allogeneic HSCT for MM that relapses or progresses following 1 or more autologous transplants.

POEMS Syndrome

Systematic Reviews

A Cochrane review published in 2012 provided a comprehensive source on treatment of POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin-changes) syndrome. (11) The reviewers performed a broad literature search and identified no RCTs, no quasi-RCTs, no historically controlled trials, or trials with concurrent controls that met selection criteria. The Cochrane review included 6 small series of patients (total N=57 patients) who underwent autologous HSCT. Two-year survival rates ranged from 94% to 100%. The results suggested that, if all published experience with autologous HSCT was pooled, TRM would be 3 (2.7%) of 112. The reviewers cautioned that long-term outcomes with autologous HSCT have not been elucidated and require continuing study.

A second 2012 review article found that case series suggest most patients achieve at least some neurologic and functional improvement using conditioning doses of melphalan ranging from 140 to 200 mg/m2. (5) Responses have been reported as durable but relapse occurs. Symptomatic progression has typically been reported as rare, with most progressions identified as rising vascular endothelial growth factor (VEGF) and radiographic. This author also reported that long-term outcomes with autologous HSCT are unclear given the sparse numbers.

Case Series

A single-center series (Mayo Clinic) published in 2012 reported a 5-year OS of 94% and a PFS of 75% among 59 patients entered between 1999 and late 2011. (53) A second series (2014) included 9 patients with advanced POEMS syndrome who had an Eastern Cooperative Oncology Group (ECOG) Performance Status scores of 3 or 4 and were treated with high-dose melphalan therapy followed by autologous stem-cell transplantation from 2004 to 2011. (54) Eight patients achieved an initial hematologic response, 4 of whom had CRs. At a median follow-up of 44-months (range, 8- to 94-months), 7 patients were alive, with 3-year OS 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 improved 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.

Section Summary: POEMS Syndrome

There is a lack of RCT evidence for POEMS syndrome, but cohort studies and case series have reported improvement in symptoms and disease progression after HSCT. POEMS syndrome is rare and treatment options are few. In addition, the natural history of POEMS does not suggest that spontaneous improvement will occur in the absence of treatment.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT00998270

A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation Compare With Allogenic Bone Marrow Transplantation in Multiple Myeloma

185

Oct 2017

NCT01208662

A Randomized Phase III Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib, and Dexamethasone (RVD) to High-dose Treatment With Peripheral Stem-Cell Transplant in the Initial Management of Myeloma in Patients up to 65 Years of Age

660

Sep 2018

NCT02322320

Continued, Long-Term follow-Up and Lenalidomide Maintenance Therapy for Patients on BMT CTN 0702 (BMT CTN #Q07LT)

450

Dec 2018

NCT01109004

A Trial of Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem Autologous Transplant With Lenalidomide Maintenance for Patients With Multiple Myeloma (BMT CTN 0702)

750

May 2020

NCT01191060

Randomized Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib and Dexamethasone to High-Dose Treatment With ASCT in the Initial Management of Myeloma in Patients up to 65 Years of Age

700

Sep 2020

NCT01208766

A Randomized Phase III Study to Compare Bortezomib, Melphalan, Prednisone (VMP) With High Dose Melphalan Followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

1500

Apr 2021

Unpublished

NCT00546988

Multi Centre Trial of DSMM for Newly Diagnosed Multiple Myeloma up to 60 Years

600

Jan 2008 (unknown)

NCT00747877

Myeloma X Relapse (Intensive): A Phase III Study to Determine the Role of a Second Autologous Stem-Cell Transplant as Consolidation Therapy in Patients With Relapsed Multiple Myeloma Following Prior High-dose Chemotherapy and Autologous Stem-Cell Rescue

460

Apr 2012 (unknown)

NCT00670631

Tandem Autotransplantation for Multiple Patients With Less Than 12 Months of Preceding Therapy, Incorporating Bortezomib With the Transplant Chemotherapy and During Maintenance

204

Apr 2014 (unknown)

Table Key:

NCT: national clinical trial.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

In 2009, Blue Cross Blue Shield Association (BCBSA) requested and received clinical input from various physician specialty societies and academic medical centers. Results of clinical input from 2 reviewers revealed one reviewer agreed with the current policy statement related to tandem autologous/RIC-allogeneic and the other disagreed. Those providing input agreed with the other policy statements. (The conclusion that allogeneic HSCT is investigational for salvage therapy was a late addition to the policy and was not sent for clinical input.)

Again in 2013, BCBSA requested and received clinical input from academic medical centers and Blue Distinction Centers for Transplant. There was near-consensus that autologous HSCT is medically necessary for POEMS syndrome, and near-consensus that allogeneic and tandem HSCT is investigational for POEMS syndrome.

In response to requests, input was received in early 2016 from 1 academic medical center, 2 Blue Distinction Centers for Transplant, and 1 specialty medical society. There was consensus that allogeneic HSCT is investigational for newly diagnosed multiple myeloma or as salvage therapy after primary graft failure or for primary progressive disease.

Practice Guidelines and Position Statements

American Society for Blood and Marrow Transplantation (ASBMT)

In 2015, the ASBMT published evidence-based guidelines for the use of HSCT in patients with MM. (55) ASBMT recognized 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 have increasingly influenced decision making and allow individual tailoring of therapy. ASBMT guidelines do not address POEMS or other plasma cell dyscrasias besides MM.

American Society of Blood and Marrow Transplantation (ASBMT) et al.

In 2015, ASBMT, European Society of Blood and Marrow Transplantation (EBMT), Blood and Marrow Transplant Clinical Trials Network (BMTCTN), and International Myeloma Working Group (IWG) published joint guidelines based on an expert consensus conference. (56) These guidelines contained the following recommendations for HSCT as salvage therapy:

“…autologous HSCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HSCT, high-dose therapy with HSCT as part of salvage therapy should be considered standard; (2) High-does therapy and autologous HSCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HSCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HSCT can be used as bridging strategy to allogeneic HSCT; (4) The role of post-salvage HSCT 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 HSCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HSCT 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 HSCT in patients with MM [multiple myeloma] relapsing after primary therapy comparing to ‘best non-HSCT’ therapy.”

Regarding allogeneic HSCT…: “(1) Allogeneic HSCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HSCT and/or with high-risk features (i.e., cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HSCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HSCT 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 HSCT in patients with MM relapsing after primary therapy.”

Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART):

Treatment of Newly Diagnosed MM:

The 2012 consensus guideline on the management of newly diagnosed symptomatic MM: updated Mayo Stratification of Myeloma and Risk Adapted Therapy (mSMART) states there is a greater emphasis on delayed high-dose therapy and autologous stem-cell transplant (ASCT). (57) With improved induction therapies resulting in deeper responses, many patients are opting to collect their stem-cells and delay ASCT while undergoing prolonged induction. Recent evidence has supported this strategy, demonstrating the ongoing benefit of ASCT even when delayed.

Treatment of Relapsed MM:

Based on the 2012 mSMART MM update, if the patient is considered transplant eligible (off study), risk status should be determined. (58) If the patient is standard risk and relapsed after autologous transplant, repeat autologous transplant is an option, after a bortezomib or immunomodulatory derivative-containing regimen. If the standard-risk patient is relapsed after conventional chemotherapy, the recommendation is to proceed to autologous HSCT or to repeat the previous regimen to maximum response or 1 year. If the patient is high risk and relapses after an autologous transplant, an autologous followed by an allogeneic transplant is an option in selected patients. If a high-risk patient relapses after bortezomib or immunomodulatory-based initial therapy, autotransplant (followed by allogeneic in selected patients), is recommended.

International Myeloma Working Group (IWG)

The conclusions and recommendations of the consensus statement on the current status of allogeneic stem-cell transplantation for MM are as follows: Myeloablative allogeneic HSCT may cure a minority of patients but is associated with a high TRM, but could be evaluated in well-designed prospective clinical trials. (59) Nonmyeloablative allogeneic HSCT as first-line therapy is associated with lower TRM but a greater risk of relapse and convincing evidence is lacking that allogeneic HSCT improves survival compared with autologous HSCT.

National Comprehensive Cancer Network (NCCN) Practice Guidelines

Autologous HSCT

The NCCN considers autologous HSCT a category 1 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. (60)

Repeat autologous HSCT as salvage therapy may be considered for:

Patients initially treated with primary therapy alone followed by the first autologous HSCT when the disease relapsed, who now have progressive disease following the first autologous HSCT (category 2A); and

Patients who have progressive disease after the first autologous HSCT (category 2A).

Tandem Autologous HSCT

The NCCN myeloma panel has recommended collecting enough stem-cells for 2 transplants in all eligible patients. (60) A tandem transplant can be considered for all patients who are candidates for HSCT, and is an option for patients who do not achieve at least a very good partial response after the first autologous HSCT (category 2A).

Allogeneic HSCT

Myeloablative allogeneic HSCT is an accepted option in the setting of a clinical trial (category 2A) in patients with responsive or primary progressive disease or as salvage therapy in patients with progressive disease following an initial autologous HSCT. (60) Allogeneic HSCT may include nonmyeloablative (mini) following an autologous stem-cell transplant or fully myeloablative preferably on a clinical trial. Current data do not support mini allografting alone.

POEMS Syndrome

NCCN guidelines do not address the treatment of POEMS syndrome. (60)

Summary of Evidence

Newly Diagnosed Multiple Myeloma (MM)

For individuals who have newly diagnosed MM who receive autologous hematopoietic stem-cell transplantation (HSCT) as initial treatment, the evidence includes several prospective, randomized controlled trials (RCTs) that compared conventional chemotherapy to high-dose chemotherapy with autologous HSCT. Relevant outcomes include overall survival (OS) and treatment-related morbidity (TRM). In general, the evidence has suggested overall survival rates are improved with autologous HSCT 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. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have newly diagnosed MM who receive tandem autologous HSCT followed by reduced-intensity conditioning- (RIC) allogeneic HSCT, the evidence includes several RCTs comparing RIC-allogeneic HSCT following a first autologous HSCT with autologous transplants, single or in tandem (these studies were based on “genetic randomization,” i.e., patients with a human leukocyte antigen- (HLA) identical sibling were offered an RIC-allogeneic HSCT following autologous HSCT, whereas other patients underwent either 1 or 2 autologous transplants). Relevant outcomes include OS and TRM. Although the body of evidence has shown inconsistencies in terms of OS and disease-free survival (DFS) rates, some studies have shown a survival benefit with tandem autologous HSCT followed by RIC-allogeneic HSCT, although at a cost of higher TRM 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 qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have newly diagnosed MM who receive allogeneic HSCT with myeloablative or nonmyeloablative conditioning for initial or salvage treatment, the evidence includes nonrandomized studies. Relevant outcomes include OS and TRM. 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. Nonmyeloablative allogeneic HSCT as first-line therapy is associated with lower TRM but a greater risk of relapse; convincing evidence is lacking that allogeneic HSCT improves survival better than autologous HSCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

Relapsed or Refractory MM

For individuals who have relapsed MM following autologous HSCT who receive autologous HSCT, the evidence includes 1 RCT and a systematic review that summarized data from 4 clinical series of patients who relapsed after a first autologous HSCT. Relevant outcomes include OS and TRM. In general, the evidence has suggested OS rates are improved with autologous HSCT 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. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have refractory MM who receive tandem autologous HSCT after failing the first transplant, the evidence includes 3 RCTs. Relevant outcomes include OS and TRM. The evidence has shown tandem autologous HSCT improves OS rates 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. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

POEMS Syndrome

For individuals who have POEMS syndrome who receive HSCT, the evidence includes case reports and series. Relevant outcomes include OS and TRM. No RCTs of HSCT 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 with respect to treatment approaches and peri-transplant support. However, for patients with disseminated POEMS syndrome, a chain of indirect evidence and contextual factors related to the disease and multiple myeloma suggests improvement in health outcomes with autologous HSCT. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. Mar 15 2008; 111(6):2962-72. PMID 18332230

2. Palumbo A, Rajkumar SV. Treatment of newly diagnosed myeloma. Leukemia. Mar 2009; 23(3):449-56. PMID 19005483

3. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. Sep 2006; 20(9):1467-1473. PMID 16855634

4. Dispenzieri A. Long-term outcomes after autologous stem-cell transplantation in patients with POEMS syndrome. Clin Adv Hematol Oncol. Nov 2012; 10(11):744-6. PMID 23271262

5. Dispenzieri A. POEMS syndrome: update on diagnosis, risk-stratification, and management. Am J Hematol. Aug 2012; 87(8):804-14. PMID 22806697

6. Bardwick PA, Zvaifler NJ, Gill GN, et al. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Baltimore). Jul 1980; 59(4):311-22. PMID 6248720

7. Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood. Apr 1 2003; 101(7):2496-506. PMID 12456500

8. 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):476-9. PMID 22338030

9. Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood stem-cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood. Nov 15 2004; 104(10):3400-7. PMID 15280195

10. Singh D, Wadhwa J, Kumar L, et al. POEMS syndrome: experience with fourteen cases. Leuk Lymphoma. Oct 2003; 44(10):1749-52. PMID 14692529

11. 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. PMID 22696361

12. Dispenzieri A. How I treat POEMS syndrome. Blood. Jun 14 2012; 119(24):5650-8. PMID 22547581

13. Reece DE. Recent trends in the management of newly diagnosed multiple myeloma. Curr Opin Hematol. Jul 2009; 16(4):306-312. PMID 19491669

14. Reece D, Harousseau JL, Gertz MA. Myeloma Management 2009: Nontransplant therapy of myeloma, high-dose therapy for myeloma, and a personalized care plan for treatment of myeloma. 2009 American Society of Clinical Oncology Annual Meeting Educational Handbook. pp. 502-9.

15. Qiao SK, Guo XN, Ren JH, et al. Efficacy and Safety of Lenalidomide in the Treatment of Multiple Myeloma: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Chin Med J (Engl). 5th May 2015; 128(9):1215-22. PMID 25947406

16. Fonseca R. Strategies for risk-adapted therapy in myeloma. 2007 ASH Annual Meeting Education Program 2007. Available at <http://asheducationbook.hematologylibrary.org> (accessed on 2008 July 3).

17. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011; 86(1):57-65. PMID 21181954

18. Larocca A, Palumbo A. Evolving paradigms in the treatment of newly diagnosed multiple myeloma. J Natl Compr Canc Netw. Oct 2011; 9(10):1186-96. PMID 21975915

19. van de Donk N, Lokhorst HM, Dimopoulos M et al. Treatment of relapsed and refractory multiple myeloma in the era of novel agents. Cancer Treat Rev. June 2011; 37(4):266-83.

20. Nishihori T, Alsina M. Advances in the autologous and allogeneic transplantation strategies for multiple myeloma. Cancer Control. 2011; 18(4):258-67. PMID 20863623

21. 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 randomized, multicentre, phase 3 trial. Lancet Oncol. Dec 2015; 16(16):1617-29. PMID 26596670

22. Attal M, Harousseau JL. The role of high-dose therapy with autologous stem-cell support in the era of novel agents. Semin Hematol. Apr 2009; 46(2):127-32. PMID 19389499

23. Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. Jul 11 1996; 335(2):91-7. PMID 8649495

24. Barlogie B, Kyle RA, Anderson KC et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial 9321. J Clin Oncol. Feb 20 2006; 24(6):929-36. PMID 16432076

25. Blade J, Rosinol L, Sureda A et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish Cooperative Group PETHEMA. Blood. Dec 1 2005; 106(12):3755-9. PMID 16105975

26. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. May 8 2003; 348(19):1875-83. PMID 12736280

27. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem-cell transplantation in multiple myeloma: upfront or rescue treatment? Results of a multicenter sequential randomized trial. Blood. Nov 1 1998; 92(9):3131-6. PMID 9787148

28. Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50-70: results of a randomized controlled trial. Blood. Nov 15 2004; 104(10):3052-7. PMID 15265788

29. 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. Feb 2007; 13(2):183-96. PMID 17241924

30. Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood. Oct 1 1996; 88(7):2787-93. PMID 8839877

31. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. Dec 25 2003; 349(26):2495-502. PMID 14695409

32. Stadtmauer EA. Multiple myeloma, 2004--one or two transplants? N Engl J Med. Dec 25 2003; 349(26):2551-3. PMID 14695416

33. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. Jun 10 2007; 25(17):2434-41. PMID 17485707

34. Garban F, Attal M, Michallet M, et al. 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. May 1 2006; 107(9):3474-80. PMID 16397129

35. 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):3914-5. PMID 1894858

36. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. Mar 15 2007; 356(11):1110-20. PMID 17360989

37. Rosinol L, Perez-Simon JA, Sureda A, et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. Nov 1 2008; 112(9):3591-3. PMID 18612103

38. Lokhorst H, Mutis, I. Allogeneic transplantation and immune interventions in multiple myeloma. Hematology Education: the education program for the annual congress of the European Hematology Association (2008). 2008; 2:106-14.

39. Bjorkstrand B, Iacobelli S, Hegenbart U, et al. 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 (Oral Sessions and Working Party) 246. Mar 2008; 41(S1):S38. Epub March 2008

40. Gahrton G, Iacobelli S, Bjorkstrand B, et al. Autologous/reduced-intensity allogeneic stem-cell transplantation versus autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. Jun 20 2013; 121(25):5055-63. PMID 23482933

41. 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. Dec 2011; 12(13):1195-203. PMID 21962393

42. Harousseau JL. The allogeneic dilemma. Bone Marrow Transplant. Dec 2007; 40(12):1123-8. PMID 17680016

43. Crawley C, Iacobelli S, Bjorkstrand B, et al. Reduced-intensity conditioning for myeloma: lower non relapse mortality but higher relapse rates compared with myeloablative conditioning. Blood. Apr 15 2007; 109(8):3588-94. PMID 17158231

44. Gahrton G, Bjorkstrand B. Allogeneic transplantation in multiple myeloma. Haematologica. Sep 2008; 93(9):1295-300. PMID 18757850

45. 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. PMID 24141007

46. Giralt S, Koehne G. Allogeneic hematopoietic stem-cell transplantation for multiple myeloma: what place, if any? Curr Hematol Malig Rep. Dec 2013; 8(4):284-90. PMID 24146203

47. Olin RL, Vogl DT, Porter DL, et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplant. Mar 2009; 43(5):417-22. PMID 18850013

48. Cook G, Williams C, Brown JM, et al. 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 randomized, open-label, phase 3 trial. Lancet Oncol. Jul 2014; 1 5(8):874-85. PMID 24948586

49. Cook G, Ashcroft AJ, Cairns DA, et al. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomized, open-label, phase 3 trial. Lancet Haematol. Jul 2016; 3(7):e340-51. PMID 27374467

50. 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; (1):4-37. PMID 12533739

51. Qazilbash MH, Saliba R, De LM, et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer. Mar 1 2006; 106(5):1084-9. PMID 16456814

52. Auner HW, Szydlo R, van Biezen A, et al. 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):1395-400. PMID 23708704

53. D'Souza A, Lacy M, Gertz M, et al. Long-term outcomes after autologous stem-cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood. Jul 5 2012; 120(1):56-62. PMID 22611150

54. 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):42-8. PMID 24724066

55. Shah N, Callander N, Ganguly S, et al. Hematopoietic Stem-cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Mar 11 2015. PMID 25769794

56. 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):2039-51. PMID 26428082

57. 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):360-76. PMID 23541011

58. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management AM J Hematol. 2012 Jan; 87 (1) 78-88. 2012.

59. 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):4521-30. PMID 20697091

60. NCCN – National Comprehensive Cancer Network. Multiple Myeloma. Clinical Practice Guidelines in Oncology, Version 3.2017. Available at: <http://www.nccn.org> (accessed on January 24, 2017).

61. High-Dose Chemotherapy with Autologous Stem-Cell Support for Multiple Myeloma. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Assessments 1996; Volume 11, Tab 14.

62. Allogeneic Bone Marrow Transplantation for Multiple Myeloma. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Assessments 1996; Volume 11, Tab 28.

63. Tandem High-Dose Chemotherapy with Autologous Stem-Cell Support for Newly Diagnosed or Responsive Multiple Myeloma. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Assessments 1998; Volume 13, Tab 8.

64. Single or Tandem High-Dose Chemotherapy with Autologous Stem-cell Support for Resistant Multiple Myeloma. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Assessments 1998; Volume 13, Tab 26.

65. Food and Drug Administration (FDA). Tissue and Tissue Products. Available at http://www.fda.gov> (accessed September 22, 2015).

66. Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 January) Therapy 8.01.17.

Policy History:

Date Reason
4/15/2018 Reviewed. No changes.
4/1/2017 Document updated with literature review. Coverage unchanged. Title changed from “Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma (MM).”
7/1/2016 Reviewed. No changes.
4/15/2016 Document updated with literature review. The following was added to coverage: 1) Autologous hematopoietic stem-cell transplant may be considered medically necessary to treat disseminated POEMS syndrome, including patients having diffuse sclerotic lesions or disseminated bone marrow involvement; and 2) Allogeneic and tandem hematopoietic stem-cell transplantations are considered experimental, investigational and/or unproven to treat POEMS syndrome. The following was removed from coverage: Allogeneic HSCT may be considered medically necessary to treat patients with stage I, II, or III MM who have completed first-line therapy; or have a human leukocyte antigen- (HLA-) identical donor. Otherwise coverage unchanged. Title changed from Stem-Cell Transplant for Multiple Myeloma (MM).
6/1/2014 Document updated with literature review. The following was added: 1) Allogeneic stem-cell support (AlloSCS) is considered experimental, investigational and/or unproven for newly diagnosed or untreated multiple myeloma (MM) or as salvage therapy after a failed course of autologous stem-cell support (AutoSCS); 3) Tandem Auto-AutoSCS may be medically necessary to treat MM in patients who fail to achieve a least a new-complete response or a very good partial response; 4) Tandem or Triple SCS is considered experimental, investigational and/or unproven in all other sequences or combinations not included in the coverage statement; the addition of a complete remission and a very good partial remission when a single AutoSCS regimen may be considered medically necessary; 5) Expanded coverage to consider a) donor leukocyte infusion (DLI) and hematopoietic progenitor cell (HPC) boost as medically necessary for MM that has relapsed, to prevent relapse in the setting of a high-risk relapse, or to convert a patient from mixed to full chimerism; b) DLI and HPC boost are considered experimental, investigational and/or unproven following an AlloSCS treatment for MM that was originally considered experimental, investigational and/or unproven for the treatment of MM OR as a treatment prior to AlloSCS; and 6) Expanded coverage to consider a) short tandem repeat (STR) markers as medically necessary when used in pre- or post-stem-cell support testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment following AlloSCS for MM; b) all other uses of STR markers as experimental, investigational and/or unproven, if not listed in the coverage section. Description and Rationale significantly revised.
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies. Stem-cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem-cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies.

Archived Document(s):

Back to Top