Coverage Policy Manual
Policy #: 2000009
Category: Medicine
Initiated: November 1992
Last Review: June 2018
  HDC & Autologous Stem &/or Progenitor Cell Support-Multiple Myeloma

Description:
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.  However, multiple myeloma rarely is cured with standard-dose chemotherapy, prompting interest in myeloablative chemotherapy with either autologous or allogeneic SCT. There has also been interest in tandem SCT to further reduce the relapse rate seen after a single course of SCT. In addition, treatment options are evolving rapidly with newer agents such as bortezomib, thalidomide, and lenalidomide.
 
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 term HDC when applicable.  HDC results in marrow ablation and thus HDC is accompanied by a reinfusion of stem cells in order to repopulate the bone marrow.  
  
Sources of Stem Cells:
Autologous stem cells may be harvested from the patient's bone marrow or peripheral blood.  Peripheral cells are harvested via one or more pheresis procedures.  Pretreatment with chemotherapy and/or hemapoietic growth factors can increase the number of circulating stem cells .Syngeneic stem cells refer to genetically identical bone marrow or peripheral stem cells harvested from an identical twin.    
 
Reimbursement for high dose chemotherapy (HDC) with stem and/or progenitor cell transplant that has been pre-authorized is made as a global fee limited to the lesser of billed charges or the average allowable charge authorized by the Blue Quality Centers for Transplant in the geographic region where the transplant is performed.  This global payment includes all related transplant services including institutional, professional, ancillary, and organ procurement.  The global period begins one day prior to the date of the transplant and continues for 48 days after the transplant.  This covers the inpatient/outpatient stay and provides a per diem outlier payment if necessary.  This global fee also includes the cost of complications arising from the original procedure when services are rendered within the global postoperative period for the particular transplant.
 
Treatment of POEMS syndrome (also known as osteosclerotic myeloma, Crow-Fukase syndrome, or Takasuki syndrome) is addressed in a separate policy # 2013036.
 

Policy/
Coverage:
Effective March 2011
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of myeloma meets primary coverage criteria for effectiveness for the treatment of:
    • newly diagnosed or responsive multiple myeloma;
    • responsive myeloma that has relapsed after a durable complete or partial remission following an initial autologous transplant.
 
Tandem high-dose chemotherapy with autologous stem-cell support to treat newly diagnosed or responsive multiple myeloma meets primary coverage criteria for effectiveness and is covered when medically indicated.  Only two (2) courses of therapy given in tandem are covered.
   
Tandem high-dose chemotherapy is considered to be a second course of myeloablative chemotherapy followed by autologous stem-cell support given within  3 to 6 months of the initial course.
  
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
An initial treatment of myeloablative chemotherapy-autologous stem cell transplant followed by non-myeloablative chemotherapy and allogeneic stem-cell support from a HLA-identical sibling donor does not meet member certificate of benefit primary coverage criteria for safety and effectiveness.  
  
Note- 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 microglobulin or monoclonal immunoglobulins, both considered tumor markers for multiple myeloma.  
  
Refractory or resistant is defined as a tumor response of less than 50%.
  
High-dose chemotherapy with autologous stem-cell support to treat multiple myeloma in a refractory relapse is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  
   
For contracts without primary coverage criteria, high-dose chemotherapy with autologous stem-cell support to treat multiple myeloma in a refractory relapse is considered investigational and is not covered.  Investigational services are exclusions in the member certificate of coverage.  
 
Effective 2007
High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of myeloma meets primary coverage criteria for effectiveness for the treatment of:
    • newly diagnosed or responsive multiple myeloma;
    • responsive myeloma that has relapsed after a durable complete or partial remission following an initial autologous transplant.
 
Tandem high-dose chemotherapy with autologous stem-cell support to treat newly diagnosed or responsive multiple myeloma meets primary coverage criteria for effectiveness and is covered when medically indicated.  Only two (2) courses of therapy given in tandem are covered.
   
Tandem high-dose chemotherapy is considered to be a second course of  myeloablative chemotherapy followed by autologous stem-cell support given within 3 to 6 months of the initial course.
  
An initial treatment of myeloablative chemotherapy-autologous stem cell transplant followed by non-myeloablative chemotherapy and allogeneic stem-cell support from  an HLA-identical sibling donor meets member certificate of benefit primary coverage criteria for newly diagnosed patients 65 years of age or less and in otherwise reasonably good health.
  
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 microglobulin or monoclonal immunoglobulins, both considered tumor markers for multiple myeloma.  
  
Refractory or resistant is defined as a tumor response of less than 50%.
  
High-dose chemotherapy with autologous stem-cell support to treat multiple myeloma in a refractory relapse is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  
   
For contracts without primary coverage criteria, high-dose chemotherapy with autologous stem-cell support to treat multiple myeloma in a refractory relapse is considered investigational and is not covered.  Investigational services are exclusions in the member certificate of coverage.  
 
 
 
Effective prior to 2007
High dose chemotherapy with autologous bone marrow, stem cell, or progenitor cell support for the treatment of myeloma meets primary coverage criteria for effectiveness and is covered:
    • to treat newly diagnosed or responsive multiple myeloma;
    • to treat responsive myeloma that has relapsed after a durable complete or partial remission following an initial autologous transplant.
 
Tandem high-dose chemotherapy with autologous stem-cell support to treat newly diagnosed or responsive multiple myeloma meets primary coverage criteria for effectiveness and is covered when medically indicated.  Only two (2) courses of therapy given in tandem are covered.
 
High-dose chemotherapy with autologous stem-cell support to treat multiple myeloma in a refractory relapse is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  
 
For contracts without primary coverage criteria, high-dose chemotherapy with autologous stem-cell support to treat multiple myeloma in a refractory relapse is considered investigational and is not covered.  Investigational services are exclusions in the member certificate of coverage.
 
An initial course of high-dose chemotherapy with autologous stem-cell support followed by non-marrow-ablative chemotherapy and allogeneic stem-cell support (i.e., “mini-transplant”) to treat multiple myeloma is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  
 
For contracts without primary coverage criteria, an initial course of high-dose chemotherapy with autologous stem-cell support followed by non-marrow-ablative chemotherapy and allogeneic stem-cell support (i.e., “mini-transplant”) to treat multiple myeloma is considered investigational and is not covered. Investigational services are exclusions in the member certificate of coverage.
 
 

Rationale:
Single Transplant
The policy on high-dose chemotherapy with autologous stem cell support (HDC AuSCS) as treatment for multiple myeloma specifically looked at patients with newly diagnosed, responsive multiple myeloma or refractory or resistant myeloma. Responsive myeloma is defined as tumors achieving a complete or partial (at least 50% tumor reduction) response to chemotherapy, while resistant or refractory multiple myeloma is defined as those tumors achieving a less than 50% reduction in tumor burden.   
 
Newly Diagnosed or Responsive Multiple Myeloma
The available data support the conclusion that HDC AuSCS is at least as effective, and may be more effective, than conventional dose chemotherapy for improving the health outcomes of the above patients. In a key randomized trial, the outcomes of high-dose therapy were clearly better than conventional chemotherapy.
  
Resistant or Refractory Multiple Myeloma
In contrast, insufficient data were available to support a conclusion regarding the outcomes HDC AuSCS in patients with refractory myeloma. Most of the data consisted of uncontrolled clinical series of patients. No randomized controlled trials were reported.
  
Tandem Transplant
This policy regarding tandem transplantation references two 1998 Blue Cross Blue Shield Association Technology Evaluation Center assessments, focusing on tandem transplants for newly diagnosed or responsive multiple myeloma and resistant multiple myeloma. The following conclusions were offered:
 
Newly Diagnosed or Responsive Multiple Myeloma
Only 5 published studies were found that provided data on the outcomes of treatment in patients receiving tandem transplant. Although one of the studies is a randomized study, the available data are still preliminary and do not permit
conclusions on survival. The University of Arkansas has reported an extensive non-randomized, single-institution case series of multiple myeloma treated with tandem transplant; however, the data compared results to historical controls
treated with conventional-dose regimens and not to a single cycle of HDC AuSCS, considered the gold standard for comparison.
When using previously published outcomes of patients receiving a single cycle of HDC AuSCS as historical controls, the policy found considerable overlap in the results reported for tandem and single transplant for nearly all of the
outcomes of interest. These data were considered inadequate to permit conclusions regarding the health benefits associated with tandem transplant.  Data on the duration of survival after tandem transplant are scant and nearly all
other outcomes data are only available from single-arm studies with highly selected patients. Thus the comparison of outcomes is subject to a high degree of patient selection bias.
  
Refractory or Resistant Multiple Myeloma
Two reports with a total of 69 patients treated at one institution and a third report with 30 patients provided the only data on the outcomes of tandem transplant for treatment of resistant multiple myeloma. There was no control group for direct comparison of outcomes in the most updated reports on the larger series of highly selected patients. The earlier report from this institution and the third paper included non-randomized control groups, but aggregated outcomes for patients with resistant myeloma and those transplanted as part of first-line therapy. In addition, insufficient detail was provided to determine if the patients given tandem transplant for resistant myeloma were sufficiently comparable to those given either single high-dose chemotherapy or conventional-dose salvage therapy to permit conclusions based on indirect
comparison of outcomes from separate studies. Thus the available data were not sufficient to permit conclusion on the outcomes of tandem transplant.
  
High-dose Chemotherapy and Allogeneic Stem Cell Support
No studies directly comparing the outcomes of high-dose chemotherapy with allogeneic stem cell support (HDC Allo SCS) with either conventional chemotherapy or high-dose chemotherapy with autologous stem cell support have been reported. One retrospective study directly compared the outcomes of allogeneic support with those of autologous support. However this report only provided outcomes that were combined for all myeloma patients, regardless of
whether their disease was responsive or refractory to treatment.  Indirect comparisons suggest that allogeneic stem cell support is associated with a 39%–55% 5-year survival, while the comparable figure for autologous stem cell support is 36%–52%.
  
A review of the literature since 1996 does not provide data to alter the above conclusion. In a 1999 review of the data regarding allogeneic stem cell support,  Kyle reported a mortality rate of 25% within 100 days and overall transplant-related mortality of approximately 40%. In addition, relapse of multiple myeloma is common such that few patients are cured.  Candidates for HDC Allo SCS tend to be younger than the average age of patients with multiple myeloma and in better overall condition and thus may have a better prognosis no matter what the treatment. Therefore, randomized trials are required to determine whether any possible benefit associated with HDC Allo SCS is truly related to the therapy rather than the underlying patient selection criteria.
  
High-dose Chemotherapy and Allogeneic Stem Cell Support After a Failed Prior Course of High-dose Chemotherapy and Autologous Stem Cell Support
The policy focused on HDC Allo SCS after a prior failed course of HDC Auto SCS in the treatment of a variety of malignancies, including multiple myeloma.  There were inadequate data to permit conclusions about this treatment strategy.
 
2007 Update
Research continues on many aspects of treatment for multiple myeloma, such as chemotherapy regimens and SCT. The Web site, www.clinicaltrials.gov, lists 305 studies relating to multiple myeloma currently recruiting patients. The current policy may change as additional results, especially with longer follow-up, are released. This review resulted in a policy statement regarding tandem SCT with an autograft followed by an allograft in younger, newly diagnosed patients.  This decision was based primarily on a recent study (Bruno, 2007) using “genetic randomization,” i.e., 80 patients with an HLA-identical sibling were allowed to chose allografts or autografts for the second transplant (58 completed an autograft/allograft sequence) and 82 without an HLA-identical sibling who 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 OS 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 autograft/allograft group; 32% of the latter group has extensive, chronic GVHD.
 
A meta-analysis of randomized controlled trials compared chemotherapy versus myeloablative chemotherapy with single auto-SCT (Koreth, 2007).  The 9 trials that met the selection criteria (N=2,411) started enrolling patients in the 1990s and include the 2 studies mentioned above that did not detect a survival benefit from myeloablative chemotherapy (Child, 2003; Attal, 1996). The authors of the meta-analysis concluded that myeloablative therapy with auto-SCT increased the likelihood of progression-free survival (hazard of progression=0.75; 95% CI: 0.59-0.96) but not OS (hazard of death=0.92; 95% CI: 0.74-1.13); the odds ratio for treatment-related mortality was 3.01 (95% CI: 1.64-5.50) in the group with auto-SCT. However, the effects of myeloablative chemotherapy and auto-SCT may have been diluted by the fact that up to 55% of patients in the standard chemotherapy group received myeloablative chemotherapy with auto-SCT as salvage therapy when the multiple myeloma progressed. This could account for the lack of a significant difference in OS between the two groups in the study.
 
Finally, results of the Bologna 96 clinical study have been released (Cavo, 2007), comparing single with double autologous SCT (n=321). Patients undergoing tandem auto-SCT were more likely than those with a single SCT to attain at least a near complete response (47% vs. 33%; p=0.008), to prolong relapse-free survival (median, 42 vs. 24 months; p<0.001), and extend event-free survival (median, 35 vs. 23 months; p=0.001). There was a difference between single and double auto-SCT only for patients who initially responded to VAD. There was no significant difference between the groups in treatment-related mortality (3%–4%). This study supports the use of tandem autografts; it does not address the costs and benefits of novel chemotherapy regimens versus auto-SCT, which is currently being studied, or of autografts versus allografts for the second round of SCT.
 
2008 Update
The policy was updated with a literature search using PubMed in June 2008. Treatment of multiple myeloma has been evolving over the past few years with the use of newer agents including bortezomib, thalidomide, and lenalidomide. A recent review (Koreth, 2007) noted that, “the need for early ASCT [autologous SCT] in an era of new drugs is the most important clinical question in myeloma today.”  
For those with primary progressive disease (disease progression during induction therapy), a risk-adapted approach to treatment is recommended (Stewart, 2007; Fonseca , 2007). This risk-adapted approach is based on several large studies that have shown that patients defined as high risk genetically do not derive durable responses to auto-SCT strategies and may relapse within 1 year of treatment. However, patients with primary progressive disease who do not have these characteristics are considered candidates for auto-SCT. Emerging studies suggest that early introduction of bortezomib results in better quality of response and prolonged survival for high-risk patients.
 
Stewart (2007) suggests an approach to separate the 25% of patients at high risk from those at standard risk. This involves the detection of t(4:14), t(14:16), or 17p deletion by FISH assay, chromosome 13 deletion or hypodiploidy by karyotyping, or plasma cell labeling index greater than 3%. Finding one abnormality identifies a patient at high risk in this approach. In addition, patients with beta-2-microglobulin levels greater than 5.5 mg per liter are often considered high risk.
 
Interest continues in use of allogeneic SCT in multiple myeloma. As noted in a recent review (Bensinger, 2007), despite improvements in survival for multiple myeloma patients, the disease remains incurable for most.  Allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. However, high transplant-related mortality with allo-SCT is a major limitation to wider use of this modality. While mortality can be reduced through the use of RIC regimens, this comes at a cost of higher rates of disease progression and relapse. Studies are ongoing in an attempt to improve overall outcomes of allogeneic SCT. In addition, the risk of chronic GVHD is significant with RIC-allo-SCT.
 
2009 Update
Using search terms myeloma and transplant at www.clinicaltrials.gov results in identification of 555 trials, 251 of which are recruiting.  A PubMed literature search through Sept 2009 was done.
 
Rotta et al (2009) reported long term results of 102 patients treated with auto/allo HCT.  Forty-two percent of the patients developed grade 2 to 4 GVHD and 74% developed chronic GVHD.  Among 95 patients with detectable disease, 59 achieved complete remissions. Five-year nonrelapse mortality was 18% with 95% of that attributable to GVHD or infection.
 
Bensinger, in another review article in 2009, continues to state that the disease remains incurable for all but a small fraction of patients despite good response rates with new drugs and the mortality associated with allogeneic transplants.
 
Vesole (2009) reported results of 32 patients enrolled in a Phase II trial of autologous stem cell transplant followed by a mini-allogeneic stem cell transplant.  Twenty-three patients completed both transplants.  There were 7 complete and 11 partial remissions, 2 with no response and 3 were not evaluable.  Acute grade III-IV GVHD was seen in 4 patients, chronic GVHD in 13 patients.  “Because a plateau in PFS or OS was not observed with this treatment approach even in patients achieving CR, we suggest that future studies use posttransplantation maintenance therapy.”
 
In a review and meta-analysis of tandem versus single autologous hematopoietic cell transplantation to treat multiple myeloma, Kumar (2009) looked at six RCTs enrolling 1803 patients meeting inclusion criteria.  Patients with tandem AHCT did not have better OS or EFS.  They did have statistically significant response rates but this was associated with a statistically significant increase in treatment-related mortality.
No literature was identified that would support a revision in the current coverage statements.
 
2011 Update
In December 2010, at the American Society of Hematology annual meeting in Orlando, Drs. Amrita Krishnan and Edward Stadtmauer presented 3-year preliminary results of a phase III trial that enrolled 710 patients with standard risk myeloma in 43 centers in the United States.  All patients received high-dose melphalan and an autologous stem cell transplant.  The 484 patients without a sibling match were to receive a second autologous transplant with Melphalan ("allo-allo").  The 226 who had a sibling match were to received a nonmyeloablative conditioning regimen followed by an allogeneic stem cell transplant and 2 Gy of total body irradiation ("allo-auto").  In each group 82% went on to a second transplant.  For those patients who received a second transplant progression free survival rates, overall survival rates and progression/relapse rates were similar in both groups.  Treatment related mortality was significantly different in the two groups; 4% for the allo-allo group and 12% for the allo-auto group.  Dr. Stadtmauer commented:  "This is a preliminary result but it certainly is not supportive of routine use of nonmyeloablative allogeneic transplant in standard-risk patients. …With longer-term follow-up, if these results hold out, then I think our enthusiasm will disappear."
 
2013 Update
A search of the MEDLINE database was conducted through September 2013. There was no new information identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through September 2014 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 (Auner, 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) 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, 2014).
 
A single-center series published in 2012 from Mayo Clinic reported a 5-year OS of 94% and a PFS of 75% among 59 patients entered between 1999 and late 2011. 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.
 
2015 Update
A literature search conducted through September 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In a multicenter, randomized, open-label, phase 3 study from 51 centers across the United Kingdom, between April 16, 2008, and November 19, 2012, Cook and colleagues recruited patients aged at least 18 years with MM who needed treatment for first progressive or relapsed disease at least 18 months after a previous autologous HSCT (NCT00747877) and EudraCT (2006-005890-24) (Cook, 2014). 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 either 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 intention to treat. A total of 297 patients were enrolled, of whom 293 received PAD re-induction 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 than in the cyclophosphamide group (19 months [95% CI, 16 to 25] vs 11 months [95% CI, 9 to 12]; hazard ratio, 0.36 [95% CI, 0.25 to 0.53]; p<0.001). Frequently reported (>10% of patients) grade 3-4 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 vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, 60 [72%] vs 4 [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). This study provides additional evidence for a net benefit of high-dose melphalan plus salvage HSCT when compared with cyclophosphamide in patients with relapsed MM eligible for intensive therapy.
 
Multiple Myeloma
The evidence for autologous hematopoietic stem cell transplantation (HSCT) for upfront treatment in patients who have newly diagnosed multiple myeloma consists of several prospective, randomized controlled trials (RCTs) that compared conventional chemotherapy with high-dose chemotherapy with autologous HSCT. Clinical outcomes of interest include overall survival (OS) and treatment-associated morbidity. In general, the evidence suggests 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. These limitations notwithstanding, the body of evidence on autologous HSCT for treatment of patients with newly diagnosed multiple myeloma is sufficient to demonstrate improvements in health outcomes
 
The evidence for autologous HSCT for treatment of relapsed MM following autologous HSCT, or refractory disease consists of 1 RCT and a systematic review that summarized data from 4 clinical series of patients who relapsed after a first autologous HSCT. Clinical outcomes of interest include OS and treatment-related morbidity. In general, the evidence suggests 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. These limitations notwithstanding, the body of evidence on autologous HSCT for treatment of patients with relapsed MM or refractory disease is sufficient to demonstrate improvements in health outcomes.
 
The evidence for tandem autologous HSCT in patients who have MM who fail to achieve at least a near complete or very good partial response after the first transplant in the tandem sequence (ie, refractory disease) consists of 3 RCTs. Clinical outcomes of interest include OS and treatment-related morbidity. The evidence shows 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. These limitations notwithstanding, the body of evidence on tandem autologous HSCT for treatment of patients with MM in this setting is sufficient to demonstrate improvements in health outcomes.
 
The evidence for tandem autologous HSCT followed by reduced-intensity conditioning (RIC) allogeneic HSCT in patients who have newly diagnosed MM comprises 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,” that is, patients with an HLA-identical sibling were offered an RIC-allogeneic HSCT following the autologous HSCT, whereas the other patients underwent either 1 or 2 autologous transplants. Clinical outcomes of interest include OS and treatment-related morbidity. Although the body of evidence shows inconsistencies in terms of OS and DFS rates, some studies have shown a survival benefit with tandem autologous-RIC allogeneic HSCT, although at a cost of higher transplant-related mortality compared with conventional treatments. Factors across studies that may account for differing trial results include different study designs; nonuniform preparative regimens; different patient characteristics (including risk stratification); and, criteria for advancing to a second transplant. These limitations notwithstanding, the body of evidence on tandem autologous HSCT followed by RIC allogeneic HSCT for treatment of patients with MM is sufficient to demonstrate improvements in health outcomes.
 
American Society for Blood and Marrow Transplantation (Shah, 2015).
In 2015, the American Society for Blood and Marrow Transplantation (ASBMT) published evidence-based guidelines for the use of HSCT in patients with MM. These guidelines are generally consistent with the conclusions of this evidence review based on published literature through December 31, 2014. ASBMT recognizes that much of the RCT evidence summarized in the 2015 guidelines comes from trials that predate the advent of novel triple therapy induction regimens. Furthermore, advances in supportive care and earlier disease detection has increasingly influenced decision making and allows individual tailoring of therapy. ASBMT guidelines do not address POEMS or other plasma cell dyscrasias besides MM.
 
2017 Update
A literature search conducted through September 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 2015 randomized controlled trial (RCT) compared autologous HCT to standard chemotherapy plus lenalidomide, a newer agent for treatment of MM (Gay, 2015). The open-label RCT from 59 centers in Europe and Australia 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 plus standard consolidation (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 the chemotherapy groups (hematologic events, 84% vs 26%; gastrointestinal complications, 20% vs 5%; infections, 19% vs 5%; all respectively).
 
Final survival data for the Myeloma X Relapse trial were reported in 2016 (Cook, 2016). The HCT group had superior median OS (67 months; 95% CI, 55 months to not estimable) compared to the chemotherapy group (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.
 
NEWLY DIAGNOSED MM
 
Early vs Delayed HCT
A 2017 retrospective analysis by Dunavin et al compared survival and relapse rates in 167 patients who were treated for MM between 2002 and 2009 with induction therapy and autologous HCT (Dunavin, 2017). In the first group (n=102), autologous HCT was given no more than 12 months after diagnosis; in the second, autologous HCT was given 12 months or more after diagnosis, although individual reasons for later procedures were not specified. Following a standard induction therapy and preceding transplantation, more patients in the early group had achieved a complete response (CR) or very good partial response than in the late autologous HCT group (46% vs 62%, p=0.036). This difference remained significant after transplantation with patients who were upgraded to very good partial response or CR (early autologous HCT, 77% vs late autologous HCT, 56%; p<0.007). No significant differences were observed between groups for progression-free survival (PFS) or overall survival (OS), which were assessed at 1, 3, and 5 years; however, a difference of 10 months between groups in median PFS was noted (28 months for early autologous HCT patients vs 18 months for late autologous HCT patients). Relapse occurred in 40% of patients in the early autologous HCT group, and 55% of the late autologous HCT group (p=0.55). A variable that did have a significant bearing on PFS between groups was that of risk, with high-risk patients in the early autologous HCT group achieving a median PFS of 25 months, compared with the 11 months achieved by their counterparts in the late autologous HCT group. The results of this study seemed to confirm the observation made by previous studies that patients who achieve a CR are more likely to remain progression-free for significantly longer than those whose response to induction therapy is not very good. Data were lacking on the reason for delayed autologous HCT; another limitation was that patients who received maintenance therapy were excluded from the study.
 
RELAPSED OR REFRACTORY MM
 
Salvage Autologous HCT for Relapsed MM
A 2013 multicenter retrospective study by Michaelis et al evaluated 187 patients drawn from the Center for International Blood and Marrow Transplantation who were treated with a second autologous HCT following relapse or progression of MM (Michaelis, 2013). All but 12% of patients received a second autologous HCT12 months or more after the initial transplantation; prior to a second autologous HCT, only 40% (n=74) of patients were in complete or partial response. In patients whose time from the first transplant to first relapse was greater than 36 months, investigators noted a decrease in the risk of relapse after a second autologous HCT(relative risk, 0.63; 95% CI, 0.49 to 0.97), and an increase in PFS and OS. For such individuals, the 3-year PFS rate was twice that of the cohort at large (26% vs 13%), and 5-year PFS rate (13%) was considerably superior to that of the larger group (5%). A comparison of OS rates showed a similar improvement: while the 5-year OS rate of 29% for the entire cohort was comparable to other studies of a second autologous HCT in relapsed MM, the 5-year OS rate for individuals with a time-to-relapse of 36 months or greater was considerably improved (48%; p=0.026). After 3 years, only 4% (95% CI, 2% to 8%) of patients experienced NRM; however, relapse or disease progression was observed in 82% of patients after 3 years (vs 68% of patients with time-to-relapse ≥36 months after initial transplant). The investigators acknowledged a lack of data on maintenance regimens, cytogenetics, or staging of individual disease; they also noted that, during the observed time frame (1995-2008), several newer therapies were introduced, which were not accounted for during analysis. However, given findings similar to other retrospective studies during the same period, the investigators concluded that a second autologous HCT is an appropriate salvage therapy for eligible patients.
 
A 2017 review by Ziogas et al included studies of autologous HCT as salvage therapy in patients whose MM has relapsed following an initial autologous HCT (either single or tandem) (Ziogas, 2017). The primary aim of the review was to summarize the circumstances in which a second autologous HCT should be administered, especially as more regimens show potential as salvage or reinduction therapy, including anti-CD38 antibodies, next-generation proteasome inhibitors, or immunomodulatory drugs. The authors noted that most studies have been retrospective, or of small patient samples; however, in 15 of the included studies, more than 40 patients were evaluated. Overall response rates ranged from 55.3% to 97.4%; following a salvage transplant, median PFS across studies varied considerably (range, 8.5-40 months). The questions examined in the review concerned the safety and efficacy of a second autologous HCT, predictors of outcome and best maintenance approach following salvage autologous HCT, and the future of the treatment. Based on general agreement from studies that showed the particular benefit of salvage autologous HCT in patients with longer intervals from the first transplant to initial relapse, reviewers recommended that the treatment is administered to patients with remission of greater than 18 months following initial autologous HCT. Given heterogeneity across studies of novel maintenance therapies, reviewers called for more prospective studies, noting melphalan as a well-established basis for treatment.
 
Tandem Autologous HCT for Relapse After First Autologous HCT
A 2016 review by McCarthy and Holstein summarized current treatment regimens for patients with myeloma who are eligible for autologous HCT or allo-HCT (McCarthy, 2016). Following discussion of studies on induction, salvage, consolidation, and maintenance therapies, reviewers offered recommendations based on the available evidence. Based on 4 studies comparing autologous HCT with chemotherapy alone, reviewers recommended autologous HCT as standard of care for patients who are eligible; additionally, they recommended autologous HCT for the first relapse, based on the pooled hazard ratio of 2 studies showing a benefit in patients given autologous HCT following relapse (hazard ratio, 0.57; p=0.037). Reviewers noted the increasing uncertainty regarding the efficacy and safety of allo-HCT compared with novel therapies; studies directly comparing allo-HCT with autologous HCT lack consistent results. However, RIC allo-HCT has been shown to have some benefit for patients whose disease is high-risk, especially in younger populations. As maintenance therapy, reviewers considered a number of studies evaluating thalidomide (n=8), which had conflicting results, as well as 3 randomized studies of lenalidomide, concluding that the latter treatment is standard of care.

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