BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Multiple Myeloma
Chapter: Transplant
Current Effective Date: December 27, 2013
Original Effective Date: July 09, 2008
Publish Date: September 27, 2013
Revised Dates: March 1, 2010; June 1, 2011; August 31, 2012; September 13, 2013
Description

Multiple myeloma (MM) is a systemic disease that affects the plasma cells in the bone marrow, which normally produce antibodies.  These cells are a specialized form of B-lymphocyte.  The condition is called MM because most patients have evidence of disease in a number of bony sites throughout the body.  Management of MM is generally related to tumor mass at diagnosis or at the time treatment is initiated.  Patients with a high tumor mass undergo systemic cytotoxic therapy, typically intermittent melphalan/prednisone (MP) or other combination therapy such as VAD (vincristine, doxorubicin, and dexamethasone) or VMCP (vincristine, melphalan, cyclophosphamide, and prednisone).  However, MM 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. 

The term responsive is defined as a tumor showing either a complete, partial, or minimal response.  Classifications have been developed to categorize response to induction treatment for patients with multiple myeloma by the EBMT (European Group for Bone and Marrow Transplant), IBMTR (International Bone and Marrow Transplant Research, and ABMTR (Autologous Bone and Marrow Transplant Research).  Responses are graded as complete response, partial response, or minimal response. 

Complete response includes:

  • absence of the original monoclonal paraprotein in serum and urine,
  • no increase in size or number of lytic lesions, and
  • disappearance of any soft tissue plasmacytomas. 

Partial response implies:

  • at least a 50% reduction in serum monoclonal paraprotein,
  • no increase in size or number of lytic lesions, and
  • disappearance of any soft tissue plasmacytomas. 

Minimal response, the least stringent category, requires:

  • at least at 25% reduction in serum monoclonal paraprotein, and
  • no increase (in size or number) of lytic bone lesions. 

No change represents cases that do not meet these response categories.

Plateau indicates stable values (within 25%) for at least three months. 

Primary progressive disease is progression that occurs during or immediately after the first conventional-dose induction regimen given to a newly diagnosed myeloma patient, i.e., before any SCT, even before the first transplant cycle in a planned tandem transplant.  Patients with primary progressive disease can be categorized as high risk or standard risk.  One approach to identifying high-risk patients (other patients are standard risk) is 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.  Patients with beta-2-microglobulin levels greater than 5.5 mg per liter are also often considered high risk.  Further details are provided in the policy Rationale.

For patients scheduled for tandem autologous transplants, mobilization before the first cycle usually yields sufficient stem cells to permit two transplant cycles.  Response generally is assessed after each treatment cycle for these patients.  Evidence summarized here (see the Rationale section) shows that the second transplant extends the duration of survival for those who fail to achieve a complete or very good partial response after the first cycle.  However, there appears to be no survival benefit from the second transplant for patients who achieve a complete or very good partial response.  In addition, patients who do not have at least stable disease after the first autologous SCT (i.e., those patients whose disease has progressed with the first autologous SCT) do not benefit from a second autologous SCT. 

The first randomized controlled trial that compared tandem with single autotransplants, IFM-94 defined a complete response as the absence of detectable paraprotein by serum and urine electrophoresis and 5% or fewer plasma cells in a bone marrow aspirate.  The trial’s protocol also defined a very good partial response as at least a 90% decrease in serum paraprotein concentration.  More recently, a joint committee of the European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry provided its definition of complete response.  This definition specifies immunofixation rather than electrophoresis to test for monoclonal paraprotein in serum and urine, requires serial samples to be free of paraprotein over at least six weeks, and retains the criterion for < 5% plasma cells in the bone marrow aspirate.  Although both the trial protocol and the joint committee’s criteria define partial response as at least a 50% decrease in serum paraprotein concentration, the joint committee did not define a very good partial response.

Few patients are considered eligible for a second autotransplant to treat myeloma that has relapsed after a complete or partial remission that followed an initial autotransplant.  Thus, it is unlikely that prospective trials will ever be conducted to rigorously compare outcomes of this strategy with alternatives.  Nevertheless, retrospective studies (summarized here in the Rationale section) report durable complete or partial responses and extended survival for patients treated this way, particularly when a long disease- or progression-free interval followed the first transplant.

The trial supporting autologous transplant followed by allogeneic transplant was done in patients age 65 or younger.  Also, in this study, criteria for “HLA-identical” included a 6 of 6 HLA match. 

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan 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 or contract, the benefit plan or contract will govern.

Coverage

Coverage for evaluation of and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of multiple myeloma (MM) is identified in the grid below.

Allogeneic:

May be considered medically necessary ONLY to treat patients with MM stage I, II, or III who:

  1. have completed first-line therapy, and
  2. have an HLA identical donor.

Is considered experimental, investigational and unproven in those patients with refractory MM, including those with primary resistant disease and those in a resistant relapse.

Monotherapy using allogeneic SCT is considered experimental, investigational and unproven:

  1. as initial therapy of MM; OR
  2. after a failed course of autologous SCT.

Autologous:

 

May be considered medically necessary for patients who have:

  • Newly diagnosed or responsive MM and who:
    1. have never been treated, OR
    2. are in a complete or partial remission, OR
    3. are in a responsive relapse; OR
  • Primary progressive MM and are not at high risk.

NOTE: A second course of autologous SCT may be considered medically necessary to treat responsive MM that has relapsed after a durable complete or partial remission following an initial autologous transplant.

Is considered experimental, investigational and unproven for:

  1. Patients with refractory MM, including those with primary resistant disease and those in a resistant relapse; OR
  2. Patients utilizing a salvage allogeneic transplant for relapse of MM after a prior failed high dose chemotherapy (HDC) with Autologous SCT regimen.

Tandem or Triple Stem-Cell Transplant:

Tandem Autologous SCT may be considered medically necessary to treat newly diagnosed or responsive Multiple Myeloma (MM).

Tandem transplantation with an initial round of autologous SCT followed by a non-marrow-ablative conditioning regimen and allogeneic SCT (i.e., “RIC-transplant”[reduced intensity conditioning]) may be considered medically necessary to treat newly diagnosed MM patients with an HLA-identical sibling donor and who are in otherwise reasonably good health. 

Tandem Autologous SCT is considered experimental, investigational and unproven for treatment of MM in a refractory relapse.

Tandem Allogeneic SCT is considered experimental, investigational and unproven for the treatment of newly diagnosed, responsive, or refractory relapsing MM.

Triple SCT is considered experimental, investigational and unproven

Donor Leukocyte Infusion:

Is considered experimental, investigational and unproven.

Rationale

Autologous Stem-Cell Transplantation (AutoSCT)

Single Transplant

The initial policy on myeloablative chemotherapy with autologous stem-cell transplantation (AutoSCT) to treat multiple myeloma was based on a 1996 Blue Cross Blue Shield Association (BCBSA) Technology Assessment Center (TEC) Assessment that summarized evidence on outcomes for patients with newly diagnosed or responsive multiple myeloma separately from those with refractory or resistant myeloma.  Patients with responsive myeloma were defined as patients who achieved a complete or partial (at least 50% tumor reduction) response to chemotherapy, while patients with resistant or refractory multiple myeloma were defined as those who achieved < 50% reduction in tumor burden.  The following conclusions were offered.

Newly Diagnosed or Responsive Multiple Myeloma:

  • The available data support the conclusion that AutoSCT is at least as effective and may be more effective than conventional-dose chemotherapy for improving the health outcomes of these patients.  In a key randomized trial, event-free and overall survival (OS) after myeloablative therapy was clearly better than after conventional chemotherapy. 

Multiple Myeloma in a Refractory or Resistant Relapse:

  • In contrast, insufficient data are available to support a conclusion regarding the outcomes of AutoSCT for myeloma patients in a refractory relapse.  Most of the data consisted of uncontrolled clinical series of patients, and outcomes were poor, since treatment-related toxicity was frequent and severe in heavily pretreated patients.  No randomized controlled trials were reported.

Reviews in 2003 summarized data from trials on newly diagnosed patients completed after the initial 1996 TEC Assessment.  These reviews confirmed that a larger proportion of patients survive after AutoSCT than after conventional dose induction therapy for newly diagnosed disease.  A randomized controlled trial (RCT) by Child et al., published after these reviews, also reported longer survival after AutoSCT, and included a meta-analysis of results from three RCTs that favored AutoSCT (odds ratio for survival, 0.70; 95% confidence interval, 0.53 to 0.93).  In contrast, another RCT that compared intensified induction chemotherapy alone with intensified induction followed by myeloablative AutoSCT reported no survival benefit from the myeloablative therapy. 

An evidence-based review and clinical guideline of the American Society for Blood and Marrow Transplantation (ASBMT) emphasize the lack of data from RCTs on outcomes of AutoSCT for salvage therapy of MM.  The review and guideline conclude that AutoSCT is preferred as de novo rather than salvage therapy, since this minimizes risks of myelodysplasia and other toxicities from extended treatment with alkylating agents.  In addition, data show that newly diagnosed patients given AutoSCT as part of de novo therapy spend more time without symptoms, treatment, or treatment toxicity than those given conventional dose induction and AutoSCT for salvage at relapse or progression.

Note that myeloma in a refractory relapse differs from primary refractory disease (newly diagnosed myeloma that does not enter a partial or complete remission after conventional-dose induction).  The RCTs on newly diagnosed patients showed that AutoSCT induces durable remissions and extends the duration of OS and disease-free survival in a substantial proportion of patients with primary refractory myeloma.

Tandem Transplant

The policy regarding tandem transplantation initially was based on two 1998 BCBSA TEC Assessments that focused on tandem transplants for newly diagnosed or responsive multiple myeloma or for resistant multiple myeloma.  The following conclusions were offered.

Newly Diagnosed or Responsive Multiple Myeloma

  • Only five published studies were found that reported data on the outcomes of treatment in patients receiving tandem transplants.  Although one of the studies was a randomized study comparing single and tandem transplants for newly diagnosed patients, the available data were preliminary, published as abstracts only, and did not permit conclusions on survival.  The University of Arkansas reported a large, nonrandomized, single-institution case series of multiple myeloma treated with tandem transplants.  However, the data compared results to historical controls treated with conventional-dose regimens and not to a single course of AutoSCT, the more appropriate comparator.
  • Using indirect comparisons of previously published outcomes for patients given a single course of AutoSCT as historical controls, results reported for tandem and single transplants overlapped substantially for nearly all outcomes of interest.  These data were considered inadequate to demonstrate superiority of tandem transplants over single transplants.  Data on the duration of survival after tandem transplants were scant and nearly all other outcomes data were only available from single-arm studies with highly selected patients.  Thus, the comparison of outcomes was 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 outcomes of tandem transplants to treat resistant multiple myeloma.  There was no control group for direct comparison of outcomes in the most updated report on the larger series of highly selected patients.  The earlier report from this institution and the third paper included nonrandomized controls, 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 transplants for resistant myeloma were sufficiently comparable to those given either single Autologous SCT or conventional-dose salvage therapy to permit conclusions based on indirect comparison of outcomes from separate studies.  Thus the available data were insufficient to permit conclusions on outcomes of tandem transplants.

Randomized Trials of Tandem Autotransplants

IFM-94 Results.  The 2003 study by Attal et al. randomized newly diagnosed myeloma patients to single or tandem Autologous transplants.  Outcomes were analyzed by intent-to-treat at 75 months’ median 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 relapsed: 34 were salvaged with another (3rd) 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 event-free (EFS; 20% vs. 10%, p = 0.03), relapse-free (RFS; 23% vs. 13%; p < 0.01), and OS (42% vs. 21%, p = 0.010).  Treatment-related mortality was 6% and 4% after tandem and single transplants, respectively (p = 0.40).  Second transplants apparently extended survival only for those who failed to achieve a complete response (CR) or very good partial response (VGPR) after one transplant (OS at seven years: 43% vs. 11%, p < 0.001).

Generalizability Issue.  An accompanying editorial by Stadtmauer raised concerns that these results might be specific to the regimens used for myeloablative therapy in IFM-94.  Patients in the single transplant arm received 140 mg/m2 melphalan 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 cites the IFM-95 study as evidence, suggesting 140 mg/m2 melphalan plus TBI may be less effective and more toxic as myeloablative therapy than 200 mg/m2 melphalan and no TBI.  Based on this, the author hypothesizes increased survival in IFM-94’s tandem arm may have resulted from greater cumulative exposure to melphalan (280 vs. 140 mg/m2).

The IFM-95 randomized trial directly compared 200 mg/m2 melphalan without TBI (n = 142) versus 140 mg/m2 plus TBI (n = 140) as conditioning regimens for single autotransplants.  The trial reported OS at 45 months of 66% in the arm given 200 mg/m2 and 46% in the arm given 140 mg/m2 plus TBI.  However, the CR rates were identical in the two arms, and there was no difference between arms in event-free survival or relapse rates.  The authors hypothesized the difference in OS might have resulted from more frequent use of a second transplant on relapse in the arm originally given 200 mg/m2 melphalan (50% of 51 relapsed patients) than in the arm originally given 140 mg/m2 plus TBI (25% of 44 relapsed patients).  The published report on this trial does not explain the reasons for this difference in salvage therapy.

Additional evidence supporting the superiority of 200 mg/m2 melphalan as the pretransplant conditioning regimen comes from a comparison of two separate single-arm studies, a registry analysis from the European Group for Blood and Marrow Transplantation, and a U.K.  retrospective analysis.  On the other hand, a Spanish registry analysis and a German retrospective study reported equivalent OS and event-free survival after either regimen.

Taken together, the evidence from IFM-95 and the series data comparing different conditioning regimens does not appear sufficiently compelling to justify considering tandem autotransplants investigational for myeloma.  The concerns regarding generalizability of IFM-94’s results appear relevant more to the clinical research agenda to identify the best pre-transplant conditioning regimen for myeloma than to the principal finding of IFM-94 that a second transplant extends survival for myeloma patients who fail to achieve a complete or very good partial remission. 

Other RCTs.  Three other randomized trials compare single with tandem autotransplants using different conditioning regimens than IFM-94.  Each has completed accrual and treatment, but requires another 1-2-years’ follow-up to mature.  Barlogie et al. summarized recent interim results in Hematology 2003.  One trial (HOVON) reports improved EFS in the tandem arm but no difference in OS, while the other two trials (Bologna 96 and MAG95) report no differences between arms for either outcome.  However, survival curves in IFM-94 did not begin to separate until after 4–5 years of median follow-up.

Autotransplant Followed by Reduced-Intensity Conditioning Allotransplant

Rationale.  The Stadtmauer editorial also stresses that all but 23% of IFM-94 patients randomized to tandem autotransplants relapsed or died by seven years.  Recent reviews and commentaries agree that tandem autotransplants rarely cure myeloma.  There is evidence of a graft-versus-myeloma effect after allotransplants, but conventional (myeloablative) allotransplants for myeloma are associated with excess early mortality.  Thus, investigators hypothesize that an autologous transplant followed by a non-myeloablative, or reduced-intensity conditioning (RIC) allotransplant might be optimal myeloma therapy for those with an HLA-matched sibling donor.  This approach uses the autotransplant to maximally reduce the malignant plasma cell burden, and the subsequent RIC allotransplant to (potentially) eradicate remaining malignant clones through a graft-versus-malignancy effect.

Uncontrolled Data.  A recent study included 54 patients (median age, 52 years; range, 29–71) with previously treated myeloma (52% refractory or relapsed disease) given an initial autotransplant conditioned with 200 mg/m2 melphalan.  Of these, 52 received a subsequent RIC allotransplant.  Investigators reported 78% OS at a median 552 days after allografting.  Treatment achieved a CR in 57% and an overall response rate of 83%.  Acute graft-versus-host disease (GVHD) developed in 38% of patients (grades III/IV in four cases; grade II in all others), and chronic GVHD requiring therapy occurred in 46%.  Twelve patients died: one from viral infection after the initial autotransplant, two from myeloma progression (three and 23 months post-RIC allotransplant), seven from GVHD, and one each from lung cancer and encephalopathy.

Ongoing RCT.  At the 2003 American Society of Hematology (ASH) meeting, the IFM group reported preliminary results from a multi-arm trial (IFM99-03 and IFM99-04) comparing autotransplant followed by RIC allotransplant with tandem autotransplants for newly diagnosed high-risk myeloma (defined by elevated beta-2 microglobulin and/or chromosome 13 deletions).  Each autotransplant cycle was conditioned with > 200 mg/m2 melphalan.  They used "biological randomization" to select those with an HLA-identical sibling donor for the auto/min-allo arm (IFM99-03 protocol; n = 47).  Those lacking a donor were selected for tandem autotransplants (IFM99-04 protocol; n = 128), and were further randomized to treatment with or without an antibody to IL-6 after the second transplant.  A preliminary intent-to-treat analysis compared the IFM99-03 patients with all those in the IFM99-04 protocol.  At median follow-up of 18 months (range, 9-39) for those still alive, estimated EFS at three years (52% vs. 54%; p = 0.37) and median EFS (21 vs. 25 months; p = 0.08) were not significantly different between groups.  Relapse rate was 45% in the auto/RIC-allo arm, without a plateau on the EFS Kaplan-Meier curve.  Also, 50% of those given an RIC allotransplant experienced chronic GVHD, which was extensive in only two cases.

Other Data.  Two additional ASH presentations reported outcomes of the auto/RIC-allo approach for managing myeloma.  One was an ongoing uncontrolled multicenter Italian trial in which 57 newly diagnosed patients have completed the protocol.  At a median 287 days (range 6-1,177) after allotransplants, OS is 84% with 58% in CR and in 25% in PR.  A registry analysis compared outcomes of RIC allotransplants used alone (n = 183) with those of the auto/min-allo strategy (n = 53) for newly diagnosed myeloma patients.  OS at two years was 50% (95% CI: 42%-59%) for those given RIC allotransplants alone and 40% (95% CI: 23%-58%) for those given an autotransplant followed by a RIC allotransplant.

Conclusions on which of the strategies yields optimal outcomes require mature data from the IFM99-03 and IFM99-04 comparison and from the NIH (National Institutes of Health)-sponsored trial.

Repeat Autotransplants for Relapse After Initial Autotransplant

Literature searches found no prospective controlled studies comparing autotransplants with alternative strategies to manage myeloma that has relapsed after a complete or partial remission in response to a first autotransplant.  This lack of controlled studies is not surprising, as patients rarely are considered eligible for a second autotransplant, either because their relapsed myeloma progresses too rapidly or because their advanced physiologic age, poor health status, or extensive prior treatment increases the likelihood of adverse outcomes.  The ASBMT-sponsored evidence-based systematic review summarized data from four relevant clinical series.  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 prior to the initial autotransplant.  Thus, clinical judgment, confirmed by external review, can play an important role to select patients for this treatment with a reasonable likelihood that potential benefits may exceed harms.

Allogeneic SCT

The policy on allogeneic SCT (AlloSCT) initially was based on a 1996 BCBSA TEC Assessment that offered the following conclusions.

  • No studies directly compared the outcomes of allogeneic stem-cell transplantation (AlloSCT) with either conventional chemotherapy or AutoSCT.  One retrospective study directly compared the outcomes of allogeneic transplantation with those of autologous transplantation.  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 AlloSCT is associated with a 39%–55% 5-year survival, while the comparable figure for AutoSCT is 36%–52%. 

In a 1999 review on AlloSCT for myeloma, Kyle reported a mortality rate of 25% within 100 days and overall transplant-related mortality of approximately 40%.  In addition, relapse of multiple myeloma was common such that few patients were cured.  Candidates for AlloSCT 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 were required to determine whether reported outcomes of AlloSCT were a true reflection of the treatment’s effectiveness or were due to patient selection bias. 

In a 2003 update, recent reviews summarized data comparing AutoSCT with AlloSCT for newly diagnosed or responsive multiple myeloma.  These included two prospective but nonrandomized controlled trials (total n = 135) and four retrospective comparisons (total n = 544), all using myeloablative conditioning regimens for those given AlloSCT.  The data summarized in these reviews do not alter the conclusions of the 1996 BCBSA TEC Assessment that treatment-related toxicity after AlloSCT exceeds potential benefits from a graft-versus-myeloma effect.  The recent ASBMT guideline also concludes that AutoSCT is preferred over AlloSCT based on presently available evidence.  However, for the rare patient with an available syngeneic donor, data from a retrospective case-matched analysis suggest outcomes of syngeneic SCT are superior to those of AutoSCT. 

Allogeneic SCT After a Failed Prior Autologous SCT

A 2000 BCBSA TEC Assessment focused on AlloSCT after a prior failed course of AutoSCT to treat various malignancies, including multiple myeloma.  The TEC Assessment found that data were inadequate to permit conclusions about this treatment strategy.

In a 2003 update, a few uncontrolled series published since the 2000 BCBSA TEC Assessment reporting outcomes of AlloSCT to treat relapse or failure after an autologous transplant were described in a review article; another study was published after the review was completed.  Most of the newer studies used reduced intensity or non-myeloablative conditioning regimens.  These were small pilot/feasibility studies that lacked control groups for comparison of outcomes. 

Additional Review of Literature Through 2008

Barlogie and colleagues published final results of the S9231 trial, initiated in 1993, which randomized 516 patients with multiple myeloma to receive either standard therapy or myeloablative conditioning with melphalan 140 mg/m2 plus total body irradiation followed by AutoSCT.  The authors reported virtually no difference in outcomes, including response rates, progression-free survival, and OS.  Fermand and colleagues reported a randomized study on newly diagnosed patients aged 55 to 65 years, and also reported no significant difference in OS between those randomized to myeloablative chemotherapy (melphalan 200 mg/m2 or melphalan 140 mg/m2 plus busulfan 16 mg/kg) and AutoSCT versus conventional dose chemotherapy.  However, the myeloablative chemotherapy group reported a significant improvement in a composite outcome (TwiSTT) that measures time without symptoms, treatment, or treatment toxicity.

The reasons for the discrepant results compared to the positive findings of other randomized trials are uncertain, but may be related to the conditioning regimen or patient age.  For example, conditioning with total body irradiation and a smaller dose of melphalan, typical of trials such as S9231 begun in the early 1990s, was later shown to be less effective than a larger dose of melphalan alone (e.g., the IFM-95 trial).  A search of the clinical trials database identified a large number of ongoing trials exploring different conditioning regimens and maintenance therapies.

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.  During this review, the policy statement regarding tandem SCT with an autograft followed by an allograft in younger, newly diagnosed patients was changed.  This decision was based primarily on a recent study 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 two 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 AutoSCT.  The nine trials that met the selection criteria (N = 2,411) started enrolling patients in the 1990s and include the two studies mentioned above that did not detect a survival benefit from myeloablative chemotherapy.  The authors of the meta-analysis concluded that myeloablative therapy with AutoSCT 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 AutoSCT.  However, the effects of myeloablative chemotherapy and AutoSCT may have been diluted by the fact that up to 55% of patients in the standard chemotherapy group received myeloablative chemotherapy with AutoSCT 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, comparing single with double autologous SCT (n = 321).  Patients undergoing tandem AutoSCT 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 AutoSCT 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 AutoSCT, which is currently being studied, or of autografts versus allografts for the second round of SCT.

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 noted that, “the need for early ASCT [autologous SCT] in an era of new drugs is the most important clinical question in myeloma today.”

Abdelkefi reported on a European study of 195 patients with de novo symptomatic myeloma younger than age 60 who were randomly assigned to receive either tandem autologous SCT transplantation up front (arm A, n = 97) or one AutoSCT followed by a maintenance therapy with thalidomide (day + 90, 100 mg/day during six months) (arm B, n = 98).  In both arms, autologous SCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with myeloablative cyclophosphamide (4 g/m2) and granulocyte colony stimulating factor.  With a median follow-up of 33 months (range, 6-46 months), the three-year OS was 65% in arm A and 85% in arm B (P = .04).  Additional trials with longer follow-up are needed to understand the role of tandem transplants in myeloma with the use of newer agents. 

For those with primary progressive disease (disease progression during induction therapy), a risk-adapted approach to treatment is recommended.  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 AutoSCT strategies and may relapse within one year of treatment.  However, patients with primary progressive disease who do not have these characteristics are considered candidates for AutoSCT.  Emerging studies suggest that early introduction of bortezomib results in better quality of response and prolonged survival for high-risk patients. 

Stewart 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 by Bensinger, 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 AlloSCT 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-AlloSCT. 

The policy statements are in concordance with current National Comprehensive Cancer Network guidelines, which indicate that AlloSCT be performed in myeloma patients on clinical trial (except as already noted in the policy statement).

Tandem and Triple SCT, and Donor Leukocyte Infusion

Search of published literature did not locate any random, controlled studies that indicate improved patient outcomes for tandem or triple SCT, or donor leukocyte infusion.

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. 

ICD-9 Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79, 203.00, 203.01, 203.02, 203.10, 203.11, 203.12, 203.80, 203.81, 203.82, V16.7 

ICD-10 Codes
C90.00-C90.0, 30250G0, 30250X0, 30250Y0, 30250G1, 30250X1, 30250Y1, 30253G0, 30253X0, 30253Y0, 30253G1, 30253X1, 30253Y1, 6A550ZT, 6A550ZV ,6A551ZT, 6A551ZV 
Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 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, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
References
  1. 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 1996; 335(2):91-7. 
  2. High-Dose Chemotherapy with Autologous Stem-Cell Support for Multiple Myeloma.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1996) 11(14):1-38.
  3. Allogeneic Bone Marrow Transplantation for Multiple Myeloma.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1996) 11(28):1-24.
  4. Powles R, Raje N, Milan S et al.  Outcome assessment of a population-based group of 195 unselected myeloma patients under 70 years of age offered intensive treatment.  Bone Marrow Transplant 1997; 20(6):435-43. 
  5. Tandem HDC/AuSCS for Newly Diagnosed or Responsive Multiple Myeloma. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1998 May) 8(13):1-17.
  6. Single or Tandem HDC/AuSCS for Resistant Multiple Myeloma.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1998 March) 15(26):1-22.
  7. Blade J, Samson D, Reece D et al.  Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation.  Myeloma Subcommittee of the EBMT.  European Group for Blood and Marrow Transplant.  Br J Haematol 1998; 102(5):1115-23. 
  8. Kyle RA.  High-dose therapy in multiple myeloma and primary amyloidosis: an overview.  Semin Oncol 1999; 26(1):74-83. 
  9. Gahrton G, Svensson H, Bjorkholm M et al.  Syngeneic transplantation in multiple myeloma: a case matched comparison with autologous and allogeneic transplantation.  Bone Marrow Transplant 1999; 24 (7):741-5. 
  10. Barlogie B, Jagannath S, Desikan KR et al.  Total therapy with tandem transplants for newly diagnosed multiple myeloma.  Blood 1999; 93(1):55-65. 
  11. Bjorkstrand B, Svensson H, Goldschmidt H et al.  EBMT registry results of autologous bone marrow and peripheral stem cell transplantation.  Proc VII Int Multiple Myeloma Workshop 1999.  Abstract 48a. 
  12. Goldschmidt H, Cremer FW, Hegenbart U et al.  Comparison of 3 high-dose regimens with autologous peripheral blood stem cell transplantation for multiple myeloma: a single center experience in 261 patients.  Proc VII Int Multiple Myeloma Workshop 1999.  Abstract 117a. 
  13. Lahuerta JJ, Martinez-Lopez J, Grande C et al.  Conditioning regimens in autologous stem cell transplantation for multiple myeloma: a comparative study of efficacy and toxicity from the Spanish Registry for Transplantation in Multiple Myeloma.  Br J Haematol 2000; 109(1):138-47.
  14. Salvage HDC/AlloSCS for Relapse or Incomplete Remission Following HDC/AuSCS for Hematologic Malignancies.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2000 August) 15(9):1-30.
  15. Moreau P, Facon T, Attal M et al.  Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial.  Blood 2002; 99(3):731-5. 
  16. 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 2003; 9(1):4-37. 
  17. Kumar A, Loughran T, Alsina M et al.  Management of multiple myeloma: a systematic review and critical appraisal of published studies.  Lancet Oncol 2003; 4(5):293-304. 
  18. Child JA, Morgan GJ, Davies FE et al.  High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.  N Engl J Med 2003; 348(19):1875-83. 
  19. Segeren CM, Sonneveld P, van der Holt B et al.  Overall and event-free survival are not improved by the use of myeoablative therapy following intensified chemotherapy in previously-untreated patients with multiple myeloma: a prospective randomized phase 3 study.  Blood 2003; 101(6):2144-51. 
  20. American Society for Blood and Marrow Transplantation.  The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Myeloma.  Available at: www.asbmt.org (accessed August 27, 2003). 
  21. Attal M, Harousseau JL, Facon T et al.  Single versus double autologous stem-cell transplantation for multiple myeloma.  N Engl J Med 2003; 349(26):2495-502. 
  22. Stadtmauer EA.  Multiple myeloma, 2004--one or two transplants? N Engl J Med 2003; 349(26):2551-3. 
  23. Barlogie B, Shaughnessy J, Jacobson J et al.  Improving disease control in myeloma.  Part IV in: Barille-Nion S, Barlogie B, Bataille et al.  Advances in Biology and Therapy of Multiple Myeloma.  Hematology 2003.  American Society of Hematology.  Available at: www.asheducationbook.org
  24. Vesole DH.  "Full length, midi, or mini": a fashion statement for transplants in myeloma.  Blood 2003; 102:3081a-2a. 
  25. Blade J, Vesole DH, Gertz M.  High-dose therapy in multiple myeloma.  Blood 2003; 102(10):3469-70. 
  26. Maloney DG, Molina AJ, Sahebi F et al.  Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.  Blood 2003; 102(9):3447-54. 
  27. Moreau P, Garban F, Facon T et al.  Preliminary results of the IFM9903 and IFM9904 protocols comparing autologous followed by miniallogeneic transplantation and double autologous transplant in high-risk de novo multiple myeloma.  Blood 2003; 102(11):43a.  Abstract 138. 
  28. Bruno B, Patriarca F, Rotta M et al.  Autografting followed by low dose TBI based non myeloablative allografting in newly diagnosed multiple myeloma: the Italian experience.  Blood 2003; 102(11):198a.  Abstract 693. 
  29. Bredeson C, Perez WS, Reece DE et al.  Non-myeloablative allogeneic transplantation (NST) as first transplant or as part of planned autologous-NST tandem transplant strategy for multiple myeloma (MM): An IBMTR study.  Blood 2003; 102(11):199a.  Abstract 696. 
  30. Einsele H, Schafer HJ, Hebart H et al.  Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning.  Br J Hematol 2003; 121(3):411-8. 
  31. Barlogie B, Shaughnessy J, Tricot G et al.  Treatment of multiple myeloma.  Blood 2004; 103(1):20-32. 
  32. Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allogeneic Stem Cell Transplant.  BCBSA Medical Policy Reference Manual (2005 September) Medicine: 2.03.03.
  33. Fermand JP, Katsahian S, Divine M et al.  High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe.  J Clin Oncol 2005; 23(36):9227-33. 
  34. 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 2006; 24(6):929-36. 
  35. Bruno B, Rotta M, Patriarca F et al.  A comparison of allografting with autografting for newly diagnosed myeloma.  N Engl J Med 2007; 356(11):1110-20. 
  36. Koreth J, Cutler CS, Djulbegovic B et al.  High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials.  Biol Blood Marrow Transplant 2007; 13(2):183-96. 
  37. 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 2007; 25(17):2434-41. 
  38. Stewart AK, Fonseca R.  Review of molecular diagnostics in multiple myeloma.  Expert Rev Mol Diagn 2007; 7(4):453-9. 
  39. Fonseca R.  Strategies for risk-adapted therapy in myeloma.  2007 ASH Annual Meeting Education Program 2007.  Available at http://asheducationbook.hematologylibrary.org (Last accessed 07/03/2008)
  40. Bensinger WI.  Is there still a role for allogeneic stem-cell transplantation in multiple myeloma? Best Pract Res Clin Haematol 2007; 20(4):783-95. 
  41. National Comprehensive Cancer Network.  Multiple Myeloma.  Clinical practice guidelines in oncology, v.2.2008.  Available at: www.nccn.org .  (Last accessed July 1, 2008.)
  42. Kyle RA, Rajkumar SV.  Multiple myeloma.  Blood 2008; 111(6):2962-72. 
  43. Abdelkefi A, Ladeb S, Torjman L et al.  Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.  Blood 2008; 111(4):1805-10.
History
June 2011 Policy reviewed; updated description, rationale, and references; policy statement changed from not medically necessary to investigational.
August 2012 Policy updated with literature search; no change in policy statements; reference numbers 13-15 and 38 added; reference 43 updated; references renumbered.
September 2013 Policy formatting and language revised.  Title changed from "Transplant: Single or Tandem Course of High-Dose Chemotherapy Plus Hematopoietic Stem-Cell Support for Multiple Myeloma" to "Stem-Cell Transplant for Multiple Myeloma".
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Stem-Cell Transplant for Multiple Myeloma