Hematopoietic Cell Transplantation for Multiple Myeloma

Number: 0497

Policy

1. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of amylodoisis, multiple myeloma (MM) or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome when the transplanting institution's written eligibility criteria are met.  In the absence of such criteria, Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of MM or POEMS syndrome when all of the following selection criteria are met: 

   1. Member must not have significant co-morbid medical conditions; and
   2. Members should not have had extensive prior chemotherapy or radiation therapy (i.e., more than 1 year of alkylator-based chemotherapy; radiation therapy to no more than 10 % of marrow producing bones); and 
   3. The member has adequate major organ function based on the transplant institution's evaluation; and 
   4. Members with indolent myeloma, smoldering myeloma, and monoclonal gammopathy of uncertain significance [MGUS] are excluded.

2. Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of MM or POEMS syndrome when the member meets the transplanting institution's protocol eligibility criteria.  In the absence of a protocol, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of MM or POEMS syndrome when 
   

   1. The member has adequate major organ function based upon the transplanting institution's evaluation; and
   2. The member has early relapse (less than 24 months) after primary therapy that included an autologous hematopoietic cell transplantation (HCT) (for members with MM only)
      
      

   Note: Aetna considers non-myeloablative allogeneic hematopoietic cell transplantation ("mini-transplant," reduced intensity conditioning transplant) medically necessary for the treatment of persons with MM or POEMS syndrome when they are eligible for conventional allografting.

3. Aetna considers tandem (also known as sequential) transplants medically necessary for the treatment of MM or POEMS syndrome when the transplanting institution's protocol eligibility criteria are met.  In the absence of a protocol, Aetna considers tandem autologous transplants or autologous transplant followed by allogeneic transplant from an haploidentical to fully matched related donor or well-matched unrelated donor (i.e., meeting National Donor Marrow Program (NDMP) criteria for selection of unrelated donors) medically necessary for the treatment of MM or POEMS syndrome when the afore-mentioned criteria 1.A – 1.D as well as all of the following selection criteria are met: 

   • Members with active myeloma; and
   • Planned first and second transplantation should be within a 6-month period.

Note: Exclusion Criteria for Single or Tandem Transplantation (any of the following):

• Inadequate cardiac, renal, pulmonary, or hepatic function or
• Presence of another life-limiting cancer or cancer that may become life-threatening with immunosuppression; or
• Presence of psychiatric disease that would interfere with the member’s ability to comply with the therapeutic regimen.

Note: A second course of autologous hematopoietic cell transplantation in members who have relapsed is not considered tandem transplantation.  A second course of autologous hematopoietic cell transplantation may be considered medically necessary for the treatment of responsive MM or POEMS syndrome that has relapsed after a durable complete or partial remission following an autologous transplantation.

Aetna considers the use of natural killer cells in autologous stem cell transplantation (ASCT) for the treatment of MM experimental and investigational because the effectiveness of this approach has not been established.

Background

Multiple myeloma (MM) is a hematological malignancy composed of an expanding clone of plasma cells within the bone marrow.  Multiple myeloma is a classic example of a monoclonal proliferation of tumor cells: in 90 % of cases the disease is characterized by the plasma cell production of a monoclonal immunoglobulin, often referred to as a M-component, which can be quantified in the serum or urine.  An M-component can be identified by serum electrophoresis if the concentration is 0.5 g/dL or higher.  Immunofixation techniques can identify smaller elevations.  Immunoglobulins are composed of 1 of 5 types of heavy chains and 1 of 2 types of light chains.  Thus, there are 4 major classes of M-component corresponding to the heavy chain (in descending order of frequency): IgG, IgA, IgD, and IgE (IgM M-component is typically not associated with MM, but is attributable to Waldenstrom's macroglobulinemia or monoclonal gammopathy of uncertain significance [MGUS]).  The 2 types of light chain are known as kappa and lambda.  Occasionally in MM, the secretion of the light and heavy chains become unbalanced or only the light chain is produced.  Excess light chains are freely filtered in the kidney and may appear in the urine, where they are known as Bence Jones protein.

The expansion of the malignant clone of cells in the bone marrow with associated destruction of bone, and the production of the M-component lead to the classic signs/symptoms of MM: lytic bone lesions with painful fractures, hypercalcemia, anemia, amyloidosis, renal failure as well as infections associated with immunodeficiency.  Approximately 50 % of patients are older than 65 years of age at diagnosis.  Multiple myeloma is staged by evaluating the systemic body burden of the tumor; and the staging system is shown below:

Stage I (all of the following)

1. Hemoglobin greater than 100 g/L (10 g/dL); and
2. Serum calcium less than 3 mM/L (12 mg/dL); and
3. Normal bone x-ray or solitary lesion; and
4. Low M-component production as evidenced by:
   
   
   1. IgG level less than 50 g/L (5 g/dL); and
   2. IgA less than 30 g/L (3 g/dL); and
   3. Urine light chain (kappa or lambda) less than 4 g/24 hr; and  
5. Estimated myeloma cell mass less than 0.6 trillion cells/m² 

Stage II

1. Fitting neither Stage I nor Stage III (overall data not as minimally abnormal as shown for Stage I and no single value abnormal as defined for Stage III); and
2. Estimated myeloma cell mass 0.6 to 1.2 trillion cells/m²
   

Stage III (one or more of the following)

1. Hemoglobin less than 85 g/L (8.5 g/dL) 
2. Serum calcium greater than 3 mM/L (12 mg/dL) 
3. Advanced lytic bone lesions
4. High M-component production as shown by:
    
   1. IgG greater than 70 g/L (7 g/dL) 
   2. IgA greater than 50 g/L (5 g/dL) 
   3. Urine light chain (kappa or lambda) greater than 12 g/24 hours 
5. Estimated myeloma cell mass greater than 1.2 trillion cells/m²

Sub-Classification:

A = Normal renal function (serum creatinine value less than 2 mg/dL)

B = Abnormal renal function (serum creatinine value greater than or equal to 2 mg/dL)

The stage of the disease, general health of the patient, and occurrence of complications of the illness usually determine treatment.  Traditionally, the primary approach to treatment of MM has been aimed at limiting the destructive action on the skeleton, kidney, and bone marrow.  Systemic anti-neoplastic therapy is the initial approach to treatment for patients with signs and symptoms of progressive disease.  For the past 2 decades, the combination of melphalan and prednisone has been the standard therapy for MM.  For patients who have proven to be resistant to this therapy, a combination of vincristine, adriamycin with dexamethasone (VAD) has been implemented.  The literature indicates that multi-drug combinations have failed to substantially improve the results originally obtained with standard melphalan and prednisone.  Approximately 40 to 50 % respond initially (using 50 % tumor reduction criteria), although the incidence of true complete remission is rare, probably lower then 10 %.  The median survival does not exceed 3 years.  About 5 % of patients, mainly those presenting with low tumor mass and responding to initial therapy, survive 10 and 15 years, but eventually succumb to their disease.

High-dose chemotherapy (HDC) bone marrow or peripheral stem cell transplant (autologous or allogeneic) has been shown to be a treatment option for patients with MM.  The basic concept behind HDC is a combination regimen of marrow ablative drugs which have different mechanism of action to maximally eradicate the malignant cells, and non-overlapping toxicity such that the doses can be maximized as much as possible.  Total body irradiation (TBI) is an additional variable.  A variety of regimens have been developed for MM, which primarily involve the use of different alkylating agents.  Patients with the disease who are responsive to standard doses of chemotherapy, and are either asymptomatic or have a good performance status and who do not have any serious co-morbidities are considered optimal candidates for HDC.

Autologous bone marrow transplant (ABMT) or peripheral stem cell transplant (ASCT) permits the use of chemotherapeutic agents at doses that exceed the myelotoxicity threshold; consequently, a greater tumor cell kill might be anticipated.  It has been suggested that the resultant effect is a greater response rate and possibly an increased cure rate.  Autologous bone marrow transplant entails the patient acting as his/her own bone marrow donor.  The patient's marrow is harvested via aspiration from the iliac crests under general or regional anesthesia.  The marrow is then preserved and re-infused following completion of a potent chemotherapy regimen.  This process provides pluripotent marrow stem cells to reconstitute (i.e., rescue) the patient's marrow from the myeloablative effects of high-dose cytotoxic chemotherapeutic agents.

Allogeneic bone marrow transplant refers to the use of functional hematopoietic stem cells from a healthy donor to restore bone marrow function following HDC.  For patients with marrow-based malignancies, the use of allogeneic stem cells offers the advantage of lack of tumor cell contamination.  Furthermore, allogeneic stem cells may be associated with a beneficial graft versus tumor effect.

Tandem (sequential or double) transplant utilizes a cycle of HDC with ASCT followed in about 6 months by a second cycleof HDC and/or TBI with another ASCT.  This is done in an attempt to obtain greater and extended response rates.  In a recent review on the treatment strategies for MM, Gisslinger and Kees (2003) stated that the use of tandem transplantation, developed to further escalate the conditioning dose, has achieved additional improvement in survival. 

Multiple myeloma also includes indolent myeloma, smoldering myeloma and monoclonal gammopathy of uncertain significance (MGUS).  With conventional-dose chemotherapy, patients with MM have a median survival of about 3 years, while the disease course of indolent and smoldering myeloma and MGUS is more uncertain.  Therefore, the distinction between these entities is important because HDC is clearly indicated only in cases of symptomatic MM.

Prior to HDC-ABMT, patients generally undergo induction therapy with vincristine, doxorubicin and dexamethasone, melphalan and prednisone or other combination salvage regimens.  Conventional dosages of these drugs can typically be given on an outpatient basis.  Hospitalization may be required due to neutropenic fever, nausea and vomiting, mucositis, diarrhea, or inadequate oral intake.

Prior to peripheral stem cell collection, an apheresis catheter may be inserted as an ambulatory surgical procedure.  The apheresis catheter can be placed during the same anesthesia procedure if a bone marrow harvest is also planned.  Apheresis is usually done as an outpatient procedure on a daily basis until adequate stem cells are collected.  From 5 to 10 procedures are usually necessary.

Stem cell mobilization, in which cyclophosphamide and/or granulocyte/macrophage colony stimulating factor (GM-CSF) are used to flush the critical stem cells from the bone marrow into the peripheral circulation, may also be part of the stem cell collection.  Protocols vary – some institutions administer intermediate doses of cyclophosphamide (4 g/m2) as an outpatient procedure, followed by apheresis in 5 to 14 days when the blood counts have recovered.  When high-dose cyclophosphamide (6 g/m2) is used, hospitalization for about 4 days is required for pre- and post-chemotherapy hydration.  After completion of the cyclophosphamide regimen, the patient can usually be discharged; apheresis can be administered on an outpatient basis once the acute period of bone marrow hypoplasia has resolved.

Hospitalization for the HDC component of the procedure depends on the regimen.  High-dose melphalan (140 to 200 mg/m2) may be given as an outpatient with home hydration therapy.  This outpatient HDC is the exception.  Other high-dose combination therapies, such as EDAP (etoposide, dexamethasone, ara-C and cisplatin) require hospitalization due to nausea and vomiting, mucositis, diarrhea and inadequate oral intake.  Any regimen that includes TBI will require a prolonged hospital stay averaging about 30 days.  Patients receiving HDC with or without TBI are initially treated in a private room for about 1 week until the blood counts start to drop.  Then patients are typically transferred to a specialized laminar flow room for the duration of their hospital stay.

Usual length of stay for patients undergoing peripheral stem cell collection with high-dose cyclophosphamide mobilization is 4 days.  Other stem cell mobilization protocols do not usually require a hospital stay.

Usual length of stay for patients hospitalized for complications related to HDC depend on resolution of fever (i.e., fever-free for 48 hours while off all antibiotics), adequate blood counts (i.e., WBC greater than 500), and resolution of other morbidity such as mucositis and diarrhea.  The patient must also be able to maintain adequate oral intake.  Hospital stays typically range from 2 to 4 weeks.  Patients can usually be discharged even if an adequate platelet count is transfusion dependent; platelet transfusions can be given on an outpatient basis.

Usual length of stay for patients undergoing HDC in conjunction with TBI is about 30 days.  Discharge parameters are similar to above: fever-free for 48 hours, adequate blood counts (WBC greater than 1,000).  Patients can usually be discharged even if an adequate platelet count if transfusion dependent; platelet transfusions can be given on an outpatient basis.

Patients with MM should generally be referred to an oncologist for the entire course of their disease, even if they should happen to achieve complete remission.  However, after the transplant is completed, patients may generally be referred back to a network oncologist for routine follow-up.

Studies on Autologous Transplant

Jagannath and co-workers (1990) reported the outcomes of 55 patients who underwent HDC-ABMT while they were in various stages of MM.  The myeloma was categorized according to its response to chemotherapy: first remission, primary resistant, second or greater remission or resistant relapse.  None of the 14 patients with a resistant relapse achieved a complete remission.  In addition, there was a 36 % incidence of early mortality in this group.  The authors concluded that HDC-ABMT can not be recommended for patients with resistant relapse.  On the other hand, patients in the other groups all achieved statistically similar complete remission rates, which ranged from 20 to 36 %.

Dimopoulos and colleagues (1993) conducted a phase II study of 40 patients with MM who received a combination of three alkylating agents as a preparative regimen prior to ABMT or ASCT.  Thirteen patients were in first partial remission (PR), 4 in second PR, 15 had primary refractory disease, and 8 had refractory relapse at the time of transplant.  Five patients (13 %) transplanted with autologous marrow experienced a treatment related death.  Except for the 1 treatment related death, all patients transplanted in 1st or 2nd PR remain free of progression from 4 to 20 months post-transplant.  The remission duration of the refractory relapse myeloma group was noted to be very short at a median of 4.1 months and the median survival time after transplant was only 4 months.  The authors concluded that this triple alkylator combination regimen is effective in producing extended remissions in selected patients with MM.  Patients with MM in refractory relapse do not appear to benefit from currently available ablative therapies.  Cunningham and associates (1994) reported the results of intensive chemotherapy with high-dose melphalan (HDM) and ABMT following conventional-dose cytoreductive chemotherapy in previously untreated patients with MM.  A total of 53 patients received induction chemotherapy every 3 weeks until a complete remission (CR) was attained or until the paraprotein level had plateaued over 2 successive courses.  Six to 10 weeks after the last course of cytoreductive therapy, HDM was administered.  Fifty-two of 53 patients (98 %) had a response to HDM – 40 patients (75 %) achieved a CR, including 27 of 38 patients who had a PR after induction chemotherapy and 4 of 6 who showed no response (NR); 11 patients achieved a PR, 1 had NR and there was 1 treatment-related death.  At the time of evaluation, 24 patients had relapsed and 28 remained in remission.  The estimated median duration of response was 23 months, with 30 % of patients free from progression at 36 months.  The investigators noted that these results were superior to that achieved with standard chemotherapy.  Twelve patients have died.  The median survival duration has not yet been reached, but 63 % of patients were expected to be alive at 54 months.  The authors concluded that HDM and ABMT after induction therapy produced response in practically all patients: CR was achieved in greater than 75 % of patients.  A considerable increase in duration of remission and survival is found, with the effect being most marked in those patients who reach CR.

Henon and colleagues (1995) compared HDC-autologous stem cell support and conventional chemotherapy in the treatment of a small number of newly diagnosed patients with MM (n = 37).  The median overall survival time was 44 months for the HDC-group compared with 8 months for the stage III, conventional chemotherapy-group, and 42 months for the stage II, conventional chemotherapy-group.  Moreover, the 5-year survival rates were 40, 27, and 0 % for the HDC-group, stage II and stage III conventional chemotherapy-groups, respectively.

Attal and colleagues (1996) published the first randomized controlled trial comparing conventional chemotherapy with HDC-ASCT for the treatment of previously untreated MM.  The study included 200 patients: 100 in the HDC-ASCT group and 100 in the conventional chemotherapy group.  All patients had stage II and stage III MM, were less than 65 years of age, and had not received prior treatment.  The complete or very good partial response rates were significantly better in the HDC-ASCT group compared to the conventional chemotherapy group, 38 versus 14 %, respectively.  The median event-free survival was 18 months for the conventional-dose group compared to 27 months in the HDC-ASCT group.  Overall patient survival was statistically significantly better in the transplanted group at 5 years (52 versus 12 %).  The survival curves at 5 years were projected based on relatively few patients actually reaching the 5-year follow-up point.  The authors did not indicate the number of patients reaching 5 years of follow-up, but the wide confidence intervals for the survival rates and the fact that the median survival had not yet been reached in the high-dose group suggested that this projection was based on relatively few patients.  This study provided strong evidence for the benefits of HDC-ASCT for MM.

A review article by Kovacsovics and Delaly (1997) discussed various intensive treatment approaches for MM, including tandem transplants.  The authors concluded that administering tandem transplants is feasible and may increase the response rate to HDC in a subset of patients.  However, there is no evidence that it leads to prolonged remissions and increased survival.  Whether tandem transplants are superior to a single transplant needs to be examined by randomized studies.

A review article by Barlogie and co-workers (1997) discussed the experience of the University of Arkansas in treating patients with MM.  Since their initiation of tandem transplants in 1989, they have enrolled over 500 patients in their tandem transplant trials, with approximately 80 % completing the 2nd transplant within 1 year.  It is stated that 37 % of patients achieved CR and median duration of event-free survival and overall survival has been reached at 43 and 62 months, respectively.  However, these results were not compared to results of single transplant trials.  The authors stated that maximum tumor cytoreduction via tandem cycles of HDC with ASCT may be "a first but not necessarily sufficient step toward long-term disease control".

Kumar et al (2012) noted that early versus delayed autologous stem cell transplantation (SCT) results in comparable overall survival (OS) in patients with MM who receive alkylator-based therapies.  It is unclear if this approach holds true in the context of new therapies, such as immunomodulatory drugs (IMiDs).  These researchers studied 290 patients with untreated MM who received IMiD-based initial therapy, including 123 patients who received thalidomide-dexamethasone (TD) and 167 patients who received lenalidomide-dexamethasone (LD) induction before SCT.  Patients who underwent a stem cell harvest attempt were considered transplantation-eligible and were included.  Autologous SCT within 12 months of diagnosis and within 2 months of harvest were considered early SCT (n = 173; 60 %); SCT greater than 12 months after diagnosis was considered delayed SCT (n = 112; 40 %).  In the delayed SCT group, 42 patients had undergone SCT at the time of the current report, and the median estimated time to SCT was 5.3 months and 44.5 months in the early SCT and delayed SCT groups, respectively.  The 4-year OS rate from diagnosis was 73 % in both groups (p = 0.3) and was comparable in those who received TD (68 % versus 64 %, respectively) and those who received LD (82 % versus 86 %, respectively) as initial therapy.  The time to progression after SCT was similar between the early and delayed SCT groups (20 months versus 16 months; p value was non-significant).  The authors concluded that these findings indicated that, in transplantation-eligible patients who receive IMiDs as initial therapy followed by early stem cell mobilization, delayed SCT results in similar OS compared with early SCT.  It is noteworthy that an excellent 4-year survival rate of greater than 80 % was observed among transplantation-eligible patients who received initial therapy with LD regardless of the timing of transplantation.

Studies on Allogeneic Transplant

Bensinger and associates (1996) examined the effect of high-dose busulfan and cyclophosphamide followed by allogeneic bone marrow transplantation in 80 patients with MM.  At the time of transplant, 71 % of the patients had disease that was refractory to chemotherapy.  The majority of patients was transplanted beyond 1 year from diagnosis and were heavily pretreated.  Results were reported as follows: 29 patients attained a CR post-transplant, 18 had a PR, 3 had NR, and 30 patients were not evaluable for response due to early death.  The overall CR rate was 36 % for all patients and 58 % for assessable patients.  A total of 53 patients died.  It was reported that 15 patients were surviving disease-free 1 to 7 years post-transplant.  According to the authors, adverse risk factors for outcome endpoints included: transplantation greater than 1 year from diagnosis; B-2 microglobulin greater than 2.5 at transplant; female patients transplanted from male donors; patients who received greater than 8 cycles of chemotherapy before transplant; and Durie stage 3 disease at the time of transplant.  The authors concluded that HDC followed by allogeneic bone marrow transplant could result in long-term disease-free survival for a minority of patients.

Bjorkstrand and colleagues (1996) performed a retrospective case-matched analysis comparing 189 patients with MM treated with allogeneic bone marrow transplant (Allo-BMT) with patients who received ASCT.  The median post-transplant follow-up for surviving patients was 46 months for Allo-BMT and 30 months for ASCT.  Results were reported as follows.  The overall response rate was higher in the ASCT group (86 versus 72 % for Allo-BMT).  However, there was no significant difference between the Allo-BMT and ASCT groups with regard to post-transplant CR (48 % for Allo-BMT versus 40 % for ASCT).  Twenty percent of the Allo-BMT patients were not evaluable for response compared to 6 % of ASCT patients.  The overall survival was better for the ASCT group (median survival of 34 months for ASCT versus 18 months for Allo-BMT); although the survival advantage was only observed in men, not in women.  The rate of relapse from CR or progression from PR was significantly higher in the ASCT group.  The relapse/progression rate at 48 months was 70 % in the ASCT group, compared to 50 % for the Allo-BMT group.  Twenty-two percent of the Allo-BMT patients and 35 % of the ASCT patients have died from progressive MM.  The authors concluded that the median survival was greater for ASCT, although Allo-BMT had a lower relapse rate.

A review article by Gahrton and Bjorkstrand (2000) stated that high-dose myeloablative treatment followed by autologous hematopoietic stem cell transplantation has significantly improved survival of patients younger than 65 years of age with MM as compared with conventional chemotherapy.  However, all patients seem to relapse.  Results of allogeneic transplantation, still hampered by high transplant-related mortality, have improved dramatically over the last 5 to 6 years and this is an option for patients younger than 50 to 55 years old.  The relapse rate for allogeneic transplantation is lower than that with autologous transplantation.

Koehne and Giralt (2012) noted that despite the curative potential of allogeneic hematopoietic stem cell transplantation (allo HSCT) for patients with MM, and reduction of transplant-related mortality (TRM) with non-myeloablative transplant approaches, rates of acute and chronic graft-versus-host disease (GVHD) and disease progression remain high.  It is unclear if non-myeloablative transplants are more effective than autologous (auto).  Novel promising drugs and maintenance treatment strategies following auto SCT may also delay allo transplantation.  These researchers summarized the emerging data on allo HSCT and provided suggestions for its optimal role in the treatment of MM.  Large co-operative group studies comparing allo HSCT with auto SCT as frontline therapy have been performed with reduced intensity conditioning regimens using unmanipulated peripheral blood stem cells from HLA-compatible donors and standard calcineurin inhibitor GVHD prophylaxis.  Two recent reports showed conflicting data.  Although the Blood and Marrow Transplant Clinical Trials Network 0102 study demonstrated no progression-free or OS advantage at 3 years, a European study demonstrated superior 5-year outcome after auto/HLA-matched sibling allo HSCT compared with tandem auto SCT in previously untreated MM patients.  The advent of maintenance therapy could potentially improve outcomes of both transplant types.  The authors concluded that high rates of acute and chronic GVHD currently limit the implementation of non-myeloablative allo HSCT.  Novel approaches are needed so that patients with MM can undergo allo HSCT before resistance develops to standard drug combinations.

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

The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements:

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

Studies of Double Transplantation

Bruno et al (2007) found that, among patients with newly diagnosed multiple myeloma, survival in recipients of a tandem hematopoietic stem-cell autograft followed by a stem-cell allograft from an human leukocyte antigen (HLA)-identical sibling was superior to that in recipients of tandem stem-cell autografts.  The investigators enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least 1 sibling.  All patients were initially treated with VAD (vincristine, doxorubicin, dexamethasone) induction chemotherapy followed by stem-cell mobilization, melphalan conditioning therapy, and autologous stem-cell transplant.  Sixty patients with an HLA-identical sibling were then scheduled to receive an allogeneic stem cell transplant.  Eighty-two patients without an HLA-identical sibling (as well as 20 who refused allogeneic transplant or whose donors were ineligible) were scheduled for second autologous stem cell transplants.  The conditioning regimens differed between the arms: patients receiving an autologous followed by allogeneic stem cell transplant received melphalan (200 mg/m2) before their autologous stem cell transplants and then non-myeloablative doses of TBI prior to their allogeneic stem cell transplants, whereas tandem autologous stem cell transplant patients received melphalan before each transplant.  Complete remission rates were higher in the group receiving autologous followed by allogeneic stem cell transplant than in the group receiving tandem autologous stem cell transplants (55 % versus 26 %; p = 0.004).  After a median follow-up of 45 months (range of 21 to 90 months), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months versus 54 months, p = 0.01; and 35 months versus 29 months, p = 0.02, respectively) (even though this analysis included all patients with matched siblings, regardless of whether they actually received allogeneic transplants).  Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft-allograft transplant group (58 patients, p = 0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43 % versus 7 %, p < 0.001).  About 2/3 of the group receiving autologous followed by allogeneic stem cell transplant developed graft-versus-host disease.  Commenting on the study by Bruno et al (2007), Williams (2007) stated that these results suggest that a beneficial graft-versus-myeloma effect occurs with allogeneic stem cell transplant.  However, the differences in conditioning regimens between the 2 arms of this study limit the conclusions that can be drawn.

In a multi-center, randomized, clinical trial, Abdelkefi and colleagues (2008) reported that single ASCT followed by maintenance therapy with thalidomide is superior to double autologous transplantation in MM.  A total of 195 patients with de novo symptomatic myeloma and younger than 60 years of age were randomly assigned to receive either tandem transplantation up front (arm A, n = 97) or 1 ASCT followed by a maintenance therapy with thalidomide (day + 90, 100 mg per day during 6 months) (arm B, n = 98).  Patients included in arm B received a 2nd transplant at disease progression.  In both arms, ASCT was preceded by 1st-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m(2)) and GM-CSF.  Data were analyzed on an intent-to-treat basis.  With a median follow-up of 33 months (range of 6 to 46 months), the 3-year OS was 65 % in arm A and 85 % in arm B (p = 0.04). The 3-year progression-free survival was 57 % in arm A and 85 % in arm B (p = 0.02).

Kumar et al (2009) performed a systematic review and meta-analysis to synthesize the existing evidence related to the effectiveness of tandem versus single autologous hematopoietic cell transplant (AHCT) in patients with MM.  These investigators searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008.  Endpoints were OS, event-free survival (EFS), response rate, and TRM.  Data were pooled under a random-effects model.  A total of 6 RCTs enrolling 1,803 patients met the inclusion criteria.  Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant versus single transplant = 0.94; 95 % confidence interval [CI]: 0.77 to 1.14) or EFS (HR = 0.86; 95 % CI: 0.70 to 1.05).  Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95 % CI: 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95 % CI: 1.05 to 2.79).  There was statistically significant heterogeneity among RCTs for OS and EFS.  The authors concluded that in previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS; and that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.

Naumann-Winter et al (2012) stated that several clinical studies have compared single with tandem (also called double) ASCT as first-line treatment in patients with symptomatic MM.  In a Cochrane review, these investigators compared tandem ASCT (TASCT) with single ASCT (SASCT) as first-line treatment in patients with symptomatic MM with respect to OS, EFS, quality of life (QoL) and TRM.  These researchers systematically identified controlled trials published between January 1995 and May 2011 in 2 bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries.  One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions.  These investigators required a minimal set of details to be reported for observational studies for the studies to be included.  They critically evaluated eligible trials with respect to quality of design and actual performance.  One researcher extracted individual trial results, which were checked by another researcher.  They recapitulated the results of the individual trials in a standardized way for the SR in order to allow a systematic assessment of potential sources of bias.  Overall, these investigators identified 14 controlled studies.  One registered RCT is still recruiting patients at the time of this review and no clinical results have been published.  Two registered RCTs have remained unpublished despite their termination.  Publications on 1 RCT had been retracted.  These researchers excluded 5 observational studies since neither patients nor treatment regimens were sufficiently characterized to allow an assessment of potential confounding by indication.  They conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the 5 included RCTs (2 full-text publications, 3 conference presentations) enrolling 1,506 patients in total.  Because these investigators identified substantial clinical and methodological heterogeneity, they refrained from conducting a formal meta-analysis.   While these investigators included only previously untreated, symptomatic patients with MM, the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms.  Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least 1e component.  Three trials were likely to have the potential of being highly biased while 2 RCTs had a moderate potential for bias.  The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients.  In addition, OS data were confounded by the treatment subsequent to first-line therapy.  Overall survival was statistically significantly improved in 1 trial only.  While EFS was prolonged in 4 of the 5 trials, the median prolongation ranged between 3 to 12 months, with an uncertain direction of bias in the individual trials.  QoL was not reported in any study.  Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality.  The authors did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases.  In addition, none of the trials integrated the so-called "novel agents" that are now considered standard treatment for MM.  To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT.  Reporting of results of TRM should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).

Combination of Natural Killer Cells and Autologous Stem Cell Transplantation

Shah and colleagues (2017) stated that MM is a disease with known immune dysregulation; and natural killer (NK) cells have shown preclinical activity in MM.  In a phase I clinical trial, these researchers conducted a first-in-human study of umbilical cord blood (CB)-derived NK cells for MM patients undergoing HDC and auto-HCT.  Patients received lenalidomide (10 mg) on days -8 to -2, melphalan 200 mg/m2 on day -7, CB-NK cells on day -5, and auto-HCT on day 0.  A total of 12 patients were enrolled, 3 on each of 4 CB-NK cell dose levels: 5 × 106 , 1 × 107 , 5 × 107 and 1 × 108 CB-NK cells/kg; 10 patients had either high-risk chromosomal changes or a history of relapsed/progressed disease.  There were no infusional toxicities and no GVHD; 1 patient failed to engraft due to poor autologous graft quality and was rescued with a back-up autologous graft.  Overall, 10 patients achieved at least a very good PR as their best response, including 8 with near CR or better.  With a median follow-up of 21 months, 4 patients have progressed or relapsed, 2 of whom have died; CB-NK cells were detected in-vivo in 6 patients, with an activated phenotype (NKG2D+ /NKp30+ ).  The authors concluded that these findings warrant further development of this novel cellular therapy.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on "Multiple myeloma" (Version 3.2017) does not mention the use of NK cells as a therapeutic option.

Outpatient Versus Inpatient Autologous Stem Cell Transplantation

Khouri and Majhail (2017) noted that ASCT is generally performed in the in-patient setting.  Several centers have shown the feasibility of performing ASCT for MM in the ambulatory setting.  These investigators reviewed the safety, cost-effectiveness, complications and outcomes of out-patient ASCT for MM.  Published studies were heterogeneous but suggested that out-patient ASCT for MM was cost-effective and associated with a shorter or no initial hospitalization, albeit there was a high rate of re-admission for complications.  The TRM rate was less than 1 %.  Stringent patient selection criteria that included emphasis on functional status, care-giving support and psychosocial aspects for each patient were critical for identifying patients most appropriate for ASCT in the ambulatory setting.  There exists considerable variability in out-patient transplant models and supportive care guidelines and data did not support preference for one delivery model over another.  Survival and other transplant-related outcomes have not been reported widely and whether patients fare better with out-patient transplantation remains to be explored.  The authors concluded that out-patient ASCT for MM was feasible and well-tolerated in selected patients.  Several care models for out-patient ASCT exist and can be implemented based on transplant resources and preference.

Martino and co-workers (2018) stated that out-patient ASCT has been demonstrated to be feasible in terms of physical morbidity and mortality outcomes, but little data exist on the impact of this procedure on QoL.  In a prospective, observational, longitudinal cohort study, these researchers compared the effects of in-patient (n = 76) and out-patient (n = 64) modes of care on QoL in patients with MM who underwent ASCT.  Patients were treated according to their preference for the in-patient or out-patient model; QoL was assessed using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) at baseline (7 days before ASCT; T1) and at days +7 (T2) and +30 (T3) after ASCT.  Overall, in-patients achieved higher mean values at each time point (86.05 ± 15.54 at T1, 89.23 ± 19.19 at T2, and 87.96 ± 13.6 at T3) compared with out-patients (85.62 ± 14.51 at T1, 87.42 ± 23.41 at T2, and 83.98 ± 20.2 at T3), although the differences did not reach statistical significance.  In-patients showed higher mean scores than out-patients in physical well-being (7.67 ± 5.7, 15.44 ± 6.34, and 12.96 ± 6.03, respectively, versus 5.89 ± 4.33, 13.92 ± 7.05, and 8.84 ± 6.33, respectively; p < 0.05).  Mean scores on social/family well-being were significantly higher in the out-patient group compared with the in-patient group (22.93 ± 13.29, 21.14 ± 5.31, and 21.64 ± 4.58, respectively, versus 20.59 ± 3.79, 19.52 ± 5.12, and 20.01 ± 3.97, respectively; p = 0.003).  There were no significant between-group differences with respect to functional well-being and emotional status.  The authors concluded that among adults at a single institution undergoing ASCT for MM, the use of out-patient care compared with standard transplantation care did not result in improved QoL during transplantation.  Moreover, they stated that further research is needed for replication and to assess longer-term outcomes and implications.

Combined Kidney Transplantation and Hematopoietic Cell Transplantation for Patients with Multiple Myeloma and End Stage Renal Disease

Baraldi and associates (2016) stated that amyloidosis, gammopathies, and MM are plasma cell dyscrasias (PCDs) characterized by clonal proliferation and immunoglobulin (Ig) over-production.  Renal impairment is the most common and serious complication with an incidence of 20 % to 30 % patients at the diagnosis.  Kidney transplantation (KT) has not been considered feasible in the presence of PCDs because the immunosuppressive therapy may increase the risk of neoplasia progression, and paraproteins may affect the graft.  However, recent advances in clinical management of MM and other gammopathies allow considering KT as a possible alternative to dialysis.  Numerous evidence indicated the direct relationship between hematological remission and renal function restoring.  The authors concluded that the combination of KT and HCT has been reported as a promising approach to re-establish end-organ function and effectively treat the underlying disease.

Domínguez-Pimentel and colleagues (2019) noted that PCDs include a number of entities (e.g., amyloidosis, MM, and monoclonal Ig deposition disease); and HCT is the only cure for a variety of hematologic and oncologic diseases.  Clinically significant renal impairment is a common feature in plasma cell myeloma, affecting 20 % to 55 % of patients at initial diagnosis; 2 % to 3 % of patients present with failure sufficiently severe to require hemodialysis.  This circumstance is associated with a high early mortality.  The necessity for immunosuppression following HCT could complicate its management and may precipitate the development of complications.  In some patients an effective alternative could be KT; however, the presence of 2 transplants will require optimal adjustment of immunosuppression and management of complications.  At present, there are few published cases of KT following HCT, and the experience of managing 2 transplants is limited.  These investigators described their experience with 4 patients who had a PCD and initially received HCT and received subsequent KT; in their experience the progress and outcome of KT following HCT were optimal.

Spitzer and co-workers (2019) noted that specific immune tolerance of transplanted organs in association with either transient or sustained lymphohematopoietic chimerism has been demonstrated in several pre-clinical animal models and clinically, in patients who are full donor chimeras following HSCT and subsequently received KT from the same donor.  Most recently, tolerance induction has been extended to patients in whom chimerism was intentionally induced at the time of KT.  Twenty years ago, these investigators reported the 1st successful HLA-matched sibling donor BMT and KT following non-myeloablative conditioning in a patient with MM and end stage renal disease (ESRD).  After 2 decades, she had normal renal function in the absence of ongoing systemic immunosuppressive therapy; 9 patients had subsequently undergone similar treatment for MM with ESRD.  In the initial patient, hematopoietic chimerism was detectable for only 105 days after the transplant.  In subsequent patients, chimerism detection ranged from 49 days to greater than 14 years.  Nevertheless, a long remission of the myeloma and long-term immunosuppression-free survival of the kidney allograft were achieved in 7 of 10 patients, 5 of whom currently survive.  The authors concluded that this initial patient demonstrated the feasibility of performing combined HLA-matched, sibling donor BMT and KT for ESRD due to MM.  This experience paved the way for extending the initial trial to 9 additional patients with MM and ESRD, and more recently, to tolerance induction strategies involving combined BMT and KT for patients with and without an underlying malignancy.

Bloodless Autologous Stem Cell Transplantation

Joseph and colleagues (2019) stated that HDC and ASCT are established components in the treatment of MM; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products (e.g., Jehovah’s Witnesses). Most transplant centers decline HDT/ASCT to these patients because of safety concerns.  In a retrospective, case-control study, these researchers examined their institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL-ASCT) among patients with MM. This trial included patients who underwent BL-ASCT and transfusion-supported ASCT (TS-ASCT) at Emory University Hospital between August 2006 and August 2016. A total of 24 patients who underwent BL-ASCT and 70 who underwent TS-ASCT were included.  The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant-related cardiovascular complications or mortality in either the BL-ASCT group or the TS-ASCT group. The median progression-free survival (PFS) was 36 months and 44 months in the BL-ASCT and TS-ASCT groups, respectively (p = 0.277), and the median OS was not reached in either group at a median follow-up of 59 months after ASCT (p = 0.627).  There was no transplant-related mortality at the 100-day or 1-year mark in either group.  The authors concluded that BL-ASCT was safe and feasible; transplant-related mortality, cardiovascular and hematologic complications were similar to those associated with TS-ASCT.  Furthermore, BL-ASCT could yield similar engraftment and survival parameters comparable to those observed with TS-ASCT.

Beck and associates (2020) noted that due to the curative potential and improvement in PFS, HDC followed by ASCT is considered the standard of care for several hematologic malignancies, such as MM, and lymphomas. ASCT typically involves support with blood product transfusion.  Therefore, difficulties arise when Jehovah's Witness patients refuse blood transfusions.  To demonstrate the safety of performing BL-ASCT, these investigators carried out a retrospective analysis of 66 Jehovah's Witnesses patients who underwent BL-ASCT and 1,114 non-Jehovah's Witness patients who underwent TF-ASCT at Cedars-Sinai Medical Center between January 2000 and September 2018.  Survival was compared between the 2 groups. Transplant-related complications, mortality, engraftment time, length of hospital stay, and number of intensive care unit (ICU) transfers were characterized for the BL-ASCT group.  One year survival was found to be 87.9 % for both groups (p = 0.92).  In the BL-ASCT group, there was 1 death prior to the 30 days post-transplant due to central nervous system (CNS) hemorrhage, and 1 death prior to 100 days due to sepsis.  The authors concluded that based on these findings, BL-ASCT could be safely performed with appropriate supportive measures, and these researchers encouraged community oncologists to promptly refer Jehovah's Witnesses patients for transplant evaluation when ASCT is indicated.

ASTCT Clinical Practice Recommendations for Transplant and Cellular Therapies in Multiple Myeloma

Dhakal and colleagues (2022) stated that over the last 10 years, therapeutic options in MM have changed dramatically.  Given the unprecedented effectiveness of novel agents, the role of HCT in MM remains under scrutiny.  Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape.  The American Society for Transplantation and Cellular Therapy (ASTCT) convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of auto-HCT, allo-HCT and CAR T-cell therapy for patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM).  The RAND-modified Delphi method was used to generate consensus statements.  A total of 20 consensus statements were generated.  The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care (SOC) option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial.  For patients not undergoing auto-HCT upfront, the panel recommended its use in 1st relapse.  Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients.  In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy.  The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial.  The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
38230	Bone marrow harvesting for transplantation
38232	autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
86813	HLA typing; A, B or C multiple antigens
86817	DR/DQ, multiple antigens
86821	lymphocyte culture, mixed (MCL)
Other CPT codes related to the CPB:
38204, 38207 - 38215	Bone Marrow or Stem Cell Services/Procedures
86920 - 86923	Compatibility test each unt
96401 - 96450	Chemotherapy administration code range
Modifier 4A - 4Z	Histocompatibility/Blood Typing/Identity/Microsatellite
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic; emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
Other HCPCS codes related to the CPB:
J9000 - J9999	Chemotherapy drugs
Q0083 - Q0085	Chemotherapy administration
ICD-10 codes covered if selection criteria are met:
C90.00 - C90.02	Multiple myeloma
D47.z9	Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue [POEMS]
E85.0 - E85.9	Amyloidosis
ICD-10 codes not covered for indications listed in the CPB:
C88.0	Waldenstrom macroglobulinemia
D47.2	Monoclonal gammopathy
D89.2	Hypergammaglobulinemia, unspecified
E63.9	Nutritional deficiency, unspecified [additional code required, see I43]
I43	Cardiomyopathy in diseases classified elsewhere [this code is to be used with E63.9]

The above policy is based on the following references: