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1 1 of 28 Number: 0497 Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB. I. 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: Last Review 09/01/2017 Effective: 02/01/2002 Next Review: 05/10/2018 Review History Definitions A. Member must not have significant co morbid medical conditions; and B. 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 C. The member has adequate major organ function based on the transplant institution's evaluation; and D. Members with indolent myeloma, smoldering myeloma, Clinical Policy Bulletin Notes

2 2 of 28 and monoclonal gammopathy of uncertain significance [MGUS] are excluded. II. 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 A. The member has adequate major organ function based upon the transplanting institution's evaluation; and B. The member has early relapse (less than 24 months) after primary therapy that included an autologous 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. III. 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 wellmatched 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 1st and 2nd transplantation should be within a 6 month period.

3 3 of 28 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,

4 4 of 28 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) I. Hemoglobin greater than 100 g/l (10 g/dl); and II. Serum calcium less than 3 mm/l (12 mg/dl); and III. Normal bone x ray or solitary lesion; and IV. Low M component production as evidenced by: A. IgG level less than 50 g/l (5 g/dl); and B. IgA less than 30 g/l (3 g/dl); and C. Urine light chain (kappa or lambda) less than 4 g/24 hr; and V. Estimated myeloma cell mass less than 0.6 trillion cells/m 2 Stage II: I. 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 II. Estimated myeloma cell mass 0.6 to 1.2 trillion cells/m 2 Stage III: (one or more of the following) I. Hemoglobin less than 85 g/l (8.5 g/dl) II. Serum calcium greater than 3 mm/l (12 mg/dl)

5 5 of 28 III. Advanced lytic bone lesions IV. High M component production as shown by: A. IgG greater than 70 g/l (7 g/dl) B. IgA greater than 50 g/l (5 g/dl) C. Urine light chain (kappa or lambda) greater than 12 g/24 hours V. Estimated myeloma cell mass greater than 1.2 trillion cells/m 2 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.

6 6 of 28 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 cycle of HDC

7 7 of 28 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

8 8 of 28 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

9 9 of 28 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

10 10 of 28 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 HDCgroup 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

11 11 of 28 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".

12 12 of 28 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

13 13 of 28 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

14 14 of 28 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 TRM with nonmyeloablative 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. Giralt and colleagues (2015) stated that the International

15 15 of 28 Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (i) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (ii) propose guidelines for the use of salvage HCT in MM, (iii) identify knowledge gaps, (iv) propose a research agenda, and (v) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: 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

16 16 of 28 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 In a randomized study, Attal et al (2003) evaluated treatment of MM with HDC followed by either 1 or 2 successive ASCT. A total of 399 previously untreated patients under the age of 60 years were randomly assigned to receive (i) a single, or (ii) double transplant. Exclusion criteria for patients in the study by Attal et al (2003) included presence of another cancer; inadequate cardiac, renal, pulmonary, or hepatic function; presence of psychiatric disease; and age of 60 years or older. A complete or a very good partial response was achieved by 42 % of patients in the single transplant group and 50 % of patients in the doubletransplant group (p = 0.10). The probability of surviving eventfree for 7 years after the diagnosis was 10 % in the singletransplant group and 20 % in the double transplant group (p = 0.03). The estimated overall 7 year survival rate was 21 % in the single transplant group and 42 % in the double transplant group (p = 0.01). Among patients who did not have a very good PR within 3 months after 1 transplantation, the probability of surviving 7 years was 11 % in the single transplant group and 43 % in the double transplant group (p < 0.001). The authors concluded that as compared with a single ASCT after HDC, double transplantation improves overall survival among patients with MM, especially those who do not have a very good partial response after undergoing 1 transplantation.

17 17 of 28 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

18 18 of 28 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 metaanalysis 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, Endpoints were OS, event free survival (EFS), response rate, and treatment related mortality (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

19 19 of 28 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

20 20 of 28 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

21 21 of 28 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, and 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 ) does not mention the use of NK cells as a therapeutic option. CPT Codes / HCPCS Codes / ICD 10 Codes 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: Bone marrow harvesting for transplantation autologous Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor autologous transplantation HLA typing; A, B or C multiple antigens DR/DQ, multiple antigens

22 22 of lymphocyte culture, mixed (MCL) lymphocyte culture, primed (PLC) Other CPT codes related to the CPB: Bone Marrow or Stem Cell Services/Procedures Compatibility test each unit Chemotherapy administration code range Modifier 4A 4Z Histocompatibility/Blood /Microsatellite Typing/Identity 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 Chemotherapy administration Q0085 ICD 10 codes covered if selection criteria are met: C90.00 C90.02 D47.z9 Multiple myeloma 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

23 23 of 28 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: 1. Jagannath S, Barlogie B, Dicke K, et al. Autologous bone marrow transplantation in multiple myeloma: Identification of prognostic factors. Blood. 1990;76: Barlogie B, Epstein J, Selvanayagam P, et al. Plasma cell myeloma New biological insights and advances in therapy. Blood. 1989;73: Dunbar CE, Nienhuis AW. Multiple myeloma. New approaches to therapy. JAMA. 1993;269: Dimopoulos MA, Alexanian R, Przepiorka D, et al. Thiotepa, busulfan and cyclophosphamide. A new preparative regimen for autologous marrow or blood stem cell transplantation in high risk multiple myeloma. Blood. 1993;82: Reece DE, Barnett JM, Connors JM, et al. Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4 hydroxyperoxycyclophosphamide. Bone Marrow Transplant. 1993;11: Dimopoulos MA, Hester J, Huh Y, et al. Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma. Br J Haematol. 1994;87: Cunningham D, Paz Ares L, Milan S, et al. High dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma. J Clin Oncol. 1994;12(4): Henon P, Donatini B, Eisenmann JC, et al. Comparative survival, quality of life and cost effectiveness of intensive therapy with autologous blood cell transplantation or conventional chemotherapy in multiple myeloma. Bone

24 24 of 28 Marrow Transplant. 1995;16: Barlogie B, Jagannath S, Vesole D, et al. Autologous and allogeneic transplants for multiple myeloma. Semin Hematol. 1995;32: Attal M, Harousseau J L, Stoppa A M, et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335: Bensinger W, Buckner C, Anasetti C. Allogeneic marrow transplantation for multiple myeloma: An analysis of risk factors on outcome. Blood. 1996;88(7): Bjorkstrand B, Ljungman P, Svensson H. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: A retrospective casematched study from the European Group for blood and marrow transplantation. Blood. 1996;88(12): Kovacsovics TJ, Delaly A. Intensive treatment strategies in multiple myeloma. Semin Hematol. 1997;34(1Suppl 1): Barlogie B, Jagannath S, Epstein J, et al. Biology and therapy of multiple myeloma in Semin Hematol. 1997;34(1Suppl 1): Bataille R, Harousseau J L. Multiple myeloma. N Engl J Med. 1997;336: Kyle RA. High dose therapy in multiple myeloma and primary amyloidosis: An overview. Semin Oncol. 1999;26: Gahrton G, Bjorkstrand B. Progress in haematopoietic stem cell transplantation for multiple myeloma. J Intern Med. 2000;248(3): Longo DL. Plasma cell disorders. In: Harrison's Principles of Internal Medicine. 15th ed. Vol. 1. E Braunwald, et al. eds. New York: McGraw Hill; 2001; Ch. 114: Imrie K, Esmail R, Meyer R; Hematology Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative. The role of high dose chemotherapy and stem cell transplantation in patients with multiple myeloma: A practice guideline of the Cancer Care Ontario Practice Guidelines Initiative. Ann Intern Med. 2002;136(8): Gisslinger H, Kees M. Therapy strategies for multiple

25 25 of 28 myeloma: Current status. Wien Klin Wochenschr. 2003;115(13 14): 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): Child JA, Morgan GJ, Davies FE, et al.; Medical Research Council Adult Leukaemia Working Party. High dose chemotherapy with hematopoietic stem cell rescue for multiple myeloma. N Engl J Med. 2003;348(19): Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood. 2004;103(1): Harousseau JL. Stem cell transplantation in multiple myeloma (0, 1, or 2). Curr Opin Oncol. 2005;17(2): Levy V, Katsahian S, Fermand JP, et al. A meta analysis on data from 575 patients with multiple myeloma randomly assigned to either high dose therapy or conventional therapy. Medicine (Baltimore). 2005;84(4): Bensinger WI. The current status of reduced intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia. 2006;20(10): 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): Williams ME. Allogeneic vs. second autologous stem cell transplantation for newly diagnosed myeloma [comment]. J Watch Oncol Hematol. 2007: Koreth J, Cutler C S, 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): van Rhee F. Commentary: Is double autologous stem cell transplantation appropriate for new multiple myeloma patients? Nat Clin Pract Oncol. 2008;5(2): Bensinger W. Stem cell transplantation for multiple myeloma in the era of novel drugs. J Clin Oncol. 2008;26(3): Kumar A, Djulbegovic B. Myeloma (multiple). In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group;