Prior Authorization Review Panel MCO Policy Submission A ... · A separate copy of this form must accompany each policy submitted for ... *Please see amendment for Pennsylvania Medicaid

Prior Authorization ReviewPanel MCO Policy Submission

A separate copy of this form must accompany each policy submitted forreview.

Policies submitted without this form will not be considered for review.

Plan: Aetna Better Health Submission Date: 11/01/2018

Policy Number: 0497 Effective Date: Revision Date:

Policy Name: Hematopoietic Cell Transplantation for Multiple Myeloma

Type of Submission – Check all that apply: New Policy Revised Policy* Annual Review – No Revisions

*All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below:

CPB 0497 Hematopoietic Cell Transplantation for Multiple Myeloma

Clinical content was last revised 09/21/2017. Additional non-clinical updates were made by Corporate since the last PARP submission, as documented below.

Revision and Update History since last PARP submission: 10/03/2018 - This CPB has been updated with additional background information and references. 05/09/2019 – Next tentative scheduled review date by Corporate .

Name of Authorized Individual (Please type or print):

Dr. Bernard Lewin, M.D.

Signature of Authorized Individual:

www.aetnabetterhealth.com/pennsylvania Updated 10/03/2018

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Hematopoietic Cell Transplantation for MultipleMyeloma

Policy His tory

Last Review

10/03/2018

Effective: 02/01/2002

Next

Review: 05/09/2019

Review History

Definitions

A dditiona l In form at ion

Clinical Policy

Bulletin Notes

Number: 0497 *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Policy

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:

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

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Hematopoietic Cell Transplantation for Multiple Myeloma - Medical Clinical Policy Bull... Page 2 of 35

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, 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 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 1st and 2nd 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)




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/m2

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/m2

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)

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/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



Hematopoietic Cell Transplantation for Multiple Myeloma - Medical Clinical Policy B... Page 10 of 35

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.

Giralt and colleagues (2015) stated that the International

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

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 double-transplant group (p = 0.10). The

probability of surviving event-free for 7 years after the

diagnosis was 10 % in the single-transplant 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.




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.

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 "+":

Code Code Description

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)

86822 lymphocyte culture, primed (PLC)

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]

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

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general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

subject to change.

Copyright © 2001-2018 Aetna Inc.



AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment toAetna Clinical Policy Bulletin Number:

0497 Hematopoietic Cell Transplantation for Multiple Myeloma

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania Updated 10/03/2018

http://www.aetnabetterhealth.com/pennsylvania

Documents

Prior Authorization Review Panel MCO Policy Submission A ... · A separate copy of this form must accompany each policy submitted for ... *Please see amendment for Pennsylvania Medicaid