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Improving Outcomes in Transplant-eligible Patients with Myeloma

Value-Based Care in Myeloma - Transplant Considerations, Multiple Myeloma
Sepideh Shayani, PharmD, BCOP

Introduction
For the newly diagnosed myeloma patient who is transplant-eligible, the standard approach to treatment is initial therapy with novel targeted agents, followed by high-dose therapy/autologous stem cell transplant (HDT/ASCT). While this strategy has led to markedly improved outcomes, patients are still at risk for experiencing significant adverse events, including myelosuppression, infection, viral reactivation, and mucositis, which need prompt attention and management. Furthermore, recent evidence suggests that some of the novel agents now used as induction, while not as damaging to stem cell harvest as older therapies, may nevertheless suppress collection. In this article, Sepideh Shayani, PharmD, BCOP, answers questions related to the use of novel agents in the transplant setting, and the management of select treatmentrelated toxicities.

What is the role of risk stratification in transplanteligible patients?

Multiple myeloma (MM) is one of the only malignancies in which cytogenetics have been used to stratify risk and guide therapy. The presence of specific genetic abnormalities in patients with MM is highly predictive of response to treatment and clinical outcomes.1 A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in patients with MM.2 This panel defined the role of risk stratification as a tool for determining disease prognosis and stratification of treatment, rather than the timing of treatment initiation.2

For newly diagnosed myeloma, it is suggested that a bone marrow biopsy be conducted and both fluorescence in situ hybridization (FISH) and conventional cytogenetics be performed to detect any cytogenetic defects.2,3 Cytogenetic abnormalities that may suggest higher risk disease include deletion of chromosome 13 (del[13]) or hypodiploidy, as detected by conventional karyotyping, as well as deletion 17p (del[17p]) and translocations t(4;14), t(14;16), or t(14;20) detected by FISH.4 Deletion of the long arm of chromosome 13 (del[13q]) detected by FISH only does not constitute an adverse prognostic factor.2-4

In addition to cytogenetic abnormalities, other factors may be predictive of high-risk MM. These include high serum beta-2-microglobulin (b2M) levels and International Staging System stage II and III disease incorporating high b2M and low albumin.2 Individual risk factors that may also be useful for prognosis include renal dysfunction, high serum free light chains or kappa/lambda free light chain ratio, extramedullary disease, and elevated lactate dehydrogenase.2 Patients with high proliferative activity of plasma cells (≥3%), as measured by the plasma-cell labeling index, and patients with primary refractory disease or early relapse are also considered to have high-risk MM.5 Current data suggest that the initial adverse prognosis of certain cytogenetic abnormalities in myeloma, such as del(13) and t(4;14), can be overcome by the use of novel agents.5,6

Successful stem cell mobilization depends on a variety of factors, including age, disease status, time from diagnosis to mobilization, and number and type of prior treatment regimens. 10,11 Older studies revealed that induction regimens using alkylating agents such as melphalan decreased the number of stem cells in the bone marrow and impaired the ability to expand the stem cell pool and mobilize hematopoietic stem cells to the peripheral blood.12,13 Prior to the advent of novel agents, this observation led practitioners to utilize induction regimens such as vincristine, doxorubicin, and dexamethasone (VAD) or high-dose dexamethasone, which had little impact on stem cell collection in patients eligible for transplant.

Recent reports suggest that, in some cases, induction therapy with novel agents may also lead to impaired stem cell mobilization.11,14-18 Multiple studies have demonstrated that the use of lenalidomide during induction therapy adversely affects the ability to mobilize and collect an adequate number of stem cells.14-16 Decreased peripheral blood stem cell yield may become more prevalent with increasing duration of lenalidomide therapy, as well as increasing age.14

There remains some controversy regarding the effect of bortezomib and thalidomide on stem cell mobilization and collection. Although data from the IFM 2005-1 trial,18 which compared bortezomib plus dexamethasone with VAD, showed a trend toward a lower number of stem cells collected among patients receiving bortezomib, other studies have not confirmed this finding.11,18,19 Thalidomide seems to have limited effect on the ability of patients to proceed to transplant, even though a reduction in the number of CD34+ cells/kg may be observed.11,17

Historically, stem cell mobilization in preparation for ASCT has been accomplished by administering growth factors, such as granulocyte colony-stimulating factor (G-CSF), with or without chemotherapy. Prior to the era of novel therapies, this approach was shown to be an effective and highly predictable modality for mobilizing stem cells in the majority of patients with myeloma.20

Recently, it has been shown that the addition of plerixafor to G-CSF significantly increases the probability of collecting the optimal number of stem cells in fewer apheresis procedures compared with growth factors alone. When added to G-CSF, plerixafor also appears to overcome the negative effect of prognostic factors associated with previous ASCT and treatment with lenalidomide.21-23

Table
IMWG Recommendations for SC Mobilization in Patients Treated with Novel Agents11
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An expert panel of the International Myeloma Working Group examined the implications of treatment with novel agents on stem cell collection and created recommendations based on their findings (Table).11 They recommend early stem cell mobilization (after 3-4 cycles of initial therapy) when transplant is being considered. For patients undergoing initial therapy with thalidomide- or bortezomib-based regimens, or for those who are <65 years of age and are being treated with fewer than 4 cycles of lenalidomide plus dexamethasone, mobilization with G-CSF alone is considered to be adequate, although a combination of cyclo phosphamide plus G-CSF may still be utilized. For patients who have received ≥4 cycles of lenalidomide or patients receiving other myelosuppressive drugs in combination with lenalidomide, mobilization with cyclophosphamide plus G-CSF should be considered as the initial regimen. For patients ≥65 years of age, the guidelines suggest a combination of low-dose cyclo phosphamide plus G-CSF, or G-CSF alone, with the addition of plerixafor before the second leukapheresis, if the first collection results in a harvest of <2 million CD34+ cells/kg.

Patients who have initially been treated with lenalidomide- containing regimens who have failed to collect adequate CD34+ cells with G-CSF alone may be rechallenged with cyclophosphamide plus G-CSF, plerixafor plus G-CSF, or granulocyte-macrophage colony-stimulating factor at 10 mcg/kg/day for 2 days, followed by G-CSF at 16 mcg/kg/day until adequate stem cell collection has been completed.11

Most transplant centers have created treatment algorithms for stem cell mobilization. These tools are used to help clinicians select a treatment approach based on factors such as age, number and type of prior treatment regimens, prior radiation to pelvis and sternum, and the number of stem cells collected after the first 1 or 2 attempts.

Oral mucositis remains a serious side effect of transplantation. How can this complication be effectively managed?

Oral mucositis is a complication associated with many types of cancer treatment, but it is particularly common and severe in patients undergoing HDT/ASCT. Development of oral mucositis has been associated with longer hospital stays, poor clinical and economic outcomes, and higher mortality rates in the transplant setting.24 The prevention and treatment of mucositis requires a multidisciplinary approach; patients, caregivers, nursing staff, prescribers, and other members of the cancer care team must work together to manage this adverse event. An important first step is to educate patients on good oral hygiene and the importance of adherence to an appropriate mouth-care treatment plan.25

Management of oral mucositis primarily relies on symptom palliation and supportive care. Patients are instructed to use alcohol-free, bland rinses and topical anesthetics several times a day. Compounded mouthwashes containing topical anesthetics with ingredients such as diphenhydramine, aluminum hydroxide, nystatin, and lidocaine may also be beneficial, along with patient-controlled analgesia with narcotics for those undergoing stem cell transplant.25,26 Unfortunately, there are a limited number of effective strategies that can be used to prevent mucositis, and sufficient clinical data to support the use of devices such as bioadherent oral gel, mucoadhesive rinse, and oral wafer is not yet available.25

Several studies have demonstrated that cryotherapy during administration of high-dose melphalan effectively ameliorates the subsequent oral mucositis caused by this agent.27-29 Patients are generally instructed to suck on ice chips or popsicles 5 to 30 minutes prior to administration of melphalan; they are asked to continue this process during the infusion and for 30 minutes to a few hours after the end of infusion. The rationale for cryotherapy is that it produces vasoconstriction in the oral cavity, which reduces blood flow to this area and decreases the exposure of the buccal mucosa to melphalan. 27-29 Cryotherapy is recommended for prevention of oral mucositis in all patients receiving high-dose melphalan.25,26

Although palifermin, a recombinant humanized keratinocyte growth factor, was originally studied for prevention of mucositis in recipients of total body irradiation (TBI) prior to transplant, efficacy of this drug has since been investigated in patients receiving non–TBI-containing chemotherapy regimens. 25 A retrospective study of patients receiving HDT/ASCT was conducted to assess the efficacy of this agent.30 All patients received a short (3-day) course of palifermin prior to melphalan therapy. Patients with normal renal function reported significantly shorter hospital stays, and less need for narcotic analgesia, parenteral nutrition, and red blood cell transfusion. However, patients with renal failure had a significantly higher risk for developing severe mucositis. Another study of palifermin prior to HDT with melphalan-based regimens reported a reduced incidence of grade ≥2 oral mucositis compared with the historical control group.31 Although palifermin may be an attractive option, the significant cost of this drug may be a limiting factor. Other agents, such as amifostine, have also been reported to reduce mucositis associated with high-dose melphalan in small studies.23,32

What guidelines should be followed for the prevention of VZV in patients undergoing transplantation? Reactivation of latent varicella zoster virus (VZV) is one of the most common and potentially serious infectious complications related to ASCT. Patients may present with localized dermatomal rash or disseminated disease. Efficacy of acyclovir for the prevention of this complication in transplant recipients has long been proven.33-35 Since most cases of VZV reactivation occur at a median of 5 months after transplant,36 long-term acyclovir prophylaxis has been investigated in clinical trials.

Guidelines for prevention of infectious complications in recipients of stem cell transplant have been developed by the American Society of Blood and Marrow Transplantation, the Infectious Diseases Society of America, and the Centers for Disease Control and Prevention. They recommend longterm (1-year) acyclovir prophylaxis for seropositive allogeneic and autologous transplant patients in order to prevent recurrent VZV infections.37 In post-allogeneic transplant patients who require systemic immunosuppression or have chronic graft-versus-host disease, acyclovir prophylaxis may be extended beyond 1 year.37 Although the recommended dose of oral acyclovir for prophylaxis of VZV in adult patients is 800 mg twice daily for 1 year, doses as low as 200 mg twice daily may be used. Valacyclovir may be alternatively used at 500 mg orally twice daily.37

By following these guidelines and consistently providing other forms of supportive care, the cancer care team can help patients with myeloma remain as comfortable and healthy as possible through the transplant process. At our center, we employ an interdisciplinary approach to treatment, based on the efficient coordination of care among all members of the oncology team.

What strategies can be used to optimize stem cell mobilization prior to transplant?

Over the past decade, we have witnessed significant changes in the treatment paradigm for myeloma. The use of induction regimens incorporating drugs such as bortezomib, lenalidomide, and thalidomide has led to response rates similar to those seen with ASCT.7-9 In the transplant setting, these new therapies are certainly less deleterious to stem cell mobilization than older regimens that included alkylators. Nevertheless, they may still affect mobilization, and this fact must be taken into account when planning a treatment strategy.

References

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Last modified: May 20, 2015
  • Rheumatology Practice Management
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