Keywords

Introduction

Multiple myeloma (MM) is characterized by the proliferation of monoclonal plasma cells in the bone marrow and usually the presence of a monoclonal protein in the serum and/or urine. Secondary end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone destruction (CRAB criteria) indicates symptomatic disease requiring therapy [1]. Furthermore, the presence of an abnormal serum free light chain ratio (>100, with involved free light chains >100 mg/l), two or more focal lesions in MRI or PET/CT as well as more than 60% monoclonal plasma cells in the bone marrow are myeloma-defining events according to the International Myeloma Working Group guidelines [2]. The introduction of novel agents and monoclonal antibodies revolutionized the treatment of MM in the last years and with every new drug approval, the value of ongoing utilization of autologous stem cell transplantation (ASCT) is questioned. However, recent phase III trials confirmed that combining novel agents with ASCT is associated with longer progression-free survival (PFS) compared to treatment with novel agents alone (Table 18.1) [3,4,5,6]. Although MM is still considered to be an incurable disease, long-lasting remissions over 10 years can be achieved making it difficult to determine if overall survival can serve as a primary endpoint for trials [7]. Furthermore, the outcome varies significantly among newly diagnosed patients based on risk stratification (Table 18.2) [8].

Table 18.1 Phase III studies comparing treatment with novel agents in combination with ASCT to treatment with novel agents alone
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Table 18.2 International Staging System (ISS) and revised-ISS [8]
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Assessment of Transplant Eligibility

There is no formal age cut-off for transplant eligibility in MM. Most phase III trials of ASCT have enrolled patients with an upper age limit of 65 years but other trials such as BMT CTN 0702 and CALGB 100104 allowed enrollment to 70 years of age. ASCT can be performed safely in older, medically fit patients [9, 10]. Therefore, transplant eligibility should be determined mostly on the basis of comorbidities. Table 18.3 summarizes the recommended assessments prior to ASCT at Roswell Park Comprehensive Cancer Center.

Table 18.3 Recommended assessments prior to ASCT
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Induction Therapy

The common practice of bortezomib-based induction therapies is supported by large meta-analyses [11]. Recent phase III trials compared different combination partners for bortezomib (Velcade®) during induction therapy before ASCT.

  1. 1.

    The initial EVOLUTION phase I/II study appeared to demonstrate that VCD (bortezomib, cyclophosphamide, and dexamethasone) and VRD had similar outcomes [12].

  2. 2.

    The German GMMG MM5 trial showed that VCD (bortezomib, cyclophosphamide, and dexamethasone) is less toxic than PAd (bortezomib, doxorubicin, and dexamethasone) [13].

  3. 3.

    The French IFM2013-04 trial demonstrated higher rates of high-quality responses for VTD compared to VCD [14].

    1. a.

      However, VTD was associated with higher rates of neuropathy compared to VCD.

    2. b.

      Although there has never been a direct prospective, randomized comparison between VTD and VRD (bortezomib, lenalidomide, and dexamethasone), many centers utilize VRD as recently applied in the IFM/DFCI2009 phase III trial [5].

  4. 4.

    Currently, second-generation novel agents such as ixazomib (Ninlaro®) (in combination with lenalidomide and dexamethasone [IRD]) [15] and carfilzomib (Kyprolis®) (in combination with lenalidomide/dexamethasone [KRD] or cyclophosphamide/dexamethasone [KCD]) [16] are being tested as induction before ASCT with promising results.

  5. 5.

    The CASSIOPEIA trial investigating VTD with or without daratumumab (Darzalex®) before and after ASCT showed for the first time superiority of an induction regimen incorporating a monoclonal antibody [17].

  6. 6.

    Further results from trials incorporating monoclonal antibodies such as elotuzumab (Empliciti®) and isatuximab (e.g., Clinicaltrials.gov identifier NCT03617731) into induction therapy before ASCT are expected in 2019/2020.

  7. 7.

    Table 18.4 summarizes recent phase II/III trials on induction therapy before ASCT.

Table 18.4 Summary of most common induction therapies before ASCT in recent phase II/III trials
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Stem Cell Mobilization

An adequate collection of mobilized peripheral stem cells is a crucial or successful outcome of autoHCT. A dose of >2 × 106 CD34+ cells/kg is considered the minimum target dose to achieve optimal engraftment [18]. The main risk factors for poor mobilization are age >60 years, thrombocytopenia [19], extensive previous treatment with radiotherapy or alkylating agents [18, 20,21,22,23], and prolonged use of lenalidomide [24,25,26,27]. Stem cell mobilization can be performed with growth factors alone, a combination of growth factors with chemotherapy, or with chemokine receptor antagonists (Table 18.5).

Table 18.5 Mobilization strategies
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High-Dose Therapy

  1. 1.

    Melphalan 200 mg/m2 is considered the standard of care [28] and usually administered intravenously in divided doses on days −3 and −2 or as a single dose on day −2 only before autoHCT.

    1. a.

      Dose reduction to 100 mg/m2 is associated with an adverse outcome [29].

    2. b.

      To prevent anticipated toxicities in medically compromised patients (e.g., elderly patients or patients with cardiac disease), the melphalan dosage might be reduced to 140 mg/m2 without apparent loss of efficacy compared to 200 mg/m2 [30].

    3. c.

      Also in patients with renal insufficiency (RI) and dialysis-dependent renal impairment, melphalan should be reduced accordingly to obtain comparable results to patients with normal/mild RI and potentially achieve dialysis independence [31].

  2. 2.

    Tandem transplantation

    1. a.

      In the past, several studies addressed the question of whether a tandem autoHCT, that is, a second autoHCT usually within 6 months after the first, should be performed [32].

    2. b.

      In the era of novel agent-based induction and maintenance therapy, conflicting results from two prospective phase III trials have been reported.

      1. i.

        While the abovementioned EMN02/HO95 phase III trial demonstrated the inferiority of single versus tandem autoHCT [6], especially in patients with the high-risk disease [33], the StaMINA trial showed no significant differences for PFS and overall survival (OS) between single and tandem autoHCT, even in patients with the high-risk disease [34].

      2. ii.

        In the author’s practice, tandem autoHCT is offered to patients with the suboptimal response after induction therapy, FISH-based high-risk cytogenetics, or those patients not in complete remission after a first autoHCT.

Supportive Care

  1. 1.

    Patients with newly diagnosed MM are prone to infections due to the impaired humoral and cellular immunity caused by the proliferation of malignant plasma cells and the production of nonfunctional antibodies.

  2. 2.

    Infectious complications are the most common cause of death during the first 3 months of therapy, and one study suggested that antibiotic prophylaxis can reduce febrile episodes and death [35]. Table 18.6 summarizes the recommended prophylaxis.

  3. 3.

    General treatment of infectious complications such as neutropenic fever is discussed separately in this book. Furthermore, vaccinations need to be repeated after autoHCT, and one suggested schedule of administration is summarized in Table 18.7; an alternative schedule of administration is provided in Appendix 9 .

  4. 4.

    Other common side effects of autoHCT for MM are nausea and vomiting as well as gastrointestinal mucositis.

Table 18.6 Summary of prophylaxis for most common transplant-related side effects
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Table 18.7 Vaccinations recommended after autoHCT for MM (Roswell Park Comprehensive Cancer Institute Guidelines)
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Maintenance Therapy After AutoHCT

Maintenance therapy in MM after autoHCT has been shown to improve OS. The commonly used agent is lenalidomide, whereas new approaches show also improved survival for maintenance therapy with bortezomib and ixazomib [3, 42,43,44,45].

  1. 1.

    Lenalidomide (Revlimid®)

    1. a.

      Lenalidomide is indicated as standard maintenance therapy after autoHCT in the United States and Europe.

    2. b.

      4 randomized trials showed significantly improved PFS with lenalidomide maintenance therapy versus placebo or observation [3, 42,43,44,45].

    3. c.

      Meta-analyses demonstrated improved OS [45].

    4. d.

      Standard dosing: 10 mg po daily continuous, increase up to 15 mg daily if tolerated [45].

    5. e.

      Main side effects [46]

      1. i.

        Hematologic toxicity (neutropenia, anemia, thrombocytopenia)

      2. ii.

        Increased risk of secondary primary malignancies

      3. iii.

        Increased risk of venous thromboembolic events (VTE)

      4. iv.

        Gastrointestinal side effects (esp. diarrhea)

      5. v.

        Drug rash

    6. f.

      Concurrent medication [47, 48]:

      1. i.

        If no other risk factors for VTE: aspirin 81 mg/d po.

      2. ii.

        If other risk factors for VTE: low-molecular-weight heparin or full-dose warfarin.

      3. iii.

        Oral anticoagulants such as apixaban (Eliquis®) were successfully evaluated for VTE prophylaxis in IMiD-treated patients [49].

    7. g.

      Duration

      1. i.

        Three out of the four randomized phase III studies involved continuing maintenance treatment until disease progression.

      2. ii.

        Administration of lenalidomide beyond the achievement of complete remission (CR) is associated with better OS and therefore should be continued until disease progression if toxicities are tolerable [50].

  2. 2.

    Bortezomib (Velcade®)

    1. a.

      Bortezomib with induction and maintenance improved PFS compared to vincristine with induction and thalidomide with maintenance [51, 52].

    2. b.

      Improves outcome in patients with del(17p) [53].

    3. c.

      Standard dosing: 1.3 mg/m2 sc every 2 weeks [51].

    4. d.

      Main side effects [54]:

      1. i.

        Hematologic toxicity (neutropenia, thrombocytopenia)

      2. ii.

        Peripheral neuropathy

      3. iii.

        Gastrointestinal side effects

    5. e.

      Concurrent medication:

      1. i.

        Herpes zoster prophylaxis with low-dose acyclovir [55]

    6. f.

      Duration: In studies discontinuation after 2 years [51]. Based on results from lenalidomide maintenance studies, treatment until progression might prolong survival and should be considered if no severe side effects occur.

  3. 3.

    Ixazomib (Ninlaro®)

    1. a.

      Improved post-autoHCT PFS by 5 months when compared to placebo [70]

    2. b.

      Standard dosing: 3 mg po every 2 weeks; may increase up to 4 mg if tolerated

    3. c.

      Main side effects:

      1. i.

        Hematologic toxicity (thrombocytopenia)

      2. ii.

        Peripheral neuropathy

      3. iii.

        Gastrointestinal side effects

    4. d.

      Concurrent medication:

      1. i.

        Herpes zoster prophylaxis with low-dose acyclovir.

    5. e.

      Duration: In studies, discontinuation after 2 years. Based on results from lenalidomide maintenance studies, treatment until progression might prolong survival and should be considered if no severe side effects occur.

Response Criteria

Historically, response criteria were based on the measurement of monoclonal protein in serum and urine as well as bone marrow plasma cell count. Response is categorized in stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD), and progressive disease (PD). Revised criteria include new parameters of minimal residual disease (MRD) measured by flow cytometry or gene sequencing (Table 18.8). Furthermore, sensitive imaging techniques can detect extramedullary residual disease [57].

Table 18.8 Revised response criteria for minimal residual disease (MRD)
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Salvage AutoHCT

Retrospective analyses demonstrated that salvage autoHCT after re-induction therapy is an option for patients with relapsed disease, particularly those with sustained remission ≥18 months after a first autoHCT procedure [58, 59]. Currently, there are only two published prospective randomized phase III trials comparing salvage autoHCT after novel agent-based re-induction therapy to treatment with a novel agent alone in relapsed MM (Table 18.9) [60, 61]. While the study from the UK showed the superiority of salvage autoHCT over monotherapy with weekly cyclophosphamide, the German study could not show any differences in the intention-to-treat analysis. While major criticism of the study from the UK was the suboptimal control arm with weekly cyclophosphamide, the final analysis of the German study is still pending.

Table 18.9 Summary of current phase III trials for autoHCT for relapsed disease
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Adoptive Cellular Therapies

  1. 1.

    Allogeneic transplantation (alloHCT)

    1. a.

      In contrast to autoHCT, alloHCT has the potential to generate an immunologic graft-versus-myeloma (GvM) effect.

      1. i.

        Studies comparing autoHCT and alloHCT as first-line therapy showed improved long-term OS for patients undergoing alloHCT, while transplant-related mortality (TRM) and toxicity mostly as a consequence of graft-versus-host disease (GvHD) were increased [62,63,64,65].

      2. ii.

        Whether alloHCTcan overcome high-risk disease features remains controversial since inclusion criteria for high-risk disease varied in the different studies [66,67,68].

      3. iii.

        As the incidence of TRM is 10–20%, alloHCT in MM should generally be reserved for young patients with primary relapsed/refractory disease, where transplant risk is relatively low (HLA-identical donor, no comorbidities) and no other novel therapy , for example, antibodies or chimeric antigen receptor T-cell is available.

    2. b.

      Studies comparing alloHCT to novel agents such as proteasome inhibitors, immunomodulatory agents, or monoclonal antibodies are lacking.

  2. 2.

    Chimeric antigen receptor T (CAR T) cell therapy

    1. a.

      CAR T cells are genetically engineered T cells utilizing a genetically engineered CAR targeting specific myeloma antigens, of which current studies are mainly directed against B-cell maturation antigen (BCMA).

    2. b.

      Phase I/II trials are presently investigating safety and efficacy for CAR T cell therapy for myeloma in heavily pretreated patients.

    3. c.

      Although overall response rates (ORR) up to 100% have been reported and the majority of patients achieved a VGPR or CR, long-term results have not been established to determine the durability of these responses [69].

    4. d.

      The observed toxicities of this therapy are similar to more established CAR T cell therapies in acute lymphoid leukemia (ALL) and aggressive lymphomas, most frequently grade 1–2 cytokine release syndrome (CRS) and neurotoxicity [69, 70].