Autologous Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Therapies

Ricardo D. Parrondo, MD; Sikander Ailawadhi, MD; Taimur Sher, MD; Asher A. Chanan-Khan, MD; Vivek Roy, MD

Disclosures

J Oncol Pract. 2020;16(2):56-66. 

In This Article

Abstract and Introduction

Abstract

Despite the evolution of the therapeutic arsenal for the treatment of multiple myeloma (MM) over the past decade, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. The advent of novel therapies, such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, has led to unprecedented levels of deep hematologic responses. Nonetheless, studies show that ASCT has an additive effect leading to additional deepening of responses. As the therapeutic agents for MM continue to evolve, the timing, duration, and sequence of their use in combination with ASCT will be crucial to understand to obtain the deepest response and survival benefit for patients with MM. This review aims to discuss the role of ASCT for the management of MM, with a particular focus on the role of ASCT in the context of novel therapies and minimal residual disease.

Introduction

Multiple myeloma (MM) is a hematologic malignancy that accounts for 1% of all cancers and 10% of all hematologic malignancies.[1] Autologous stem-cell transplantation (ASCT) has been the standard treatment of MM in transplantation-eligible patients since the 1990s and its use has increased in the United States over the last decade.[2] Until the advent of novel agents, traditional chemotherapy was used for induction therapy before ASCT. Several phase III randomized clinical trials (RCTs) were performed comparing chemotherapy with high-dose therapy and ASCT. A meta-analysis of these trials reported a progression-free survival (PFS) benefit, but not an overall survival (OS) benefit, with ASCT.[3]

Because of superior response rates, PFS, and OS, standard-of-care induction regimens now include both a proteasome inhibitor and an immunomodulatory agent for newly diagnosed MM.[4,5] Induction regimens incorporating novel therapies have resulted in median PFS of more than 30 months and 5-year OS rates of more than 70%.[6] Phase III RCTs incorporating novel agents into induction therapy have all resulted in superior PFS but only half have demonstrated an OS benefit[5,7–9] (Table 1). A meta-analysis of the four RCTs that assessed novel agent induction followed by ASCT revealed a PFS benefit favoring ASCT (hazard ratio [HR], 0.55; 95% CI, 0.41 to 0.74; P < .001), but not an OS benefit (HR, 0.76; 95% CI, 0.42 to 1.37; P = .36).[10] The continued development of more potent next-generation novel therapies, including proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, is currently being evaluated in clinical trials as part of either induction, consolidation, or maintenance therapies to deepen the responses and survival rates achieved by ASCT.

In this review, we aim to discuss patient selection; the role of ASCT at different stages of disease; agents used for induction, consolidation, and maintenance; the role of tandem ASCT; the role of minimal residual disease (MRD) negativity in the setting of ASCT; and future directions of ASCT, all in the context of the available novel agents in the therapeutic armamentarium for MM.

Eligibility for ASCT

Most clinical trials assessing the efficacy and safety of ASCT in MM enrolled patients younger age 65 years; however, the safety and feasibility of performing ASCT in patients with MM older than age 65 has been demonstrated retrospectively.[11] Retrospective registry data have suggested that a higher hematopoietic stem-cell transplantation comorbidity index score can predict worse outcomes in patients with MM undergoing ASCT.[12] ASCT is generally avoided for patients with an Eastern Cooperative Oncology Group performance status of 3 or 4, New York Heart Association functional status of class III or IV, frank liver cirrhosis, or diffusing capacity for carbon monoxide less than 50%. Patient selection should be based on overall health status and organ function rather than just chronologic age.

The depth of response to initial induction therapy is associated with superior depth of response and PFS in the post-ASCT setting.[13] The IFM 2005–01 trial, which evaluated 482 patients who underwent induction—with either bortezomib (V) and dexamethasone (D) or vincristine, doxorubicin, and D—followed by ASCT found that patients who achieved a very good partial response or better after induction had a longer PFS compared with those who achieved a very good partial response after ASCT (41 v 31 months; P = .01);[14] however, depth of response is a marker of the biology of MM rather than an independent marker of outcomes. In a retrospective study of 539 patients who achieved less than a partial response after initial induction therapy, there were no PFS or OS differences among patients who received additional treatment to deepen response before ASCT compared with those who proceeded directly to ASCT.[15] As such, depth of response to induction therapy should not dictate eligibility for ASCT.

Timing of ASCT

Although many trials have confirmed the survival improvements of ASCT compared with not undergoing this treatment, how these survival improvements are related to the timing of ASCT after diagnosis of MM remains uncertain. Albeit before the era of novel agents, the first phase III RCT to address the timing of ASCT demonstrated that, whereas upfront ASCT is associated with superior PFS, no differences are observed in OS by delaying ASCT to the time of relapse.[16] Results of the IFM 2009 trial prospectively confirmed these findings by showing that, with novel agent triplet induction therapy using V, lenalidomide (R), and D, upfront ASCT improved median PFS (50 v 36 months), but had similar 4-year OS compared with ASCT upon experience of first relapse.[5]

Such factors as standard-risk versus high-risk disease, age, performance status, comorbidities, and pace of disease should be taken into account when considering upfront versus delayed ASCT. A retrospective study has estimated that there is an approximate 12% risk of becoming transplantation ineligible when opting for delayed ASCT as a result of worsening performance status, comorbidities, and aggressive disease relapse.[17] While patients with standard-risk MM may be able to wait, those with high-risk MM derive the best PFS with upfront ASCT within 12 months of diagnosis.[18] Upfront ASCT offers the best chance of achieving a deep hematologic response, particularly MRD-negative status, which is associated with superior PFS and OS.[5,19] As such, patients with high-risk MM should undergo upfront ASCT if possible. In any case, stem cells should definitely be collected within 4 to 6months of diagnosis in all transplantation-eligible patients.

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