PerspectivePerspectives in the Rapidly Evolving Treatment Landscape of Multiple Myeloma: Expert Review of New Data Presentations from ASH 2019
Introduction
Multiple myeloma is one of the most common, yet incurable, hematologic malignancies1; accounting for approximately 10% of all hematologic cancers, it affects mainly elderly individuals, with a median age at diagnosis of 72 years.2
Recent years have seen a dramatic increase in the number and type of therapeutic options available to treat patients with multiple myeloma, resulting in improved patient outcomes.1 These include immunomodulatory agents, such as thalidomide, lenalidomide, and pomalidomide; proteasome inhibitors, such as bortezomib; second-generation proteasome inhibitors, such as carfilzomib and ixazomib; first-in-class small-molecule inhibitors venetoclax (a B-cell lymphoma 2 [BCL-2] inhibitor) and selinexor (a chromosomal region maintenance protein 1 [CRM1] inhibitor); bendamustine, an alkylating agent; panobinostat, a histone deacetylase inhibitor; and monoclonal antibodies, such as elotuzumab and daratumumab.
However, although these therapies offer exciting opportunities to significantly improve patient outcomes, physicians are faced with several challenges, such as keeping abreast of the latest developments, and determining which agents and which combinations/sequences of agents (of those that are locally available/reimbursed) to use across different settings. Furthermore, the adoption and optimal use of these novel therapies may be compromised, not only by limited funding, but also by the absence of necessary infrastructure, such as molecular testing facilities and national registries to provide real-world evidence.
This article reviews some of the most compelling new clinical data presented on multiple myeloma at the 61st Annual Meeting of the American Society of Hematology (ASH) held in Orlando, Florida (December 7-10, 2019), and offers perspectives and insights into how these latest developments may fit within the rapidly evolving treatment landscape, based on expert discussions at a Scientific Debrief meeting held at ASH. Gaps in treatment practice relating to the optimal use of approved and investigational agents across Asia-Pacific regions relevant to the ASH 2019 data are identified, and practicalities and challenges in patient management among Asian and Western countries are discussed. The often limited applicability of clinical trial data to the real-world setting, and the considerable value of information collected through registries and investigator-initiated trials, are also considered.
As mentioned above, the data reviewed in this article were reported in congress abstracts/presentations rather than in the peer-reviewed literature. The abstracts selected for review are those that the authors consider will most likely be impactful across the multiple myeloma treatment landscape in the foreseeable future, especially within Asia-Pacific regions, and are grouped into 3 main sections: newly diagnosed multiple myeloma (NDMM), relapsed/refractory multiple myeloma (RRMM), and novel therapies. The aim is to provide insights and perspectives with a regional context, which are based on expert opinion, rather than treatment recommendations based on unpublished data.
Section snippets
Defining Functional High-risk Patients to Inform Response-adaptive Strategies
In the management of NDMM, it is necessary to identify functional high-risk patients (median survival < 24 months from diagnosis) at an early stage of treatment – a group with ongoing unmet therapeutic needs. The Revised International Staging System3 is the most commonly used risk-stratification model in multiple myeloma, but this does not capture all functional high-risk disease, and there are barriers to risk stratification in some jurisdictions (owing to limited access to cytogenetic or
Discussion
It is important to note that the data reviewed in this article are based on congress abstracts/presentations rather than peer-reviewed publications. However, they reflect the rapidly evolving treatment landscape for multiple myeloma, with impressive new data for targeted therapy combinations, including proteasome inhibitors, and immunomodulatory and antibody-based approaches, together with early yet promising data on investigational BCMA-directed immunotherapies such as bispecific antibodies
Summary
In summary, the heterogeneity of multiple myeloma requires an individualized approach to treatment, requiring consideration of many factors. As highlighted in the data presented at ASH, patient risk stratification, identification and effective use of predictive biomarkers of response, and elucidation of optimal combinations and sequences of novel targeted therapies will all contribute to improved long-term patient outcomes while ensuring an appropriate balance between response and toxicity.
Disclosures
This work was supported by Amgen Asia Holding Ltd. Chng Wee Joo has received grants from Amgen, Janssen, Celgene, and AbbVie, and honoraria from Amgen, Janssen, Celgene, AbbVie, and Takeda. Hang Quach has received research grants from Amgen, Celgene, Karyopharm, and GlaxoSmithKline; research drug supplies from Sanofi; and is an advisory board member for Amgen, Celgene, Karyopharm, GlaxoSmithKline, Janssen Cilag, and Specialized Therapeutics. Noopur Raje has received research funding from
Acknowledgments
The authors would like to thank the following additional contributors who attended the Scientific Debrief meeting at ASH 2019 and contributed to the discussions: Kihyun Kim (Korea), Amit Khot (Australia), Junya Kuroda (Japan), Lugui Qiu (China), Tran-Der Tan (Taiwan), and Sung-Soo Yoon (Korea). Medical writing assistance was provided by Rachel Mason of Lighthouse Medical Communications US, a Lucid Group company, and was funded by Amgen.
References (37)
- et al.
Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2017) - et al.
Real-world outcome for newly diagnosed patients with functional high-risk myeloma - a myeloma and related diseases registry analysis
Blood
(2019) - et al.
Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update
Blood
(2019) - et al.
Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study
Lancet
(2019) - et al.
A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma
Clin Lymphoma Myeloma Leuk
(2019) - et al.
T(11;14) and high BCL2 expression are predictive biomarkers of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma: biomarker analyses from the phase 3 Bellini study
Blood
(2019) - et al.
Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): Primary analysis results from the randomized, open-label, phase 3 study Candor (NCT03158688)
Blood
(2019) - et al.
Practical considerations and role of daratumumab retreatment for relapsed refractory multiple myeloma
Clin Lymphoma Myeloma Leuk
(2019) - et al.
Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma
Blood
(2019) - et al.
Preliminary results from a phase 1b study of TAK-079, an investigational anti-CD38 monoclonal antibody (mAb) in patients with relapsed/refractory multiple myeloma (RRMM)
Blood
(2019)
First clinical study of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269 in patients (pts) with relapsed/refractory multiple myeloma (RRMM): interim results of a phase 1 multicenter trial
Blood
Long-term follow-up of a phase 1, first-in-human open-label study of LCAR-B38M, a structurally differentiated chimeric antigen receptor T (CAR-T) cell therapy targeting B-cell maturation antigen (BCMA), in patients (pts) with relapsed/refractory multiple myeloma (RRMM)
Blood
Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against b-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM)
Blood
Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma
Blood
Clinical responses and pharmacokinetics of MCARH171, a human-derived BCMA targeted CAR T cell therapy in relapsed/refractory multiple myeloma: final results of a phase I clinical trial
Blood
JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a phase 1/2 multicenter study (EVOLVE)
Blood
Low dose of human scFv-derived BCMA-targeted CAR-T cells achieved fast response and high complete remission in patients with relapsed/refractory multiple myeloma
Blood
Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM)
Blood
Cited by (4)
The Burden of a Multiple Myeloma Diagnosis on Patients and Caregivers in the First Year: Western European Findings
2022, ClinicoEconomics and Outcomes ResearchExpression of Cysteine-Rich Secreted Acidic Protein in Multiple Myeloma and Its Effect on the Biological Behavior of Cancer Cells
2021, Evidence-based Complementary and Alternative Medicine