Emerging and current treatment combinations for transplant-ineligible multiple myeloma patients

ABSTRACT

Introduction

Availability of new classes of novel agents has led to a radical switch in treatment paradigms for newly diagnosed transplant-ineligible multiple myeloma (NDTIMM) patients, providing an opportunity to significantly enhance the depth of response and extend survival outcomes.

Areas covered

Treatment regimens including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and/or monoclonal antibodies (mAbs), have achieved recent regulatory approval for NDTIMM, while novel combinations and newer agents are currently being explored. This review discusses the current landscape and possible treatment development of NDTIMM.

Expert opinion

Bortezomib-lenalidomide-dexamethasone (VRd), daratumumab-bortezomib-melphalan-prednisone (DaraVMP) and daratumumab-lenalidomide-dexamethasone (DaraRd) represent new standard of care (SOC) treatments for NDTIMM patients, based on phase III trials showing their superior efficacy as compared with previous SOCs. The possibility of improving results by incorporating second generation PIs or using quadruple regimens has also been explored and different trials are still ongoing. Newer agents and innovative immunotherapies targeting B-cell maturation antigen have the potential to change the therapeutic landscape in coming years. Personalized approaches based on frailty-adapted, risk-based and minimal residual disease driven paradigms are under investigation.

KEYWORDS:

• Elderly patients
• immunomodulatory drugs
• monoclonal antibodies
• multiple myeloma
• newly diagnosed
• novel agents
• proteasome inhibitors
• transplant-ineligible

Article highlights

• The availability of IMiDs, PIs and mAbs provides an opportunity to significantly enhance the depth of response and extend survival outcomes in NDTIMM

• NDTIMM are a heterogeneous population that varies greatly in fitness levels, hence proper identification of fit and frail patients is crucial to avoid undertreatment or overtreatment

• A phase III trial has demonstrated a significant advantage in terms of response, PFS and OS from adding bortezomib to Rd (VRd) for NDMM patients without immediate destination for ASCT

• Two randomized phase III trials have demonstrated a significant advantage in terms of response (including MRD), PFS and OS from the combination of daratumumab with Rd or VMP

• Outcome improvements achieved with these novel regimens have been registered across different patient subgroups, even though the prognostic value of high-risk cytogenetic abnormalities has not been abrogated

• The inclusion of second-generation PIs has also been explored. Carfilzomib failed to demonstrate superior efficacy over bortezomib for the treatment of NDMM not eligible or not scheduled for ASCT and with a standard or intermediate-risk profile. Ixazomib may be a valuable option for patients who could benefit from an oral PI

• Ongoing and planned clinical trials will evaluate triple and quadruplet regimens including IMiD, first- or second-generation PI, and different mAbs

• Newer approaches are in the pipeline for NDTIMM including novel agents targeting specific molecules and targets (e.g. selinexor) and innovative immunotherapies (e.g. CAR-T, ADCs)

• Personalized approaches based on frailty-adapted, risk-based and MRD-driven paradigms are under investigation.

Declaration of interest

P Tacchetti has received honoraria from Amgen, Bristol-Myers Squibb/Celgene, Jannsen, Takeda, AbbVie, Sanofi, GlaxoSmithKline and Oncopeptides. M Cavo has received honoraria from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Takeda, AbbVie, Sanofi, Adaptive Biotechnologies, and is a member of Janssen’s and Celgene’s Speakers Bureau. S Rocchi has received honoraria from Amgen, GlaxoSmithKline and Janssen. E Zamagni has received honoraria from Janssen, Bristol-Myers Squibb, Amgen and Takeda. L Pantani has received honoraria from Janssen and Amgen. K Mancuso has received honoraria from Celgene, Takeda, Amgen, Sanofi and Janssen. I Rizzello has received honoraria from Amgen, GlaxoSmithKline and Sanofi.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Disclosure statement

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.