Are triplet therapies really living up to their hype as the “standard of care” for multiple myeloma and what else is needed?

KEYWORDS:

• Autologous stem cell transplantation
• induction
• multiple myeloma
• transplant-ineligible
• triplet therapies

1. Introduction

Treatment of multiple myeloma (MM) has changed dramatically over the last two decades and has led to a significant improvement in outcomes for patients of all ages. Triplet combinations are now widely accepted as standard induction therapies for transplant-eligible patients and are also emerging for relapsed/refractory disease, thus evoking considerable enthusiasm among the myeloma community. However, given the ultra-fast development of new treatment regimens, the treating physician will face new challenges in terms of risk-adapted use of these protocols, optimal sequencing and ultimately management of patients with multi-class refractory disease.

2. Triplet therapies for induction prior to autologous HSCT

The concept of multi-drug regimens is not entirely new – conventional protocols such as VAD (vincristine, doxorubicine and dexamethasone) have been introduced some thirty years ago [1], but shown only modest activity at the cost of substantial adverse effects. Major advances were seen with the incorporation of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) into induction protocols. These ‘true’ triplets containing at least one of the newer compounds yield overall response rates of more than 90% and, more importantly, a substantial increase in patients entering complete remission (CR). With the use of PI/IMiD combinations, yet another level of remission quality in terms of minimal residual disease (MRD) negativity can be achieved. Not surprisingly, reports of a 68% MRD negativity rate in a phase 2 study of RVd (lenalidomide, bortezomib and dexamethasone) before and after high-dose therapy and autologous stem cell transplantation (HDT/ASCT) [2] and the demonstration of an overall survival (OS) advantage in these patients in the phase 3 trial [3] is able to generate a considerable ‘hype’ and results in the widespread use of RVd in Europe and the US. Another important finding from studies with triplet regimens is that only around 10% of patients fail to enter pre-planned HDT/ASCT [4] which is less than one third of the rate with doublet protocols such as TD (thalidomide and dexamethasone) .

However, several uncertainties remain to be addressed. First, upfront HDT/ASCT is still needed and associated with superior progression-free survival (PFS) despite the stellar responses seen with RVd. Second, up to 50% of patients will fail to achieve a CR despite undergoing HDT/ASCT and those with primary refractory disease feature an extremely adverse prognosis [4]. With these limitations in mind, investigators are now exploring even more potent triplets such as KRd (carfilzomib, lenalidomide and dexamethasone) in previously untreated patients. Impressive results have been reported in phase 2 trials and in a large phase 3 trial, identical rates of MRD negative responses were seen in patients receiving KRd with or without an autologous stem cell transplantation. Of note, recent data from the ‘FORTE’ trial suggest that incremental benefit of HDT/ASCT might be limited to high-risk disease.

Taken together, we would argue against a ‘one-size-fits-all’ approach and call for risk-adapted and, not least, cost-effective treatment strategies [5]. To this end, standardized tools for evaluation of response, specifically MRD, and identification of high-risk patients [6] need to be readily available in clinical practice and future (investigator-driven) trials must seek optimized approaches based on these variables. Conversely, current (industry-sponsored) studies are exploring antibody-based quadruplet regimens as induction for all patients which will almost certainly result in high-quality response but may restrict remaining options in the likely event of relapse. The aim of these studies, however, should result in a significant cure fraction allowing to identify true high-risk patients requiring treatment with alternative approaches such as bispecific antibodies or CAR-T cells.

3. Combination treatment in transplant-ineligible patients

The largest impact of contemporary treatment protocols has been seen in those patients who are not able to undergo HDT/ASCT [7]. However, the implementation of triplet therapies in this patient population has proven challenging due to limited efficacy and/or increased toxicity. VMP (bortezomib, melphalan and prednisone), for example, results in a PFS of less than 24 months but causes grade 3/4 toxicities in 90% of (selected) patients within the registration trial. Thus, a considerable proportion of patients is not able to tolerate triplet regimens containing conventional cytotoxic drugs such as melphalan and will benefit from dose-attenuated doublets. Breakthrough studies have recently reported a superior PFS with RVd compared to Rd (lenalidomide and dexamethasone) in the non- (or non-immediate) transplant setting [8] and unprecedented response rates including a significant proportion of MRD negative patients with the use of the anti-CD38 antibody daratumumab in frontline treatment [9,10]. Remarkably, antibody-based protocols seem to have the greatest impact in standard-risk patients while those with (FISH-defined) high-risk disease will draw substantial benefit from VRd. This observation together with the availability of validated tools to assess patient-related factors such as comorbidities and functional status paves the way for true individualized treatment. Specifically, careful dose modifications will be necessary in unfit or frail patients to ameliorate treatment-related toxicity. However, dose-attenuated triplets incorporating novel agents such as ‘RVd lite’ can also be tolerated by these patients without having to necessarily go to a doublet.

4. Triplet therapies for relapsed/refractory myeloma

For relapsed myeloma, physicians can now choose among a plethora of triplet combinations after careful assessment of the type, response to and toxicities of prior treatment lines as well as patient-related factors. Not all triplets are created equal, with highly effective combinations such as KRd and daratumumab-based regimens for aggressive and ‘medium effective’ triplets containing ixazomib and elotuzumab available to those with more indolent relapse. The results reported in the registration trials were justifiably welcomed with great enthusiasm, but they do have relevant limitations in daily practice.

First, most studies were limited to early relapse, i.e. to subjects with one to three prior lines. Second, the majority used a backbone of Rd and were conducted in subjects who were either non-refractory or lenalidomide-naïve. As discussed previously, most patients will now have received single-agent lenalidomide maintenance following HDT/ASCT or as continuous Rd treatment in the non-transplant setting with subsequent development of lenalidomide-refractory disease [11]. Interestingly, in this situation carfilzomib-based doublets play out as effective strategies [12]. As a matter of fact, we are still lacking convincing data that a combinatorial approach (i.e. favoring triplets over doublets, thus having fewer sequential options) unequivocally leads to a prolonged OS. However, there are well-grounded hopes that triplets incorporating anti-CD38 monoclonal antibodies will break this wall [13]. The fact that a considerable proportion of patients gets lost with every subsequent treatment line due to death from progressive disease would support the early use of these regimens at relapse [14].

5. What else is needed?

Taken together, we clearly need a more precise understanding of what defines refractoriness (to a certain compound) and which mechanisms of acquired resistance can be tackled by subsequent approaches. When highly effective triplet or even quadruplet combinations move to first-line therapy, substantial effort is needed to achieve clinically meaningful responses at relapse. Agents with novel mechanisms of action like histone deacetylase inhibitors and, more recently, the exportin-1 (XPO-1) inhibitor selinexor elicit only modest responses when used as a single agent, but just like conventional cytotoxic drugs (cyclophosphamide, bendamustine or doxorubicine) they will play out in combination. Thus, triplet regimens are increasingly used even in later disease stages but may be poorly tolerated by heavily pretreated patients. We need convincing strategies to mitigate and hopefully prevent toxicities which are often associated with the use of these intensive protocols. Conversely, novel immunotherapies such as antibody-drug conjugates, bispecific antibodies, and CAR-T cells are showing up with very impressive single agent activity and may reduce the number of patients requiring multi-drug combinations.

In conclusion, triplets are here to stay – at least for quite a while. This is mainly because the dream of breakthroughs with molecularly targeted therapy for MM has largely failed. Even with an elaborated approach utilizing ‘multi-omics’, the truly individualized regimens are confined to a minority of patients with disease indolent enough to wait for readouts and to be stabilized for three or four months [15]. Combination treatment will thus dominate the field for the near future, with some of the initial hype fading and turning towards strategies with even higher novelty.

Declaration of interest

S Knop has received honoraria from Celgene, Janssen, BMS, Amgen and Takeda as well as travel grants from Celgene and Amgen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.