The treatment landscape of relapsed/ refractory multiple myeloma (RRMM) has undergone rapid changes over the past 2 decades, with over a dozen drug approvals by the FDA. Between December 2019 and September 2020, 4 new drugs received approval: the oral selective inhibitor of nuclear export selinexor (Xpovio), the anti-CD38 monoclonal antibody isatuximab-irfc (Sarclisa), the subcutaneous formulation of daratumumab (Darzalex Faspro), and the anti-BCMA antibody-drug conjugate belantamab mafodotin-blmf (Blenrep) (

). With multiple drug options available within 7 classes of antimyeloma agents in various combinations, therapeutic sequencing in RRMM has become increasingly complex. Moreover, it has been shown that response rates and duration of response diminish with each successive line of therapy,

 making the early use of efficacious regimens to achieve and sustain remissions critical.

Timeline. Drug Approvals in Multiple Myeloma, June 2019 to September 2020

Numerous randomized studies of novel agents added to an immunomodulatory drug (IMiD) or proteasome inhibitor (PI) backbone in RRMM have shown improvement in outcomes compared with doublet controls. However, cross-trial comparisons are limited by differences in patient populations and study designs, and it is important to not simply compare outcomes such as overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) among trials but to also appreciate the relative benefit from the novel agent over the control arm via the HR. Additionally, clinicians must take into account factors such as frailty and comorbidities, symptom burden and disease biology, as well as toxicities and patient response to prior therapies, when making therapeutic decisions. Recent reviews summarizing current treatment paradigms in RRMM have been published,

 from which a basic framework for choosing therapies in early and late relapses can be drawn using data from major phase 3 randomized IMiD- and PI-backbone studies in RRMM.

Investigators have conducted multiple large phase 3 randomized studies of lenalidomide (Revlimid)– and bortezomib (Velcade)–backbone regimens in RRMM. These agents in combination have demonstrated a consistent PFS benefit when triplet regimens are used compared with doublet control across studies.

Specifically, investigators examined lenalidomide and dexamethasone (Rd) alone versus Rd in combination with a third agent, including carfilzomib (Kyprolis) in ASPIRE (NCT01080391), 

ixazomib (Ninlaro) in TOURMALINE-MM1 (NCT01564537), elotuzumab (Empliciti) in ELOQUENT-2 (NCT01239797), and daratumumab (Darzalex) in POLLUX (NCT02076009).

Further, studies using the backbone regimen of bortezomib and dexamethasone (Vd) versus Vd and a third agent included carfilzomib in ENDEAVOR (NCT01568866), panobinostat in PANORAMA-1 (NCT01023308), elotuzumab in a phase 2 study (NCT01478048), daratumumab in CASTOR (NCT02136134), and most recently, pomalidomide (Pomalyst) in OPTIMISMM (NCT01734928), venetoclax (Venclexta) in BELLINI (NCT02755597), and selinexor in BOSTON (NCT03110562).

In many of these studies, patients were not heavily pretreated, having received a median of 1 to 2 lines of prior therapy. Of the Rd- and Vd-backbone studies, data from the daratumumab combination studies—POLLUX and CASTOR—have shown the lowest PFS HRs (0.43 and 0.31, respectively). Notably, patients with translocation t(11;14) in the BELLINI study had a remarkable PFS HR of 0.10, which might be considered the first example of personalized medicine in MM.

Initial results of the ongoing phase 3 BOSTON study evaluating selinexor in combination with Vd (SVd) versus Vd in RRMM have also shown a PFS benefit (13.9 vs 9.5 months, HR, 0.70) with SVd compared with Vd.

 Whereas most novel therapies to date have resulted in an improvement in PFS for high-risk patients but have not shown the ability to overcome high-risk status,

 it is notable that patients enrolled in the BOSTON study with 17p deletion had a PFS HR of 0.38, suggesting a possible benefit of this combination in patients with high-risk disease.

Importantly, with long-term follow-up, data have shown that a PFS benefit can translate to an OS benefit in some studies. Of the Rd-backbone studies, an OS or PFS2 benefit has been reported in 3 studies. In ASPIRE, the median OS was 40.4 months versus 48.3 months in the Rd versus carfilzomib plus Rd arms, respectively (HR, 0.79).

 The median OS for patients enrolled in ELOQUENT-2 was 39.6 months with Rd compared with 48.3 months with elotuzumab plus Rd (HR, 0.78).

 In POLLUX, the median PFS2 favored the combination of daratumumab plus Rd versus Rd alone (53.3 vs 31.6 months, respectively; HR, 0.54).

Similarly, in the Vd-backbone studies, data from ENDEAVOR demonstrated an improvement in OS, with a median OS of 47.8 months for carfilzomib and Vd and 38.8 months for Vd (HR, 0.76). The most recent analysis of CASTOR showed that daratumumab plus Vd (DVd) significantly prolonged PFS2 compared with Vd alone (34.6 vs 20.7 months; HR 0.47), with a trend toward improved 3-year OS rates.

When considering the above, it is important to appreciate that OS outcomes across studies can be confounded by differing access to drugs at time of progression. Of note, although the BELLINI study demonstrated improved PFS with the addition of venetoclax to Vd overall, a nearly 2-fold-higher risk of death was observed in the venetoclax arm (HR, 1.47). The increase in deaths was due mainly to treatment-emergent infections. Further, in a subgroup analysis, 3 groups of patients did not benefit from the addition of venetoclax to Vd: patients without t(11;14), those with high-risk cytogenetics, and those with low expression of BCL-2.

Selecting an evidence-based regimen based on refractoriness to the backbone control arm is of critical importance. When considering the above Rd- and Vd-backbone studies, in lenalidomide- and bortezomib-sensitive patients, using daratumumab combination regimens in early relapses is efficacious and likely to attain a greater PFS benefit, as suggested by the PFS HR data. However, many of the Rd-backbone studies in RRMM have excluded lenalidomide-refractory patients. As seen in the Vd-backbone studies OPTIMISMM, CASTOR, and ENDEAVOR, the median PFS of lenalidomide-refractory patients is inferior to that of the total study population. 

For lenalidomide-refractory patients, specifically, the median PFS for each trial was 9.5 versus 5.6 months (pomalidomide and Vd [PVd] vs Vd), 9.3 versus 4.4 months (DVd vs Vd), and 8.6 versus 6.6 months (carfilzomib and dexamethasone [Kd] vs Vd), respectively. In comparison, the median PFS for the total study populations was 11.2 versus 7.1 months (PVd vs Vd), 16.7 versus 7.1 months in (DVd vs Vd), and 18.7 versus 9.4 months (Kd vs Vd).

Thus, the use of second-generation IMiDs and PIs in patients who are refractory to lenalidomide or bortezomib at relapse becomes necessary. Moreover, as daratumumab moves to the front-line setting, the use of second-generation IMiDs and PIs should be considered in patients who may be refractory to daratumumab and lenalidomide or bortezomib at the time of first relapse.

In subsequent relapses, early use of a second-generation IMiD- and PI-based triplet regimen should be considered based on recent data from major randomized studies. The IMiD-based pomalidomide and dexamethasone (Pd) combination studies include ELOQUENT-3 (NCT02654132), investigating Pd alone or in combination with elotuzumab (EPd), and ICARIA-MM (NCT02990338) examining isatuximab and Pd (Isa-Pd) versus Pd alone. The PI-based Kd studies include CANDOR (NCT03158688) comparing daratumumab plus Kd (KdD) versus Kd alone, and IKEMA (NCT03275285), Isa-Kd vs Kd).

A significant PFS benefit with the triplet regimen versus doublet control has been seen in both the randomized phase 2 ELOQUENT-3 and phase 3 ICARIA-MM studies, in which the patient populations were heavily pretreated, and the majority were lenalidomide refractory. The median PFS in ELOQUENT-3 was 10.3 versus 4.7 months with EPd vs Pd, respectively (HR, 0.34), and 11.5 months versus 6.5 months with Isa-Pd vs Pd in ICARIA-MM (HR, 0.60). Additionally, early data have shown an improvement in OS in both studies, with a 68% 18-month OS rate versus 49% for EPd versus Pd, respectively (HR, 0.54), and 72% versus 63% for Isa-Pd vs Pd, respectively.

Based on these trials, the addition of elotuzumab or isatuximab to a Pd backbone therapy offers considerable benefit in patients with heavily pretreated RRMM. Pd is also being studied in combination with daratumumab in RRMM in the ongoing phase 3 APOLLO study (NCT03180736). Daratumumab in combination with Pd previously received FDA approval based on data from the phase 1 EQUULEUS study (NCT01998971) study of approximately 100 patients.

Two major phase 3 Kd-backbone studies, CANDOR and IKEMA, have similarly shown a significant PFS benefit in heavily pretreated MM patient populations. In CANDOR, the median PFS was not reached with KdD compared with 15.8 months for Kd alone (HR, 0.63). The median PFS in IKEMA was not reached with the triplet regimen of Isa-Kd versus 19.2 months for Kd alone (HR, 0.53). Although OS data are not yet mature, PFS HRs favor the triplet combinations across clinically important subgroups including lenalidomide-exposed and lenalidomide-refractory patients. Notably, numerous clinical trials of carfilzomib to date, CANDOR and IKEMA, are the first to use Kd at a dose of 56mg/m

Based on the trials above, for patients who are refractory to lenalidomide and bortezomib at relapse, clinicians should highly consider subsequent therapy with a CD38 monoclonal antibody in combination with Pd or Kd. Additionally, they should base their choice of the IMiD or PI backbone on patient character

istics including age, cardiovascular risk, and cytopenias. For example, a CD38 monoclonal antibody in combination with a Pd backbone would be an ideal choice in patients without cytopenias, those with a cardiac history, elderly patients (> 70 years), and those who desire to minimize parenteral therapies. A CD38 monoclonal antibody in combination with a Kd backbone may be a more optimal treatment selection for patients with cytopenias, a thrombotic history, and those who have t(4;14).

Patients who have become refractory to existing therapies have a very poor prognosis, in particular those who are penta refractory (or refractory to a CD38 monoclonal antibody plus 2 IMiDs plus 2 PIs) and those who are triple refractory and quad refractory (refractory to a CD38 monoclonal antibody plus 1 or 2 IMiDs plus 1 PI, or a CD38 monoclonal antibody plus 1 IMiD plus 1 or 2 PIs).

 The development of novel agents for the treatment of such patients is a critical need.

The novel agent selinexor, a first-in-class selective inhibitor of nuclear export, has been approved in combination with dexamethasone in RRMM.

 Selinexor is further being studied in combination with several other MM backbone therapies, including in combination with Rd and Pd as well as daratumumab and dexamethasone (Dd) and Kd in the ongoing multiarm phase 1/2 STOMP study (NCT02343042). Early results of selinexor in combination with Rd and Pd arms of the STOMP trial have shown promising activity.

 Moreover, initial results of selinexor in combination with Dd have demonstrated activity in patients with IMiD- and PI-refractory MM.

Belantamab mafodotin, a first-in-class anti-BCMA antibody-drug conjugate, is another novel agent under clinical development for MM. It recently received accelerated approval from the FDA based on the promising preliminary results of the ongoing phase 2, randomized DREAMM-2 trial (NCT03525678) as monotherapy for adult patients with RRMM who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a PI, and an IMiD.

 From the safety data available to date, an important toxicity observed with belantamab mafodotin is keratopathy. Thus, a Risk Evaluation and Mitigation Strategy program is required to manage the risks of ocular toxicity with the administration of belantamab mafodotin. The agent is also being studied in combination with IMiD and PI backbones including Rd and Vd in the DREAMM-6 trial (NCT03544281).

Melflufen, an aminopeptidase with an alkylating payload, has shown clinical activity in patients with heavily pretreated RRMM and triple-class refractory disease and has been granted priority review by the FDA.

In conclusion, the major trials of combination therapies in RRMM to date have shown superior efficacy of the triplet regimens over double controls. An important factor in selecting subsequent therapy is a patient’s sensitivity to lenalidomide and bortezomib, as well as daratumumab, at time of relapse.

Daratumumab-based combinations in early relapses likely confer a greater benefit in PFS. For patients who are refractory to lenalidomide and bortezomib at relapse, clinicians should consider subsequent therapy with a CD38 monoclonal antibody in combination with a second-generation IMiD and PI. The should also continuously access clinical trial options should be continuously assessed throughout the disease course.

Results of the aforementioned ongoing clinical trials of novel agents as well as others in clinical development for RRMM—such as anti-BCMA antibody-drug conjugates, bispecific T-cell engagers, chimeric antigen receptor T-cell therapies, and the next-generation cereblon E3 ligase modulator iberdomide (CC-220)—will undoubtedly further change the treatment landscape.

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Articles

The treatment landscape of relapsed/ refractory multiple myeloma has undergone  rapid changes over the past 2 decades, with over a dozen drug approvals by the FDA. 

Larysa J. Sanchez, MD

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Navigating the Increasing Complexity of Therapeutic Sequencing for Relapsed/Refractory Multiple Myeloma