Expanded Combinations, Novel Agents, and MRD-Informed Trials Transform Myeloma Paradigm

Laura Finn, MD

The treatment paradigms of newly diagnosed and relapsed/refractory multiple myeloma have changed rapidly in recent years with the introduction of quadruplet-based regimens, several novel agents, cellular therapy, and the growing utility of minimal residual disease (MRD) negativity as an indicator of improved outcomes, said Laura Finn, MD. More data, she added, are needed to flesh out the optimal use of these new approaches.

“It is nice that we are seeing developing areas of research for those patients with newly diagnosed multiple myeloma and those with relapsed/refractory disease. These evolving data for cellular therapy and the use of MRD are really exciting,” said Finn in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma, which she chaired. Finn is associate program director of the Hematology/Oncology Fellowship Program and the Bone Marrow Transplant Program at Ochsner Medical Center of Ochsner Health.

“The data regarding the utility of MRD are maturing. As a cancer community, we need to acknowledge [MRD] and hopefully universally define it. Once we can do that, it will become more available as a covered test that can be available outside of the research setting. We can start using it in real-world practice to make sure we are seeing the same correlation between MRD-negative disease and outcomes,” Finn explained.

During the interview, Finn provided a deep dive into pivotal data with combinations and novel agents that have changed the paradigm for patients with newly diagnosed, early relapsed, and late relapsed multiple myeloma.

OncLive^®: During the IPC meeting, your colleague Andrew Dalovisio, MD, of Ochsner Medical Center, discussed frontline therapy for patients with multiple myeloma. Starting with the transplant-eligible setting, what studies have moved the needle forward in terms of adding CD38-directed antibodies to the paradigm?

Finn: Dr Dalovisio did a lot of the legwork in discussing the collection of studies utilizing CD38-directed antibodies as up-front therapy in patients eligible for transplant. Those were the GRIFFIN [NCT02874742], Cassiopeia [NCT02541383], and GMMG HD7 [NCT03617731] trials.

The final analysis of the GRIFFIN study was presented at the 2021 American Society of Hematology [ASH] Annual Meeting & Exposition. This was a study of bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [VRd] vs that triplet with daratumumab [Darzalex]. This [regimen] was followed in this patient population by transplant and consolidation with the triplet or quadruplet and followed additionally by maintenance therapy, which could be daratumumab and lenalidomide or lenalidomide alone. The 3-year follow-up analysis showed that after 12 months, once patients got through to maintenance therapy, the stringent complete response [CR] rate was [higher] in those receiving daratumumab compared with those who did not, after induction, transplant, and consolidation.

[The results] showed that the addition of daratumumab throughout the phases of initial therapy for multiple myeloma led to an improvement in disease response and in achieving CR.

The Cassiopeia study was also done in the first-line, transplant-eligible setting. This was the European counterpart to our GRIFFIN study and compared daratumumab, bortezomib, thalidomide [Thalomid], and dexamethasone [dara-VTd]— because there is more use of thalidomide in Europe than in the United States—with VTd as a triplet therapy. Again, [treatment] was followed by transplant, consolidation, and daratumumab maintenance. At a 3-year follow-up, the median progressionfree survival [PFS] was not reached in the daratumumab arm and 64% of patients were MRD negative after the maintenance [portion] compared with 57% with observation alone. We are seeing a recurring theme that adding daratumumab to your regimen elicits deeper responses.

The GMMG HD7 trial was a study of VRd vs isatuximabirfc [Sarclisa] with that triplet regimen. Achievement of MRD negativity was the primary end point in this study in patients with newly diagnosed multiple myeloma.

MRD-negative remission was achieved in 50% of those patients who had the addition of isatuximab compared with 35% of patients with the triplet. The evidence is building for the addition of a CD38-directed antibody to induction regimens to achieve CRs. What is evolving is the importance of [achieving] MRD-negative disease.

Finally, the FORTE trial [NCT02203643] followed along the line of achieving MRD [negativity]. This was a study of carfilzomib [Kyprolis], lenalidomide, and dexamethasone induction and consolidation with transplant. Patients were randomized prior to maintenance to carfilzomib/ lenalidomide or just lenalidomide. MRD was highest in those patients who had combination maintenance therapy with the proteasome inhibitor and immunomodulatory drug [IMiD]. Just like we learned that triplet therapies are better than doublet therapies, quadruplets may be better than triplets. The addition of these combination therapies is deepening responses, and [the results are] going to emphasize how important MRD-negative disease really is.

How have the results of the MAIA trial (NCT02252172) solidified a role for daratumumab in the transplant-ineligible setting?

MAIA was a phase 3 trial of daratumumab, lenalidomide, and dexamethasone compared with doublet therapy of lenalidomide and dexamethasone as frontline therapy in patients who were ineligible for transplant because of frailty from age or comorbidities that prohibit transplant.

Updated PFS and overall survival [OS] data were published in Lancet Oncology in October 2021. This was a 56-month follow-up. After almost 5 years, the median PFS has not been reached in the daratumumab arm compared with 34 months in the doublet arm. The median OS has not yet been reached in either arm.

There were no new safety concerns [with the additional follow-up] in either cohort. This informs us that triplet therapy is indicated in older patients, even those who are frail or might have significant comorbidities that were severe enough to preclude transplant. We have learned that very few patients are so frail that minimal or doublet therapy is indicated in the frontline setting.

In the early-relapsed setting, data from the ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) trials have shed light on the utility of isatuximab in multiple myeloma. What did those results demonstrate?

ICARIA was a phase 3 study of pomalidomide [Pomalyst] and dexamethasone with or without isatuximab in relapsed/ refractory multiple myeloma. Eligible patients had received at least 2 prior lines of therapy. The IKEMA study was a phase 3 study of carfilzomib and dexamethasone with or without isatuximab.

At publication, with almost 1 year of follow-up of the ICARIA-MM study, the median PFS of isatuximab plus pomalidomide and dexamethasone was 11.5 months, compared with almost half that—6.5 months—with pomalidomide/dexamethasone alone. Similarly, in the IKEMA study, PFS was not reached at the time of the published analysis and was 19 months in the doublet arm of carfilzomib/ dexamethasone. Similar to the daratumumab studies, we see that the addition of isatuximab significantly improves PFS in combination with dexamethasone and either pomalidomide or carfilzomib.

Moving to your presentation on relapsed/refractory multiple myeloma, what is intriguing about the mechanism of action of belantamab mafodotin-blmf (Blenrep)? How is it being utilized in multiple myeloma management?

Belantamab mafodotin is a humanized [immunoglobulin] G monoclonal immunoconjugate that targets BCMA [B-cell maturation antigen]. BCMA is found primarily on the plasma cells but not really on other cells within the hematopoietic system. Belantamab mafodotin carries a drug conjugate [with] monomethyl auristatin F. Its mechanism of action is not just direct cytotoxicity; it also recruits macrophages and natural killer cells for antibody-dependent cellular phagocytosis of myeloma cells.

This is different than other BCMA-directed agents, which fall into more classic categories of cellular therapy, such as bispecific T-cell engager [BiTE] therapy or CAR [chimeric antigen receptor] T-cell therapy, that utilize T cells as the mechanism of action against the myeloma cell. Both of those classes of agents carry the toxicity of cytokine release syndrome [CRS] and neurotoxicity, which is not seen with belantamab mafodotin. Conversely, [belantamab mafodotin] carries a unique adverse effect of ocular or eye toxicity.

Belantamab mafodotin is also more readily available [vs BiTEs or CAR T-cell therapies] to treating physicians outside of cellular therapy centers. [Belantamab mafodotin] is FDA approved for patients who have progressed on 4 lines of therapy, and oncologists can sign up as a treating physician for this therapy through a [Risk Evaluation and Mitigation Strategies] program provided by the sponsor.

Several trials have evaluated belantamab mafodotin. Could you speak to some of the key data that underscore its utility in the relapsed/refractory setting?

DREAMM-2 [NCT03525678] was a 2-arm, open-label, phase 2 study of belantamab mafodotin for patients with relapsed/ refractory multiple myeloma who had received 3 or more prior lines of therapy. The study also led to [belantamab mafodotin’s] FDA approval. [DREAMM-2] compared 2 doses of intravenous belantamab mafodotin: 2.5 mg/kg or 3.4 mg/kg. The primary end point was overall response rate [ORR], which was similar between the 2 arms at 31% for the lower dose and 34% for the higher dose.

The greatest takeaway from the DREAMM-2 trial is that the toxicity, especially the ocular toxicities like blurred vision and dry eyes, was lower in the 2.5-mg/kg dose cohort. Therefore, this is the dose approved and what has been selected for future studies with the agent.

Important information came from the 2021 ASH meeting with regard to the DREAMM-5 study [NCT04126200], which is an ongoing phase 1/2 platform study, demonstrating that belantamab mafodotin can be safely combined with feladilimab. [Feladilimab] is a co-stimulatory T-cell molecule and is the first of its kind. This is an important first step to considering the future of belantamab mafodotin not only as a single agent but where it will go next in combination therapy with other drugs.

At this point, we only have the preliminary safety data from the ASH abstract for DREAMM-5. Now we are looking forward to the outcome data that should soon follow in manuscript form or [be presented] at an upcoming meeting in 2022.

How is selinexor (Xpovio) being utilized? Could you speak to some of the key findings from the ongoing STOMP trial (NCT02343042)?

Selinexor is another unique drug that is new for use. It is a selective inhibitor of nuclear export and works by blocking the action of exportin-1. Downstream from that, the agent blocks several proteins involved in cancer cell growth that lead to cell cycle arrest and apoptosis.

[Selinexor] is currently FDA approved in combination with dexamethasone for a doublet therapy or with bortezomib and dexamethasone for a triplet therapy for patients refractory to at least 4 prior lines of therapy. We are still talking about a patient population that is in late relapse.

The STOMP study results were updated at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting in abstract 8018. [The findings] demonstrated that selinexor was safely combined with pomalidomide and dexamethasone for a potential new all-oral triplet regimen for patients with relapsed/refractory multiple myeloma. The ORR was 57% [in patients previously treated with an CD38-directed antibody], with a 12-month median PFS [in pomalidomide-naïve or -nonrefractory patients]. The outlook is excellent for this triplet combination.

What have updated results from the KarMMa trial (NCT03361748) of idecabtagene vicleucel (ide-cel; Abecma) indicated about the use of CAR T-cell therapy in relapsed/refractory multiple myeloma? Is anything known about how to best treat patients who progress on this therapy?

[The KarMMa trial] looked at fourth- or later-line treatment for patients with relapsed/refractory multiple myeloma. In the study, patients had to have received a prior proteasome inhibitor, IMiD, and a CD38-directed antibody, so it was a very heavily pretreated patient population. The ORR was 73%, with 33% [of patients] achieving a CR or stringent CR. Updates seen at ASCO 2021 in abstract 8016 with a [24.8-month] follow-up showed that the higher dose of 450 x 10⁶ CAR+ T cells [induced] the highest ORR at 81% and a median PFS of [12.2] months. Responses were seen in very high–risk patient populations, including those with stage III [Revised International Staging System; ISS] multiple myeloma with extramedullary disease and high tumor burden, which is important for us to know as treating physicians that we should refer these patients who are hard to treat with cellular therapy.

Additional updates were presented in abstract 2743 at the 2021 ASH Annual Meeting & Exposition and showed that patients who did progress after ide-cel successfully responded to subsequent standard-of-care therapy or alternative BCMAdirected therapy, which would primarily be belantamab mafodotin. The ORR was 76% in those treated with alternative myeloma therapy and 91% in those treated with other forms of BCMA-directed therapy, which was surprising and important to know. We thought patients becoming refractory to, not responding to, or progressing after CAR T-cell therapy would be a population unlikely to respond to other agents, but the ASH update proved otherwise.

How do the results observed with ciltacabtagene autoleucel (cilta-cel) stack up against those with ide-cel?

We have 2 studies looking at cilta-cel: CARTITUDE-1 [NCT03548207] and CARTITUDE-2 [NCT04133636]. CARTITUDE-1 was published in Lancet in 2021. It was a singlearm phase 1/2 study of patients with relapsed/refractory multiple myeloma who had received 3 or more prior lines of therapy. The primary end point of the study was safety.

[The results showed] that 95% of patients had CRS, but only 4% had grade 3/4 CRS. [Additionally], 21% of patients had neurotoxicity, but only 9% [had grade 3/4 neurotoxicity]. These were low rates of CRS and neurotoxicity and expected hematologic toxicities that we would see as treating physicians.

The ORR was [97% with 67% of patients] achieving stringent CRs and 93% of evaluable patients [achieving] MRD negativity. We saw an ASH update in abstract 3988 that showed when broken down by risk, no subgroup did not respond to cilta-cel; however, [those with] stage III ISS disease and those with baseline plasmacytomas did have a detectably lower duration of response [DOR], PFS, and OS.

The CARTITUDE-2 manuscript was published in the Journal of Clinical Oncology in 2021. It was a phase 2 study of cilta-cel in patients who had received 1 to 3 prior lines of therapy who were lenalidomide refractory.

The ORR was also high, at 95%, with 75% of patients achieving a stringent CR. An update of this study, which was presented in abstract 3866 [at ASH], showed that with longer follow-up, responses deepened, and the CR rate improved from 75% to 85%; 92% of evaluable patients were MRD negative.

The important outcomes of these studies are that we are seeing very high response rates and, especially in those patients achieving CRs, we know those populations have a better DOR. We also need to see which patients, over a long follow-up period, will achieve a CR.

These are higher ORRs and CR rates than seen with ide-cel, but we have to realize that there may be manufacturing differences and enrollment criteria differences, so we can’t compare across studies. It is acknowledged that with the information we have, we are seeing outcome results that are on the more favorable side for cilta-cel [vs ide-cel].

What research efforts are needed to address unanswered questions in multiple myeloma?

We are trying to figure out how we can achieve long, durable remissions in our patients with newly diagnosed multiple myeloma. We’re figuring that out as more studies incorporate MRD negativity as part of their outcomes or even sometimes as a surrogate for other outcomes.

How do we achieve effective therapy for late relapsed patients? The CAR T-cell therapies induce high response rates in multiply relapsed patients with very high CR rates and MRD-negativity rates, so that is encouraging in that arena.

One important area of research right now is the combination of novel therapies. The greatest example is the DREAMM-5 study of belantamab mafodotin with unique agents, as well as studies from the KarMMa trial showing that patients can be treated after relapse on CAR T-cell therapy. We all had worries and suspicions, but they may not actually be true in practice.

We haven’t made strides yet in cancer research for the diversity of patient enrollment. We are still seeing that most patients in these studies are of nonminority populations. We know that [minority] populations are affected [by multiple myeloma] at younger ages and have often poor outcomes. We don’t fully understand why. [Surveillance, Epidemiology, and End Results] database [studies] and retrospective reviews have their role, but I hope to see a greater effort to prospectively enroll these patients so we can further understand the patient populations affected by multiple myeloma.