Multiple Myeloma Landscape Grows At Rapid Pace With Quadruplets and BCMA-Directed Therapy

Douglas W. Sborov, MD, MS

The introduction of quadruplet therapies, minimal residual disease (MRD)–adapted approaches, and novel immunotherapeutics—including antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies—is reshaping the treatment paradigm of newly diagnosed and relapsed/refractory multiple myeloma, said Douglas W. Sborov, MD, MS.

“It comes as no surprise to academic or community physicians that the world of multiple myeloma treatment is changing at a breathtaking pace. Because of this, our patients are now living longer, and we can provide them [with] better-tolerated drugs and improved supportive care,” said Sborov in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma.

Sborov was the chair of the IPC meeting. He is an assistant professor, Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah School of Medicine; director, Multiple Myeloma Program and Division of Hematology Biorepository; member, Huntsman Cancer Institute (HCI) Experimental Therapeutics Program; physician leader for multiple myeloma/bone marrow transplant, HCI Clinical Trials Office; member, HCI Protocol Review and Monitoring Committee; and a Huntsman Translational Scholar at HCI.

During the interview, Sborov discussed key data and therapeutic developments that have reshaped the treatment of patients with newly diagnosed and relapsed/refractory multiple myeloma, both transplant ineligible and transplant eligible; the emergence of ADCs, bispecific antibodies, and CAR T-cell therapies in the later-line setting; and how to best manage common toxicities associated with some of these therapies in the paradigm.

OncLive^®: During the IPC meeting, Manni Mohyuddin, MD, of HCI, discussed management strategies for transplant-ineligible and transplant-eligible newly diagnosed multiple myeloma. Starting with the transplant-ineligible space, what are some of the key trials that have reshaped practice patterns in this setting?

Sborov: It wasn’t too long ago that we had a relatively easy algorithm for the treatment of patients with newly diagnosed [multiple myeloma]. Across the board, the option of bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [VRd] was never the wrong answer. Much has changed, however, and we are starting to see the data from several key studies mature.

The first study to highlight is the MAIA trial [NCT02252172]. This was a phase 3 trial that investigated daratumumab [Darzalex] plus lenalidomide and dexamethasone [DRd] vs lenalidomide and dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma. Simply put, this trial was a game-changer, and the results supported the use of [DRd] as standard of care in patients able to tolerate triplet therapy. I make that claim based on several f indings. First, the triplet was associated with improved overall response [rate] and deeper responses, including almost half of the patients achieving a complete response [CR] or better and a rate of MRD negativity of 24%. That was nearly 3.5 times that seen with lenalidomide plus dexamethasone. Additionally, at a median follow-up of 56 months, the estimated 5-year progression-free survival [PFS] rate was 52.5%, which, in my opinion, established a new standard for this patient population. Lastly, we know that daratumumab, especially when injected rather than infused, is generally well tolerated. In an older population, this is an extremely important consideration if we want to minimize visits and time in the infusion room to optimize quality of life.

What trials should be highlighted in the transplant-eligible setting?

In the transplant-eligible population, there are several trials to highlight for different reasons. The results of the FORTE trial [NCT02203643] were recently published and [showed] several important findings. The highlights include the continued importance of autologous stem cell transplant in newly diagnosed disease and the use of doublet maintenance therapy, most notably in those patients with high-risk disease. FORTE was a randomized phase 2 trial conducted in Europe that included 2 randomizations. The first randomization was to 1 of 3 arms: carfilzomib [Kyprolis]/cyclophosphamide/ dexamethasone [CCd] followed by transplant followed by consolidation CCd; carfilzomib/lenalidomide/dexamethasone [KRd] followed by transplant and consolidation; or KRd for 12 cycles without transplant. The second randomization for maintenance included 2 arms: carfilzomib/lenalidomide vs lenalidomide alone.

Results of the trial showed that KRd plus transplant was associated with improved PFS compared with KRd alone or CCd with transplant. Additionally, we saw that this PFS benefit was evident across the board, even in those patients with high-risk genetics except for amplification 1q21. When looking at PFS at the second randomization, we saw similar results that carfilzomib plus lenalidomide was associated with improved PFS in all patients other than those with amplification 1q21.

The second trial in [the transplant-eligible] setting is GRIFFIN [NCT02874742]. This is a trial that is setting the table for the use of daratumumab, bortezomib, lenalidomide, and dexamethasone [dara-VRd] for newly diagnosed patients. It is a randomized phase 2 trial in which patients received dara-VRd or VRd induction followed by transplant and consolidation followed by daratumumab plus lenalidomide or lenalidomide maintenance. The primary end point of the trial was the rate of stringent CR after consolidation. Although the primary end point was met, the trial was not powered for PFS. This has kept many providers from fully adopting this treatment strategy.

That said, at the 2021 American Society of Hematology Annual Meeting & Exposition, the updated results following 24 months of maintenance were presented, and the data were impressive. The quadruplet was associated with a CR or better rate of 82% after 2 years of maintenance. This was associated with more than 40% of patients maintaining MRD negativity for at least 12 months. These are deep and prolonged responses. Although the median PFS and overall survival have not been reached in either arm, the 36-month PFS rate was nearly 90% in the quadruplet arm.

These data set up the Perseus trial [NCT03710603] nicely, as this is a study with a similar trial design but powered for PFS. We’ll see more providers adopting this quadruplet as the preferred frontline approach.

The last trial to highlight in this space is MASTER [NCT03224507]. This is a phase 2 trial investigating daratumumab combined with carfilzomib, lenalidomide, and dexamethasone [dara-KRd] followed by transplant and up to 8 cycles of dara-KRd consolidation followed by lenalidomide maintenance. It is an extremely important trial for several reasons. Not only is it investigating the very powerful dara-KRd combination, but it is investigating an MRD-adapted treatment approach such that following confirmation of MRD negativity, patients enter a treatment-free phase.

In this trial, 71% of patients were placed on surveillance based on their MRD-negativity status and 80% of patients achieved MRD negativity of 10^–5, even those patients with 2 or more high-risk genetic features. Lastly, the 2-year PFS rate was 58% in those patients with 2 or more high-risk genetic features, which was impressive. This represents the new benchmark for patients with ultra high–risk disease.

Amandeep Godara, MBBS, of HCI, discussed updates in the relapsed/refractory setting for patients with multiple myeloma. What additional considerations need to be made regarding treatment selection in this setting that may not have to be considered in the frontline space?

Dr Godara [spoke to] some of the recent data highlighting isatuximab-irfc [Sarclisa]–based triplet regimens, as well as emerging data regarding the use of iberdomide, a next-generation CELMoD [cereblon E3 ligase modulating drug]. Although IKEMA [NCT03275285] and ICARIA-MM [NCT02990338] were important trials, there are many considerations that we are thinking about for all the different treatment options in the relapsed/refractory setting.

First and foremost, we need to consider the degree of refractoriness that each patient has. That is to say, we need to think about what drugs may work and which may not. It’s very clear that patients should be considered for at least triplet therapy at the time of progression, assuming their fitness level supports the use of multiple agents. When considering which triplet to use, in general, I favor utilizing the next best options.

With the emergence of novel immunotherapeutics like CAR T-cell therapies and T-cell redirecting bispecific antibodies, I would, in general, favor enrolling patients on clinical trials [that are evaluating some of these novel agents]. If that is not an option and assuming “nonrefractoriness,” I would choose an anti-CD38 monoclonal antibody–based treatment with an immunomodulatory drug or a proteasome inhibitor that the patient is not yet refractory to. Then, in later lines, we now have the emergence of other standard-of-care options, including idecabtagene vicleucel [ide-cel; Abecma], a CAR T-cell therapy; belantamab mafodotin-blmf [Blenrep], our first ADC; and selinexor [Xpovio] in various combinations. The key to utilizing these agents will be to best understand the kinetics of a patient’s disease progression, their ability to tolerate drug-specific toxicities, and access to these available drugs.

Do you have anecdotal experience with bispecific antibodies and CAR T-cell therapy that may inform sequencing with these therapies?

That is a great question, but I have no good answer for it. The best answer I can give is that we just don’t know how to sequence the CAR T-cell therapies and bispecific antibodies. I look forward to seeing these data emerge in the next couple of years, but for now, I base my decision on what is available. As most of us know, it has been terribly difficult to get ide-cel for our patients. Many of our patients are not able to wait for a spot to open for this treatment [because] these are, in general, late-line patients. In those cases where we can’t wait for a CAR T-cell therapy, the bispecific antibodies are an incredible off-the-shelf option if we have these trials available.

It is safe to say that we are all looking forward to the potential upcoming approvals of ciltacabtagene autoleucel [cilta-cel] and teclistamab. The data supporting cilta-cel are impressive and pointing toward this construct outperforming ide-cel. The data for teclistamab, especially in combination with daratumumab, are almost jaw-dropping in the late-line setting. I suspect that both drugs will come with similar indications as belantamab mafodotin. Once the earlier-line data mature, it is clear to me that these are agents that, at a minimum, will be used in the early relapsed setting.

Finally, Brian McClune, DO, of HCI, discussed toxicity management in multiple myeloma. What are some of the key toxicities that require nuanced management? How are these adverse effects mitigated with preventative or proactive strategies?

As Dr McClune pointed out, each of our new drugs, especially the novel immunotherapeutics, are associated with their own unique toxicities. With bispecifics and CAR T-cell therapies, the most consistent and notable toxicities include cytopenias, cytokine release syndrome [CRS], and neurotoxicity or immune effector cell–associated neurotoxicity syndrome [ICANS]. In most patients treated with these different drugs, CRS and ICANS are predominantly low grade, and the inflammatory response can be relatively easily mitigated using supportive care and/or tocilizumab [Actemra] with or without steroids.

Overall, although the statement “well tolerated” may be a stretch, the toxicities are manageable. In most cases, based on the impressive responses we see with these agents, if we think a patient is fit enough, the potential benefit gained from the drugs far outweighs the risk of early toxicities.

Selinexor is certainly a unique drug that has been shown to be quite effective, especially when used in combination regimens. That said, it can be toxic for patients; the most significant toxicities are gastrointestinal [in nature] and fatigue. We generally take a stepwise approach to introducing the drug to patients, and we consider an initial dose reduction during the first cycle [of treatment with selinexor] to assess and support patients through any issues they may have. Every patient gets olanzapine and ondansetron [Zofran], which is a long-acting antiemetic. We consider a thrombopoietin receptor agonist for thrombocytopenia, granulocyte colonystimulating factor for neutropenia, and electrolytes for hyponatremia and other abnormalities. Interestingly, we find that if we can get patients through that first cycle of therapy, we are able to increase drug dose if necessary and get them feeling much better.

Lastly, it is worth mentioning the ocular toxicity associated with belantamab mafodotin. The off-target effect of the drug can cause damage or apoptosis to the corneal epithelial layer. This results in some degree of keratopathy in about 70% of patients. That said, we find that about one-fourth of patients develop blurry vision or dry eyes. Although these ocular toxicities can be profound, they are reversible in all patients; [still], based on the long half-life of the drug, they can persist for days, weeks, or months.

Because of their increased risk of ocular toxicities, patients [receiving belantamab mafodotin] are required to enroll in the [Risk Evaluation and Mitigation Strategy] program, which mandates that they see an eye care professional prior to each dose. We make sure patients are safe as they are going through this treatment. Patients are also instructed to utilize eyedrops multiple times per day. If patients have significant symptoms, we hold the drug. If the drug is working, even when 1 or more dose holds are required, disease responses can persist.

What are the take-home messages about the rapidly evolving multiple myeloma paradigm?

Quadruplets up front are here to stay and represent the next wave of treatment options for patients with newly diagnosed disease.

MRD-adapted treatment strategies are being explored and will likely identify subsets of patients who don’t have to stay on continued therapy indefinitely.

The relapsed/refractory setting is complex, and for those patients who aren’t refractory to anti-CD38 monoclonal antibodies like daratumumab or isatuximab, a triplet regimen should be considered at the time of first relapse.

Lastly, immunotherapeutics, including ADCs, CAR T-cell therapy, and bispecific antibodies, are game-changers in the later-line setting, and they will inch closer to frontline treatment over the next several years.