The landscape of multiple myeloma (MM) management is evolving rapidly. In this commentary, I will review key areas of recent expansion, including the management of smoldering MM, treatment options for patients with high-risk MM, and novel immunotherapy constructs.

Smoldering Myeloma
Gaining a better understanding of the precursor phases of MM, which include monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM, has been of great interest. Smoldering MM, which represents a transitional phase between MGUS and active MM, has been one of these topics of interest—especially in the past few years, as we have developed better ways to diagnose and risk stratify patients, and as therapies have improved in both efficacy and toxicity.

The diagnostic criteria for MM were revised in 2014, when we were able to better characterize a subgroup of patients with smoldering MM at an extremely high risk of progression to active disease—approximately 80% risk of progression by 2 years. This group of patients was included in the definition of active MM in the revised diagnostic criteria based on a set of biomarkers. That led to further efforts in developing additional diagnostic criteria for smoldering MM, as well as readdressing the question of risk stratification for these patients.

Historically, we have not treated patients with smoldering MM. Rather, we have observed them until their progression to active disease. There were 4 aspects to the rationale for this “watch and wait” approach.

1. We were not sure which patients were likely to progress to active MM. Since then, we have developed better risk-stratification systems to identify those at the highest risk.
2. We did not want to use treatments that are likely to cause toxicity with limited efficacy. Now, we have more effective treatment options that are less likely to cause toxicity.
3. We were unsure whether treating patients with smoldering MM would improve their outcomes. Now, we have clinical trials demonstrating that early intervention leads to better survival outcomes in patients with high‑risk smoldering MM.
4. Finally, there was concern that early treatment would promote drug resistance. Now, we have evidence that this is unlikely.

Recently, the International Myeloma Working Group and investigators at the Mayo Clinic developed the 20/2/20 risk-stratification system to identify patients with smoldering MM who have a high risk of progression in the first 2 years after their diagnosis based on the free light chain ratio (> 20), serum monoclonal protein levels (> 2 g/dL), and the bone marrow plasma cell percentage (> 20%) with or without the presence of cytogenetic abnormalities. These patients are considered to have high‑risk smoldering MM and represent a group for whom we could consider early intervention. These patients are considered to have high‑risk smoldering MM and represent a group for whom we could consider early intervention. The rationale for early intervention in smoldering MM is that we are unable to cure patients with active MM with current therapies and, therefore, an open question is whether we can intervene earlier—at the smoldering phase—and potentially cure some of these patients.

To this end, we now have data from 2 phase III trials. In the QuiRedex trial, Mateos and colleagues showed that treating patients with high‑risk smoldering MM with lenalidomide/dexamethasone improved time to progression to active MM as well as OS vs observation (HR: 0.43; P = .024). An important criticism of this study was that it did not use advanced imaging, which means that some patients—possibly up to 25% of those in the study—may have had active MM. The second trial was the ECOG E3A06 trial, which randomized patients with high‑risk smoldering MM to receive lenalidomide alone or observation. This study used advanced imaging consistent with the new definition of high-risk smoldering MM and demonstrated that treatment improved PFS vs observation in this setting.

To address the possibility that early treatment in patients with high‑risk smoldering MM may promote resistant disease, leading to poorer outcomes, data from the QuiRedex trial suggest that patients who received lenalidomide/dexamethasone as early intervention had similar outcomes with their myeloma treatment at the time of their transition to active MM vs those in the observation arm. OS from the start of subsequent therapy in patients who progressed to active disease was similar for patients who received lenalidomide/dexamethasone vs observation. 

Many of our concerns have been allayed by these clinical trial data, but multiple outstanding questions remain. It is unclear whether we should pursue an approach of delaying time to progression to active MM with one agent, such as lenalidomide, or treat with multidrug combinations, as we would with newly diagnosed MM, with the hope of achieving a prolonged remission or cure. To this end, the phase III ECOG DETER-SMM trial (NCT03937635) is comparing daratumumab/lenalidomide/dexamethasone with lenalidomide/dexamethasone in patients with high-risk smoldering MM. At the same time, we and others are pursuing ongoing phase II trials evaluating intense combination therapies comparable to what we use for patients with active MM to determine whether we can eradicate the disease clone and potentially cure patients with high-risk smoldering MM. These include the single-arm phase II GEM-CESAR trial of patients receiving carfilzomib/lenalidomide/dexamethasone followed by melphalan and autologous stem cell transplantation (ASCT), which to date has shown results comparable to what we might expect in patients with newly diagnosed MM. Meanwhile, the ASCENT trial (NCT03289299) is evaluating a combination of daratumumab/carfilzomib/lenalidomide/dexamethasone without transplant to see if we can achieve similar results. 

The current approach for patients with high‑risk smoldering MM in my routine clinical practice is to discuss the results of the phase III trials and offer patients who are willing to receive treatment either lenalidomide alone, lenalidomide/dexamethasone, or participation in ongoing phase III trials (my preference). If patients do not wish to pursue treatment either on or off trial, we should monitor them closely—at least once every 3 months—to make sure that we quickly capture any signs of progression and start treatment.

High‑Risk MM
There is increasing awareness that MM—typically thought of as one disease—may consist of multiple subsets of diseases with different underlying genetic characteristics, presentations, and outcomes. The heterogeneity of disease and outcomes is based primarily on underlying genetic abnormalities, but also other patient‑related factors, such as age and comorbidities, and the resulting frailty that can affect patient outcomes. In terms of tumor‑related characteristics, genetic abnormalities are probably the most important drivers of the heterogeneity in MM outcomes. However, other tumor‑related factors, such as the tumor cell proliferation rate and tumor burden, can influence the outcome. Finally, patient-specific characteristics can be important in determining the outcome. The best examples of these are patients with renal dysfunction and patients with significant frailty, both of whom tend to have poorer outcomes.

Clearly, the subgroup of patients who have a poor prognosis—whether because of cytogenetics or other factors—should be treated differently from those with standard‑risk MM. With this increasing awareness of the need for risk‑adapted therapy, there is significant interest in trying to better define specific risk groups in patients with newly diagnosed MM and developing treatments targeted toward each type of risk group. In addition to our current risk assessment tools—especially the International Staging System (ISS) and FISH, both of which are combined into the revised International Staging System (R-ISS)—ongoing studies are looking at genomic characteristics and immune determinants of risk in patients with MM.  

We have to tailor therapies for patients with high‑risk disease so that we can improve their long-term outcomes. The general approach has been to employ a particular class of agents that works best in high‑risk patients or to try a different treatment approach for high‑risk patients. For example, we know that proteasome inhibitors (PI) seem to be particularly beneficial for high‑risk patients. Data from phase III trials clearly demonstrate that early induction therapy with a bortezomib‑based combination, followed by maintenance therapy with a PI/immunomodulatory (IMiD) drug combination, leads to better outcomes in patients with high‑risk abnormalities such as t(4;14) and del(17p). In addition, using a tandem ASCT for high‑risk patients have led to improved outcomes vs a single ASCT, especially in those with high‑risk genetic abnormalities.

Another treatment strategy is to try to achieve a minimal residual disease (MRD)–negative state in patients with high‑risk disease. In general, we know that MRD negativity translates to better survival outcomes—particularly PFS, but also OS. Although we do not routinely change therapy in MM based on MRD status, achieving an MRD‑negative state with any given therapy usually translates to a much better outcome for patients with high‑risk MM. In our practice, we have been trying to change or intensify therapy in patients with high‑risk disease who have residual disease after standard therapy, with the goal of achieving MRD negativity. 

Another area of development is using regimens that target specific genetic abnormalities. We know that certain abnormalities, including del(17p) or mutation of the p53 gene, can predict poor outcomes in patients with MM. New trials are being designed to investigate whether we can achieve better outcomes by sequencing MM tumor cells and matching patients with specific treatment combinations that target their tumor mutations. For example, the phase I/II MyDrug trial is an ongoing effort in MM that is looking at a variety of actionable genetic targets with patients enrolled in treatment arms based on the presence, or absence, of mutated genes.

In our clinic, patients with newly diagnosed high‑risk MM receive a 4‑drug combination such as daratumumab/bortezomib/lenalidomide/dexamethasone. Patients who are transplant eligible would go on to receive ASCT, followed by maintenance with a PI/IMiD combination. If they are ineligible for ASCT and can tolerate a quadruplet combination therapy, we would use a quadruplet. If they cannot tolerate a quadruplet, we would use the bortezomib/lenalidomide/dexamethasone combination until disease progression.

In the ASCT‑eligible patient population, we would certainly consider a tandem transplant, or least have a discussion with the patient to see whether they would consider it. Alternatively, we would treat patients who are high risk for other reasons, such as renal failure at diagnosis, with a PI–based combination, particularly bortezomib. We are increasingly using a combination of daratumumab/bortezomib/dexamethasone in patients with renal insufficiency. We also use risk‑adapted therapy for frail patients, typically starting with a 2‑drug combination and adding drugs based on individual tolerability.

At present, we have the tools to adopt a risk‑adapted therapy approach for patients with MM, as we have a better understanding of who high‑risk patients are and better treatment options for distinct patient populations, and this will continue to be refined in the future.

Emerging Role of Immunotherapies
The treatment paradigm in MM is continuing to rapidly evolve with the introduction of a variety of immunotherapies. First came the monoclonal antibodies (mAbs), which represented a paradigm shift in how we treat all stages of MM. The initial mAbs included daratumumab, which targets CD38 on the surface of MM cells, and elotuzumab, which targets SLAMF7. These were followed by isatuximab, which also targets CD38. These agents have clearly shown significant activity and improved PFS in both newly diagnosed and relapsed MM, regardless of ASCT eligibility. Since that first wave of mAbs, several new platforms have been developed.

Antibody–Drug Conjugates
Antibody–drug conjugates were an important advancement in treatment and are best exemplified by belantamab mafodotin. This agent is a mAb targeting B‑cell maturation antigen (BCMA) that is conjugated to a microtubule-disrupting agent, monomethyl auristatin F (MMAF). Single-agent therapy with belantamab mafodotin has been associated with a response rate > 30% in patients with multiple previous lines of therapy, including those who have stopped responding to PIs, IMiDs, and mAbs such as daratumumab. The drug is now being studied in combination with standard of care agents in both upfront and relapsed settings. In addition, several other conjugate drugs targeting BCMA are under investigation in clinical trials, some of which will be presented at the ASH 2020 virtual meeting.

CAR T-Cell Therapy
Other promising approaches for MM include CAR T-cell therapy and bispecific antibodies. CAR T-cell therapy has been effective in several different disease types, but in MM, the initial wave of CAR T‑cells that target BCMA have shown remarkable efficacy. Idecabtagene vicleucel (bb2121) was one of the first CAR T‑cell therapies to be evaluated in a large clinical trial in MM, and initial results showed very high response rates, even in patients with highly refractory disease who had stopped responding to current agents such as IMiDs, PIs, and mAbs. In the phase II KarMMa trial, 73% of patients with heavily pretreated, relapsed/refractory MM responded to idecabtagene vicleucel; median PFS was 8.8 months at all doses tested and 12.1 months for the highest dose tested (450 x 10⁶ CAR T-cells). Furthermore, patients who achieved CR or stringent CR had a median duration of response of 20.2 months.

At least 2 other CAR T-cell constructs have shown a remarkable degree of efficacy in clinical trials of MM. These include the BCMA-directed CAR T-cell JNJ-4528, which was studied in the CARTITUDE-1 trial and showed a high degree of efficacy with deep responses, including MRD negativity, and fairly durable responses. The EVOLVE trial evaluated a different BCMA-targeted CAR T-cell, orvacabtagene autoleucel. This trial also showed significant activity with deep responses that appear to be quite durable.

Cytokine release syndrome (CRS) and neurotoxicity are well-described adverse effects of CAR T-cell therapy, regardless of target or tumor type. In the MM trials, the majority of CRS events tended to be grade 1 or 2, with a very limited number of patients experiencing grade 3 or higher. Most patients with CRS were easily managed with tocilizumab and other standard measures. Neurotoxicity has not been a significant issue in any of these MM CAR T-cell trials, with most cases responding to current management measures. 

Other CAR T-cell therapies are being evaluated in MM; some will be presented at ASH 2020. Again, we are seeing remarkable efficacy for CAR T-cells directed against BCMA across the board. The question is whether we can go after other targets. We will see some early results at ASH 2020 from CAR T-cells directed against targets including GPCR5D and FCRHL5, both of which appear to be good for development of immunotherapies.

Bispecific Antibodies
Another platform that has shown significant activity in patients with MM is bispecific antibodies. These antibody constructs are designed to bring T-cells closer to the tumor cell by targeting both cell types simultaneously, thereby promoting a stronger T-cell response and immune synapse formation to help eliminate MM cells. The first bispecific antibody, AMG‑402, showed significant efficacy in relapsed/refractory MM. Since then, several other bispecific antibodies have entered clinical trials. We have seen the data from CC-93269 and teclistamab, both of which seem quite effective in obtaining responses in heavily pretreated disease. With bispecific antibodies, we see some reports of CRS—most cases have been easily managed—and very little neurotoxicity. Increased risk of infection has also been observed and requires further investigation.

Similar to CAR T-cell constructs, bispecific antibodies are being developed against an array of targets in MM. We expect to see early results of bispecific antibodies directed at other targets presented at ASH 2020.

One disadvantage of CAR T-cell therapy is the extended timeline of the manufacturing process. Patients must first undergo apheresis to collect their T-cells and then wait 3-4 weeks before their manufactured CAR T-cells can be reinfused. This delay in treatment can be challenging for patients with rapidly progressing relapsed/refractory disease who need immediate treatment. In addition, although many patients respond to CAR T-cell therapy, some have responses that are not long-lasting, and many relapse despite achieving deep responses. We may be able to overcome both of these problems by moving CAR T-cell therapy into the earlier lines of treatment. Indeed, ongoing phase III trials are evaluating CAR T-cell therapy in patients with ≤ 2 previous lines of therapy, as well as in newly diagnosed high‑risk patients. 

There is also an attempt to avoid the need for apheresis and the extended manufacturing process by using allogenic CAR T‑cells. For example, phase I data from the UNIVERSAL trial with allogeneic CAR T‑cells—ALLO-715 (anti-BCMA) and ALLO-647 (anti-CD52)—will be presented at ASH 2020, and the data seem quite encouraging. Still, bispecific antibodies and antibody-drug conjugates have the advantage of not having to wait to start therapy; we could potentially treat our patients on the same day, avoiding those delays.

Based on these and other data, newer immunotherapy platforms are poised to significantly alter the landscape of MM treatment going forward.

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