How do you manage patients with smoldering multiple myeloma (MM)?
Managing patients with smoldering MM, remains a controversial topic. In general, I do not currently recommend initiating MM therapy for patients with the current definition of high risk smoldering MM. Patients who have > 60% plasma cells in their bone marrow, or a free light chain ratio > 100, or > 1 bone lesion on MRI used to be considered to have “ultrahigh”-risk smoldering MM and now, by definition, are considered to have active MM, and I treat them with standard MM induction therapy. However, beyond that, I have not been initiating therapy for patients with smoldering MM.

The new high-risk categories for patients with smoldering MM, known as the Mayo 20/2/20 characteristics, which refer to having > 20% plasma cells in the bone marrow, serum M-protein > 2 g/dL, or a free light chain ratio > 20, identifies patients as high-risk when they have 2 or 3 of these features . Overall, these patients have a 2-year risk of progression rate to active MM of approximately 45% to 50%. Some MM experts may consider initiating therapy for patients with these high-risk smoldering MM features; however, I take these markers as a sign that I should follow these patients very closely with blood and urine tests and possible x‑rays/imaging to try and identify which of these patients have the highest chance of progressing to active disease. I like to follow their disease course over a period of time—which can be months to years—before considering therapy. Obviously, some will need therapy and for those that have signs of “evolving” disease, I may start therapy before any myeloma defining criteria are met. Close follow-up will help to identify those that have more indolent disease suggestive of monoclonal gammopathy of undetermined significance (MGUS) and will not need therapy. We should also consider enrolling patients with high-risk smoldering MM on available clinical trials.

Overall, the best strategy for monitoring these patients with smoldering MM is with active surveillance and I recommend seeing patients every 3 months for at least the first year, performing laboratory testing every 3 months for the first 2 years, obtaining x‑rays/imaging at least yearly, and performing a bone marrow biopsy if there is any evidence of progression. For people who have clinical evidence of evolving disease (ie, with decreasing hemoglobin levels, increasing serum M-protein levels, or evolving free light chain ratios that are progressively getting higher), there is a greater chance they will be in the 50% of patients who will progress to active MM within 2 years. In these cases, I will initiate treatment even if they have not reached the current criteria for active MM. For example, if a patient’s serum M-protein levels double in less than 3 months, I would recommend beginning therapy in the next 6-12 months, and then I discuss with them when they would want to start treatment and counsel them on the potential dangers of waiting too long.

If you decide to treat patients with smoldering MM, what approach do you use?
Initial studies in high-risk smoldering MM have assessed the use of lenalidomide plus dexamethasone (phase III QuiRedex trial) and lenalidomide as a single agent (the phase III E3A06 trial) as initial therapy. These studies tested strategies are less aggressive than current frontline therapy for active MM with the premise that these treatments could provide potent anti-myeloma and pro-immune effects while preventing progression to active MM (ie, prolong PFS) with fewer adverse events.

The optimal treatment for patients with high-risk smoldering MM is unknown, and additional clinical trials are being performed to better define best treatment practices for these patients who are at high risk of progression to active disease. In my mind, there are 2 ways that will likely be optimal. One approach will be to treat patients with high-risk smoldering MM with aggressive therapy (aimed at a cure) like the way we treat patients with active MM—with triplet or quadruplet induction therapy, an autologous transplant, and then maintenance therapy. This approach could result in measurable residual disease (MRD) negativity—similar to what was recently reported for the phase II GEM-CESAR trial.

The second approach may be to treat patients with high-risk smoldering MM with newer immunotherapies such as those targeting BCMA. I think bispecific T-cell engagers that activate T-cells in the local environment are the next generation of therapeutics that should be tested for high-risk smoldering MM. These agents are potent immunotherapies that could potentially be used as single agents without the risk or toxicity of alkylating agent-based therapy, transplant, or other MM therapy. In addition, CAR T-cell therapies have shown promising response rates and durable responses in relapsed/refractory MM, and trials are underway for patients with newly diagnosed active disease. By moving these novel agents into earlier disease stages, we may be able to utilize a patient’s own immune system to either halt disease progression or potentially to eradicate the disease before it becomes active.

Overall, although I applaud the studies that have been done in smoldering MM, I do not think the data are strong enough to suggest that every patient with high-risk smoldering MM should be treated at this time. I am waiting for more definitive data to recommend this approach in my practice.

Is it time to individualize frontline treatment based on any disease characteristics?
For patients with newly diagnosed active MM, I generally put them into one of 3 categories. The first category includes patients who are not eligible for transplant, for whom I consider the goal of therapy to be inducing a deep remission without significant adverse events. I am a proponent of using monoclonal antibodies in frontline therapy, and the only one approved for newly diagnosed MM right now is daratumumab. For patients who are not eligible for transplant, daratumumab/lenalidomide/dexamethasone (DaraRd) is approved by the FDA and is my preferred regimen. I continue therapy while assessing patients for stringent CR. In the future, we may be able to analyze these patients for MRD negativity with the eventual goal of potentially stopping therapy when a deep response is achieved.

The second category includes transplant-eligible patients who do not have high-risk cytogenetics or other high-risk features. For these patients, we have very effective treatment options, including lenalidomide/bortezomib/dexamethasone (VRd) followed by a single autologous stem cell transplant (ASCT) and lenalidomide maintenance, which has demonstrated a median PFS of ~5 years. The phase II GRIFFIN trial has investigated VRd plus daratumumab (DaraVRd) compared with VRd alone as frontline therapy before ASCT in patients with newly diagnosed MM. Following ASCT, patients in the trial received 2 cycles of consolidation and then continue on daratumumab plus lenalidomide or lenalidomide maintenance therapy. At 24 months, 95% of patients receiving daraVRd remain progression free, and these data are quite promising, suggesting an improved PFS.

The third category of patients are those who are eligible for transplant but have high-risk cytogenetics, including del(17p), t(14;16), t(14;20), gain(1q) plus another abnormality, or multiple/complex abnormalities. Patients with these cytogenetic abnormalities tend to have a worse prognosis, and I treat them more aggressively. For these patients, I often recommend carfilzomib/lenalidomide/dexamethasone (KRd) as the induction strategy. Going forward, I think it will be interesting to determine if adding daratumumab to KRd will further improve outcomes in high-risk patients. I think achieving MRD negativity is one of the most important endpoints for high-risk patients—or any patients with newly diagnosed MM. Overall, the best way to consolidate patients with The best way to consolidate MM patients with HR cytogenetics is still a matter of debate but continuous therapy seems necessary and  high-risk cytogenetics is still a matter of debate but continuous therapy seems necessary.

Many studies, including the recent CASSIOPET substudy of the phase III CASSIOPEIA trial, have shown that patients who achieve MRD negativity (regardless of risk) have much better outcomes whereas patients who remain MRD positive have shorter median PFS.

Do you use MRD negativity to help plan your treatment approach?
In my practice, we have routinely performed MRD testing in patients achieving CR following initial/frontline therapy. We have used both NGS and NGF testing and perform serial MRD assessments. We include all of our high-risk patients who achieve CR as well as standard-risk patients who achieve and remain in CR. We generally perform the testing initially at 3 months post-transplant, at 1 year post-transplant and then yearly thereafter. However, we are not making treatment decisions based on MRD status because there are no prospective trials that suggest optimal treatment strategies for patients who do or do not achieve MRD negativity. MRD results can sway some decision making. For example, patients who are persistently MRD negative but are experiencing adverse events to therapy may sometimes choose to take a break from therapy based on their MRD negativity. In these patients, we can continue to follow MRD to look for early signs of progression.

For ASCT-eligible patients with newly diagnosed MM, how many cycles of induction are enough? Are you using consolidation or do you just go straight to maintenance?
The saying I use to sum up my thoughts about induction, transplant, consolidation, and maintenance therapy for patients with newly diagnosed MM is: “You can pay me now or you can pay me later.” What I mean by this is: if somebody gets 4 cycles of induction therapy and only achieves a PR, we can continue induction therapy for an additional 2-4 cycles to try to get a deeper response before ASCT or we can proceed to ASCT and then consider consolidation therapy after ASCT. Our goal is the deepest remission possible and we make adaptive decisions after induction and after transplant on what additional therapy is needed for consolidation and/or maintenance to achieve the best response. However, there is not 1 defined formula, and each decision is based on individual patient needs. 

In day-to-day practice however, we generally recommend 4 cycles of induction and then a single ASCT. However, if a patient only achieved PR after 4 cycles of induction, we would consider an additional 2-4 cycles followed by ASCT. Alternatively, as above, we may proceedto ASCT and then decide if 4 more cycles of the induction therapy regimen after ASCT is needed as a consolidation therapy. In my practice, we use the patients disease characteristics and response to initial induction therapy to decide how many induction cycles to give with the goal to achieve at least a VGPR before ASCT. Then, the goal of transplant, consolidation, and maintenance therapy is to hopefully reach a stringent CR and MRD negativity and maintain that response for the long term.

Should we be looking at age, fitness, or both to determine ASCT eligibility?
In our institution, we generally determine ASCT eligibility using fitness rather than age. Age is no longer a barrier to successful ASCT and we will consider an ASCT in somebody who is older than 75 years of age as long as he or she is fit enough to tolerate the procedure. In general, however, we do not consider ASCT for a patient who is 80 years of age or older. Of importance, as part of the ASCT process at our institution, we have all of our patients aged 70-80 years meet with a geriatric physician as part of their workup before ASCT to help us assess patient’s fitness, optimize medications (assess for drug–drug interactions), and create an action plan for how to manage the patient before and after ASCT for best outcomes. The mortality rate following ASCT for MM at our institution is very low—far less than 1%— and the majority of patient who are unfit for transplant have cardio-pulmonary disease that precludes transplant.

What is on the horizon for treatment of newly diagnosed MM?
First and foremost, I think adding monoclonal antibodies to frontline regimens will likely have a significant impact on improving the duration of first remission. Going forward, I think that CAR T-cells may replace ASCT and consolidation therapy for transplant-eligible patients with newly diagnosed MM. CAR T-cells have had promising results in the relapsed/refractory setting, and it will be interesting to see the data as we move CAR T-cells frontline. Ongoing trials are testing CAR T-cell therapy immediately following induction therapy in place of ASCT in high-risk patients. I think that it is a very distinct possibility that CAR T-cells will alleviate the need for ASCT because they will provide a deeper remission with less morbidity.

I think for patients who are not eligible for ASCT, the new immunotherapies including anti-BCMA BiTE therapy and antibody–drug conjugates (ADC) could have an impact as part of frontline or consolidation therapy, either as single agents or in combination with current agents. Hopefully, we will be able to investigate these agents in the frontline setting within the next 5 years.

How would you manage a patient with relapsed/refractory MM who received daratumumab as frontline therapy?
Now that we are recommending daratumumab-based therapy in the frontline setting, we must ask: When daratumumab is used frontline, what comes next in the second line? This becomes an issue because in current recommendations for most patients with their first relapse following previous induction therapy, daratumumab has been the preferred option. It is very well tolerated and can help patients achieve MRD negative status even in the early relapse setting.

As the data evolve and daratumumab is being used in the frontline setting, a different therapy option will need to be used at first relapse. Of note, if a patient starts induction therapy that includes daratumumab today, it likely will be more than 4 years before relapse occurs (ie, until we have to worry about treating patients who received frontline daratumumab). The data in the nontransplant setting with frontline DaraRd (MAIA trial) likely has a median PFS of > 50 months based on the current KM curve and a 30-Month PFS rate of 70.6%. The use of DaraVRd, followed by ASCT, and then daratumumab plus lenalidomide as maintenance (GRIFFIN trial) has an expected PFS of 5-7 years, with a 24-Month PFS rate of 96%. Therefore, we are talking about what we will do 5-7 years from now, and it is going to be a whole new world in terms of the therapies available for the treatment of relapsed MM. In the future, we will likely have anti-BCMA ADCs, bispecific T cell engagers, bispecific antibodies, and/or CAR T-cell therapy approved for use in daratumumab-refractory patients at relapse.

For now, if patients receive DaraVRd, followed by a single ASCT with daratumumab plus lenalidomide as maintenance and relapse on maintenance, they likely will be daratumumab and lenalidomide refractory. For these patients, I would consider a triplet containing carfilzomib and/or pomalidomide with another partner (ie, KPd, KCd, EloPd, etc) for their next therapy. Of course, any of these patients should also be considered for clinical trials.

After multiple relapses, we typically cycle through the available treatment regimens and try to include at least 1 new agent or class of agents in each line of therapy. Selinexor—an oral nuclear export inhibitor—is also currently approved for patients who have received ≥ 4 prior therapies and whose disease is refractory to ≥ 2 proteasome inhibitors, ≥ 2 IMiDs, and an anti-CD38 monoclonal antibody. We may consider using selinexor for patients who have relapsed on multiple lines of therapy as indicated by the current FDA approval; however, selinexor can induce a fair amount of nausea that tends to be more severe than nausea associated with other MM therapeutics, and patients often require dose adjustments and close monitoring for adverse events while receiving selinexor. Some patients do really well on selinexor and achieve an optimal response, but others may wish to discontinue the drug after a few weeks due to the toxicity. This is something to keep in mind, and these patients should be monitored very closely.

How are you treating patients with difficult-to-treat disease, such as central nervous system (CNS) disease and extramedullary disease?
Patients with CNS disease, which represents a minority of MM patients, are very difficult to treat. If a patient has a single or multiple parenchymal brain lesion(s), I typically consider irradiation of the brain lesions, and then recommend daratumumab/pomalidomide/dexamethasone since these drugs likely can cross the blood–brain barrier. There are also next-generation IMiDs, cereblon-modulating agents (CELMoDs), that are being investigated for their ability to control CNS disease. In addition, the novel proteasome inhibitor marizomib has been shown to be the only proteasome inhibitor that crosses the blood-brain barrier, but there are no active trials in this setting and it is not FDA approved.

Patients with extramedullary disease (EMD) are also difficult to treat and the optimal therapy has not been identified. EMD can manifest with organ involvement (ie, liver, pulmonary, and gastrointestinal lesions) and/or soft tissue disease. Many retrospective analyses have shown that the median OS in patients with relapsed MM and EMD is typically < 1 year. In our practice, we tend to use cyclophosphamide-based intensive chemotherapy to try to achieve remission in patients with extramedullary disease and then put them on a maintenance-type therapy with a next-generation IMiD, such as pomalidomide, and a monoclonal antibody like daratumumab.

These cases are challenging and each case can be different depending on the location of relapse, the organs involved, and the patient’s previous treatments. Each patient needs an individual plan, with the hope that, at some point, they will qualify for a clinical trial. It will be very interesting to see if EMD and CNS disease can be treated with the newer immunotherapies such as CAR T-cells and bispecific T-cell engagers. The immune microenvironment surrounding these lesions is certainly different than in the bone marrow space and more research is needed to help optimize treatment for these patients.

What other novel agents are in development that you expect to affect MM treatment options in the near future?
In addition to the agents I mentioned above, there are 3 new agents in the pipeline that I think have the potential to affect MM care. The first is belantamab mafodotin, which is a humanized afucosylated IgG1 BCMA-targeted ADC that releases the linked cytotoxic agent monomethyl auristatin F (MMAF) once internalized. The phase II DREAMM-2 trial demonstrated an ORR of approximately 30% and a median PFS of 3-5 months in patients with progression after ≥ 3 lines of therapy and were refractory to IMiDs, PIs, and anti-CD38 antibodies who received single agent belantamab mafodotin. These data are very promising especially considering the refractory population and treatment with a steroid-free single agent. We all believe this agent will combine nicely with other agents like immunomodulatory drugs and proteasome inhibitors, and look forward to seeing combination data as well as results when it is used in earlier lines of therapy. Based on these data, we are expecting belantamab mafodotin to be approved in the next 3-6 months, and I think there will be significant use of this novel therapeutic agent. The one notable and unique adverse event seen with belantamab mafodotin is keratopathy, dry eyes and blurry vision. This adverse event is likely a consequence of free MMAF toxin and was seen in ~70% of patients (mostly Grade 1-2). Oncologists will need to develop relationships with their local eye-care specialists to optimize therapy with belantamab mafodotin and manage these adverse events successfully.

The second drug in the pipeline that is important is venetoclax. Venetoclax is a first-in-class BCL‑2 inhibitor approved for use in chronic lymphocytic leukemia/small lymphocytic lymphoma and acute myeloid leukemia and is currently in development for patients with MM. It has been most effective in patients with the t(11;14) translocation, and some experts are using this off label for patients who have relapsed MM based on clinical trial data in this setting. We previously used venetoclax often in our practice for patients who had daratumumab-refractory aggressive MM, whether or not they had the t(11;14) translocation. In fact, we recently published data demonstrating an ORR of approximately 30% in unselected relapse/refractory MM who received venetoclax. However, the data are more impressive with using venetoclax in patients who specifically have the t(11;14) translocation. Recently, the phase III BELLINI trial suggested that there was a survival disadvantage in patients with relapsed MM who received venetoclax plus bortezomib/dexamethasone (Vd) compared with Vd plus placebo in an unselected patient population. This was likely due to more infectious deaths and cardiac complications which were seen with venetoclax + Vd. However, in a subgroup analysis of BELLINI presented at ASH 2019, the addition of venetoclax to Vd significantly improved ORR and PFS in t(11;14) and BCL-2^high patient populations and OS was similar to that of the control group. Based on these data, we have stopped using venetoclax in patients without a t(11;14) translocation in our practice, but we continue to use it in patients who do have a t(11;14) translocation. Additional studies patients with t(11;14) are ongoing and this is an excellent therapeutic option for these patients.

The third drug in development that I think may affect treatment options for MM is melflufen. Melflufen is a novel, lipophilic peptide-conjugated alkylator-based therapeutic that can increase the concentration of the melphalan derivative intracellularly in cells that over-express aminopeptidases (including myeloma cells and other cancer cells). It has been granted orphan drug designation for the treatment of relapsed/refractory MM and will likely be submitted for FDA approval later this year based on phase II data. The phase II HORIZON trial evaluating melflufen showed a 30% response rate in heavily pretreated patients with myeloma, with the majority being penta-refractory. Furthermore, a recent update from IMW 2019 suggested that melflufen has the potential to induce similar outcomes with reduced toxicity compared with other outpatient regimens for patients with extramedullary relapsed MM. The phase III OCEAN study of melflufen/dexamethasone vs pomalidomide/dexamethasone in patients with relapsed lenalidomide-refractory MM is ongoing. As more data are presented, it will be interesting to see how this drug works in combination with other therapies, even as frontline therapy or in patients not eligible for transplant because I think it has the potential of being less toxic than standard melphalan.

As a final thought on relapsed/refractory MM, I do think as we move forward, relapsed/refractory disease may potentially become quadruple-class refractory—refractory to IMiDs, proteasome inhibitors, anti-CD38 antibodies, and BCMA targets. With this in mind, we will continually need to identify additional targets that can be used for therapy. Thankfully, we already have some new targets identified, including GPRC5D which is a cell surface receptor, predominantly found in the plasma cell lineage. Novel therapeutics including a CAR T-cell and a bispecific antibody targeting GPRC5D are in clinical trials. SLAMF7 is also a target for an allogeneic CAR T-cell therapy for MM, and I think future bispecific antibodies and other CAR T-cell agents will target SLAMF7. Even with these new targeted agents in development, we need to continue our correlative science studies and continue to expand our ability to find new targets and novel therapeutics for the treatment of MM.

Your Thoughts
What questions do you have about the care of patients with MM? Please leave a comment or question in the comment section.