Sagar Lonial, MD

Treatment options for patients with MM continue to evolve, and many important studies on the treatment of MM were presented at the 2019 ASH annual meeting. In this commentary, I discuss some of these clinical data and share my thoughts on their implications and relevance for treatment strategies for patients with MM.

Managing Patients With Smoldering MM
How to manage patients with smoldering MM has become an important area of discussion, particularly after the phase II/III E3A06 was presented at ASCO 2019.²⁸ In this trial, patients with high‑risk smoldering MM were randomized to receive either lenalidomide or observation to assess whether single-agent lenalidomide decreases the risk of progression. Data from this study showed significant improvement in PFS, particularly in the Mayo 2018 highest‑risk group category.

Phase II GEM‑CESAR Study
At ASH 2019, Mateos and colleagues²⁹ presented data from the Spanish, multi‑institutional, open-label phase II GEM‑CESAR trial. The goal of this study was to use a regimen with a curative intent to treat patients with high‑risk smoldering MM. In this trial, 90 patients were enrolled to receive 6 cycles of carfilzomib/lenalidomide/dexamethasone (KRd), followed by high‑dose melphalan and ASCT, an additional 2 cycles of KRd consolidation, and maintenance therapy with lenalidomide/dexamethasone (Rd) for up to 24 months. The GEM-CESAR design included much more of an MM‑based treatment approach than the E3A06 study and patients who received this more intensive approach achieved very deep responses, with an ORR of 100% and more than 60% achieving MRD negativity after consolidation and 1 year of maintenance. The most common AEs included infection, rash, asthenia, and cytopenia. Additional AEs that could significantly affect patients included a small number of patients with cardiac failure, hypertension, atrial fibrillation, and pneumonia, which raises a question about safety for patients with smoldering MM.

Clearly, we achieved a significant depth of response and 92% of patients remained progression-free at 35 months. However, this is identical to the 91% 3‑year PFS rate from the E3A06 trial.²⁸

What these data suggest to me is that although using more intensive therapy for patients with high‑risk smoldering MM is an important clinical trial question, it is not an approach I would currently adopt as a standard of care. I do, however, consider lenalidomide or Rd for patients with smoldering MM and the highest risk of progression, based on the E3A06 trial and the phase III Spanish QuiReDex trial.³⁰

Optimal Treatment for Patients With Newly Diagnosed MM: ASCT Eligible

Phase II GRIFFIN Study
There were several different trials for patients with newly diagnosed MM presented and/or updated at ASH 2019. Of those, an update of the GRIFFIN study in ASCT‑eligible patients is the first one worth noting. This multicenter, randomized phase II trial enrolled more than 200 ASCT-eligible patients with newly diagnosed MM to examine whether the addition of daratumumab to VRd induction and consolidation and to lenalidomide in the maintenance setting offered any benefit over standard VRd induction, ASCT, consolidation, and lenalidomide maintenance.³¹ The primary endpoint of this trial was stringent CR by the end of consolidation. Findings presented at ASH 2019 showed a much deeper depth of response with the addition of daratumumab: By the end of consolidation, rates of responses ≥ VGPR were 90.9% vs 73.2%. In addition, patients receiving daratumumab also achieved higher rates of MRD negativity (51% vs 20% without the addition of daratumumab), although this was measured at a level of 10^‑5. After approximately 24 months, there is also the beginning of a separation in the PFS curves, suggesting that the addition of daratumumab to standard VRd therapy may improve survival outcomes. To me, this was an important new piece of information and may provide good rationale for adding daratumumab to VRd in clinical practice. In fact, daratumumab plus VRd has now become the standard go-to regimen at our center for standard‑risk MM.

CASSIOPET: Substudy of Phase III CASSIOPEIA
The phase III CASSIOPEIA trial was conducted in ASCT-eligible patients with newly diagnosed MM and showed that the addition of daratumumab to bortezomib/thalidomide/dexamethasone (VTd) induction and consolidation improved PFS, OS, response rates, and MRD negativity vs VTd alone. This companion study, CASSIOPET, assessed a subset of patients from CASSIOPEIA to determine the prognostic value of PET/CT at diagnosis, the rate of PET-CR after consolidation, and the concordance of MRD negativity and PET-CR.³² Unsurprisingly, the CASSIOPET study demonstrated that patients who received daratumumab in combination with VTd had better responses, deeper responses, and improvements in PFS vs those who received VTd alone. Patients who received daratumumab were more likely to develop PET negativity, and PET negativity was associated with longer PFS. Furthermore, patients who were PET negative at diagnosis had better prognostic outcomes. Although this finding may not be a surprise, no previous studies have actually evaluated the utility of PET negativity at diagnosis as a predictor of long‑term outcome for patients with MM, and the data from CASSIOPET helped solidify this for clinical practice.

Phase II MASTER Trial
Another often-discussed study from the ASH 2019 meeting was the MASTER study, a small phase II clinical trial that enrolled 81 patients with newly diagnosed MM to receive daratumumab plus KRd followed by ASCT and consolidation with daratumumab plus KRd and lenalidomide maintenance.³³ Consolidation therapy in this trial consisted of “blocks” of 4 cycles of daratumumab plus KRd followed by MRD evaluation, and patients who achieve MRD negativity will discontinue consolidation and forgo maintenance therapy, while those who remain MRD positive can receive up to 3 blocks of consolidation followed by lenalidomide maintenance. The goal of this study was to assess whether MRD negativity can guide duration of therapy. Of importance, there was a significant number of high‑risk patients enrolled in this trial. With this treatment approach, a significant fraction of patients achieved MRD negativity at 10^‑5: 74% post-ASCT and 82% during consolidation. In addition, 63% of patients achieved MRD negativity < 10^‑6 during consolidation. This was true for both standard-risk patients and those with high-risk disease. There were, in fact, some patients for whom therapy was discontinued.

Based on the small number of patients and the short follow-up period in this presentation, I am hesitant to draw any conclusions yet. I do think that additional follow-up of this trial may reinforce the potential for discontinuing therapy based on MRD negativity. However, in the absence of a randomized trial, I would not recommend this approach in clinical practice.

Optimal Treatment for Patients With Newly Diagnosed MM: ASCT Ineligible

Update of Phase III ALCYONE Trial
Now, we will switch topics and talk about ASCT‑ineligible patients with newly diagnosed MM. An update of the phase III ALCYONE trial was presented at ASH 2019.³⁴ This open-label phase III trial assessed the addition of daratumumab to bortezomib/melphalan/prednisone (VMP) vs VMP alone in this patient population. With a longer follow-up of 42 months, the estimated rate of PFS was 48% with the addition of daratumumab compared with only 14% with VMP alone. Of more importance, OS data were also presented: The 42-month OS was 75% with daratumumab plus VMP vs 62% with VMP alone. The HR was 0.60 (95% CI: 0.46-0.80) favoring the addition of daratumumab, with a P value of .0003, suggesting that this OS benefit is statistically significant.

Additional analyses explored PFS and OS by MRD status. Patients who are MRD negative tend to have increased median PFS and OS vs those who are MRD positive, regardless of whether they received daratumumab. This hints at the idea of using a depth of response rather than a treatment approach to determine duration of therapy and prognostic outcomes. 

Phase III GEM‑CLARIDEX Study
As we continue to look at this particular patient population, there is another trial worth discussing. The GEM-CLARIDEX study was a randomized phase III trial of clarithromycin plus Rd vs Rd alone in ASCT‑ineligible patients with newly diagnosed MM.³⁵ Clarithromycin is an antibiotic but also acts as an immunomodulator and antineoplastic drug that may optimize the effect of glucocorticoids. The addition of clarithromycin to immunomodulatory drugs has been theorized to resensitize patients and lead to improved responses and long‑term outcomes in patients with MM.

Data from this trial showed an increased response rate with the addition of clarithromycin to Rd (81% vs 74.5% with RD alone); however, this did not translate into a PFS benefit (P value of .12) or an OS benefit (20-month OS rate: 75% with clarithromycin plus Rd vs 73% with Rd alone). There was actually a decrement in OS that likely occurred as a consequence of an increased rate of infections and death. Based on these data, I would not recommend using clarithromycin in clinical practice.

Optimal Treatment for Patients With Newly Diagnosed MM: Regardless of ASCT Eligibility
Finally, there is one study that enrolled patients regardless of ASCT eligibility that is worth mentioning.

Phase II Trial of Daratumumab Plus Ixazomib Plus Rd
Next, we look at an update of a 2-arm phase II trial by the Mayo Clinic assessing treatment with daratumumab plus ixazomib/lenalidomide/dexamethasone (IRd) in ASCT-eligible or ASCT-ineligible patients with newly diagnosed MM.³⁶ There was a striking ORR, with 11% of patients achieving a stringent CR in Arm A (daratumumab plus IRd) and 15% of patients achieving a stringent CR in Arm B (daratumumab plus IRd with dose-modified dexamethasone) and an ORR of 97% to 100%. These data suggest that daratumumab plus IRd is a very active and important regimen. There was a relatively low rate of dose reductions and this regimen is patient friendly, given that 3 of the 4 agents can be given orally. We have not introduced this treatment regimen in clinical practice, so it will be interesting to see additional data with longer-term follow-up.

R/R MM: Current and Emerging Treatment Approaches
Now we will discuss trials in the R/R MM setting. Among these presentations were several that I think are important and likely will have some practice‑changing or practice‑modifying implications. 

The Phase III CANDOR Trial
The CANDOR trial is a multicenter, randomized phase III study of 466 patients with R/R MM that examined the safety and efficacy of daratumumab with carfilzomib/dexamethasone (Kd) vs Kd alone and was presented as a late‑breaking abstract at ASH 2019.³⁷ Baseline characteristics of the 2 study arms were similar. Response rates and the depth of response favor the patients who received daratumumab with Kd: The ORR was higher with daratumumab plus Kd at 84% vs 74% with Kd alone, the rate of VGPR or better was 70% for the triplet vs 50% for the doublet, and 18% of patients receiving daratumumab plus Kd achieved MRD negativity (10^-5 threshold) at 12 months. Patients receiving daratumumab plus Kd also experienced prolonged PFS vs those receiving Kd (median PFS: not reached vs 15.8 months, respectively, with HR: 0.63; P = .0014). Overall, the rates of AEs were also relatively similar, although we are starting to notice an increased risk of infections, particularly those that may require IV immunoglobulin supplementation, in patients who receive long‑term daratumumab‑based therapy. Cardiac disorders are a concern for patients receiving carfilzomib, but the rate of cardiac failure was slightly lower for those receiving daratumumab.

These data led to the conclusions from this trial that the triplet regimen of daratumumab plus Kd is a new treatment option to consider for patients with R/R MM. Given that many of our patients with MM are progressing on lenalidomide‑based maintenance, the use of daratumumab plus Kd as a first salvage option now has the support of this randomized phase III data.

Phase Ib/II CARTITUDE Trial
Some of the most exciting new agents for MM are those targeting B-cell maturation antigen (BCMA), and include various CAR T-cell therapies, bispecific T-cell engagers (BiTEs), and antibody drug conjugates. The phase Ib/II CARTITUDE trial was conducted in the United States and assessed the safety and efficacy of the anti-BCMA CAR T-cell construct JNJ-4528 in 29 heavily pretreated patients with R/R MM.³⁸ JNJ-4528 is similar to the CAR T-cell construct, LCAR-B38M, which was used in the phase I LEGEND-2 trial in China. Patients enrolled on the CARTITUDE trial received leukapheresis, bridging chemotherapy, lymphodepletion with fludarabine/cyclophosphamide, and then infusion of JNJ-4528 (from 0.5 x 10⁶ cells up to 1 x 10⁶ cells). In this group of patients, the median number of previous lines of therapy was 5, with a range of 3‑18 lines. Quite striking was the 100% ORR, with 86% of patients achieving a VGPR or better and 53% of patients achieving 10^‑6 MRD negativity at Day 28. At a median follow-up of 6 months, 27 of 29 patients remained progression free. The AEs associated with JNJ-4528 were similar to those seen with other CAR T-cell constructs and included cytokine release syndrome (CRS) and some neurotoxicity, although rates of grade 3/4 events were low.

These data are certainly very exciting and encouraging. These results confirm data from the LEGEND-2 trial, but ultimately we need a larger, randomized trial with more patients and longer follow-up to really understand how to use CAR T-cell therapy for our patients with MM.

Phase I LEGEND‑2 Trial
Also presented at ASH 2019 was a longer-term follow up of the LEGEND‑2 trial that, as mentioned above, uses the same, or similar, construct as in the CARTITUDE study.³⁹ In LEGEND-2, 57 heavily pretreated patients with R/R MM received leukapheresis, lymphodepletion with cyclophosphamide, and then infusion of LCAR-B38M with dosing of 0.07-2.1 x 10⁶ CAR+ T-cells/kg with 20% given on Day 1, 30% on Day 3, and the remaining 50% on Day 7. In this trial, patients had received a median of 3 lines of previous therapy, with a range of 1-9 lines of therapy. In this trial, 78% of patients achieved a VGPR or better and the median duration of response was 27 months in all patients with a relatively quick median time to response of 1.1 months. With this longer follow-up, the median PFS was 19.9 months and the median OS was 36.1 months. These data suggest a substantially longer PFS than data seen in other trials with CAR T-cell therapy; but again, additional research is needed to further elucidate the long‑term outcomes for patients with these CAR T-cell constructs.

Phase I CC‑93269-MM-01 Trial
Another interesting BCMA targeting approach is using BiTEs that bind BCMA on MM cells with CD3 on T-cells. The phase I trial of CC-93269 enrolled 30 patients with R/R MM with progressive disease after ≥ 3 previous lines of therapy to assess the safety and efficacy of CC-9326.⁴⁰ CC-93269 is an anti-BCMA BiTE with bivalent, specific BCMA binding and a flexible linker to CD3ε-binding Fab domains. A safety analysis demonstrated CRS in 77% of patients, which is consistent with much of the data with these immune‑based approaches that activate T-cells. However, only 3% of patients experienced grade ≥ 3 CRS. Of more importance, there was a very high ORR of 88.9% in the higher dosing cohorts, suggesting that even in a heavily pretreated patient population, BiTE technology can effectively engage the immune system to kill MM cells. Although the follow-up in this report was relatively short, the data showed that some of these responses are extending beyond 6 months, indicating that this could be an exciting treatment approach for patients with MM. A larger phase II study is currently underway to further evaluate CC-9326 therapy.

There are other anti-BCMA BiTEs also in development. The BiTE AMG 420 has shown promising efficacy and safety in a recent phase I study; however, this agent is not without AEs, particularly infections and neuropathy or, less commonly, a Guillain‑Barré–like syndrome. Another important agent, belantamab mafodotin (formerly GSK2857916), has also shown promising efficacy and safety in the DREAMM-1 and DREAMM-2 trials. Data from these trials suggest that targeting BCMA with “off-the-shelf” treatment approaches may be a very successful approach to improve outcomes for patients with refractory MM.

Phase I/II STOMP Trial
When considering therapy for patients with refractory MM, the use of selinexor should also be considered. Selinexor, in combination with dexamethasone, was granted accelerated approval by the FDA for the treatment of patients with R/R MM after ≥ 4 previous lines of therapy and whose disease is refractory to ≥ 2 proteasome inhibitors, ≥ 2 IMiDs, and an anti-CD38 antibody. At ASH 2019, Chen and colleagues⁴¹ presented an update of the open-label phase I/II STOMP study, a relatively small dose-escalation and expansion study of 51 patients assessing safety and efficacy of selinexor plus pomalidomide/dexamethasone (Pd) after disease progression on previous treatment. This trial included 2 dosing strategies for selinexor (weekly dosing or twice weekly dosing) to determine the maximum tolerated dosing and recommended phase II dosing for this combination. Similar AEs for selinexor were seen as in previous trials, including fatigue, neutropenia, thrombocytopenia, and asthenia. All AEs appeared to occur with similar frequency regardless of the dosing strategy used, although there may be a slightly higher rate of AEs in the twice weekly dosing schedule. Overall, 50% of patients achieved a response to selinexor plus Pd and 74% of patients had stable disease or better. For patients who were naive to pomalidomide, 56% of patients responded, whereas only 36% of those previously exposed to pomalidomide responded. The recommended phase II dosing from this trial is 60 mg of selinexor once weekly with full‑dose Pd. Overall, these data suggest that selinexor may be able to be safely combined with Pd as a reasonable treatment approach for patients with refractory MM.

Clinical Trials With Venetoclax in R/R MM
The last agent that we will discuss is venetoclax. In March 2019, a clinical hold was put on venetoclax use in MM due to some safety concerns. The hold was lifted in June 2019 and now we have additional data that continues to support its safety and efficacy in patients with refractory MM, particularly those patients with a t(11;14) translocation.

Previously reported data from the phase III BELLINI study with venetoclax plus bortezomib/dexamethasone (Vd) vs Vd alone suggested that some patients might have a survival decrement due to an increased risk of infections and early deaths. However, a subgroup analysis of BELLINI presented at ASH 2019 demonstrated that patients without t(11;14) translocations did not benefit from the addition of venetoclax and the OS favored placebo in this population.⁴² However, patients with a t(11;14) translocation did benefit from the combination of venetoclax with Vd and did not have a survival decrement. These patients with t(11;14) translocations had a higher response rate, longer median PFS, and no significant impact on OS. 

Another phase I/II trial presented at ASH 2019 assessed the efficacy of venetoclax/dexamethasone in patients with t(11;14) and showed a median time to progression of approximately 12 months, with an ORR of 50% to 60%.⁴³ Some infections were observed (grade ≥ 3 sepsis in 5% to 10% of patients and grade ≥ 3 pneumonia in 3% to 5% of patients depending on the phase of study), but only 1 patient died due to infection in this trial. So certainly venetoclax/dexamethasone is a very active combination, particularly for patients with t(11;14), and this has now become incorporated as a standard treatment approach in clinical practice.

Another interesting study was a randomized phase I/II dose escalation and expansion trial that investigated the efficacy of venetoclax with daratumumab/dexamethasone with or without bortezomib in 2 separate cohorts of patients with R/R MM.⁴⁴

Patients in cohort 1 had t(11;14) translocations and had received ≥ 1 previous therapy including a proteasome inhibitor and an immunomodulatory drug. They received venetoclax plus daratumumab/dexamethasone. Patients in cohort 2 did not have to have a t(11;14) translocation and had progression following 1-3 lines of previous therapy but could not be refractory to proteasome inhibitors. Patients in cohort 2 received venetoclax plus daratumumab/dexamethasone plus bortezomib.

The ORR was 96% in cohort 1 (patients receiving venetoclax/daratumumab/dexamethasone) and 92% in cohort 2 (patients receiving venetoclax/bortezomib/daratumumab/dexamethasone). ORRs were also similar in patients with t(11;14) (93%) and those without t(11;14) (95%). Serious infections were noted in 17% of patients in both cohorts, but no major toxicities occurred and safety was not an issue in this trial.

Taken together, these results indicate that the use of venetoclax with dexamethasone or in various combination approaches (bortezomib from the BELLINI trial or daratumumab) is safe and effective for patients with t(11;14) translocations. In my clinical practice, we tend to recommend venetoclax as early as possible for patients with R/R MM and a t(11;14) translocation, even as early as the first relapse.

More ASH 2019 Conference Coverage on the CCO Web Site!
These are just a few of the interesting and important abstracts selected by hematology experts from ASH in 2019. Downloadable slideset summaries of these studies and more are available on our Web site, along with additional ClinicalThought commentaries.