Introduction
Treatment options for patients with multiple myeloma (MM) continue to expand rapidly. At the ASH 2019 meeting, interesting data were presented on new treatment strategies in MM. In this commentary, I review some of the most impactful clinical data presented and share my thoughts on how these data may affect practice in Europe.

Smoldering MM
A particularly challenging group of patients to treat are those with newly diagnosed smoldering MM. We are now able to identify patients with high-risk smoldering MM—those who have a ≥ 50% chance of progression to active disease in fewer than 2 years. Two randomized studies have already demonstrated a benefit in terms of delay of progression to active MM and one of them (QuiRedex) also has shown some benefit in terms of OS: the phase III E3A06 trial with lenalidomide vs observation presented at ASCO 2019 and the phase III QuiRedex trial with lenalidomide/dexamethasone vs observation.

Phase II GEM‑CESAR
At ASH 2019, Mateos and colleagues presented the phase II GEM-CESAR study, a multicenter, open-label trial that assessed the possibility of an early intervention in patients with high‑risk smoldering MM, with a goal not to delay progression but rather to potentially cure these patients. In this trial, 90 patients were treated with a regimen similar to what we use for patients with active MM who are transplant candidates: induction with six 28-day cycles of carfilzomib/lenalidomide/dexamethasone (KRd) followed by high‑dose melphalan therapy (HDT) and autologous stem cell transplantation (ASCT), followed by consolidation with 2 additional cycles of KRd and then 2 years of maintenance therapy with lenalidomide and dexamethasone. The primary endpoint for this study was sustained minimal residual disease (MRD) negativity after HDT with ASCT and at 3 and 5 years after HDT-ASCT. The median age of participants was 59 years, with an upper age limit of 70 years since enrolled patients were candidates for transplant. One third of the patients were ultrahigh risk and 23% of the patients had high‑risk cytogenetics.

It is interesting to mention that this study included not only patients with high‑risk disease but also included patients considered to be “ultrahigh risk” (33% of patients), defined as those who have an approximately 80% probability of progression in fewer than 2 years. By current standards, these ultrahigh-risk patients are now recognized as having active MM (> 60% clonal plasma cells in the bone marrow, a free light‑chain ratio > 100, and/or > 1 MRI focal lesion) requiring treatment but were not defined as such at the time of the design of the study.

After 6 induction cycles, 41% of patients achieved a CR and 30% of patients achieved MRD negativity, with no differences in response rates observed between high‑risk (n = 60) and ultrahigh-risk (n = 30) patients. Analysis of the adverse event profile during this induction showed what is to be expected for KRd: grade 3/4 neutropenia and thrombocytopenia in 3% and 5% of patients, respectively, and grade 3/4 infections in 10% of the patients. Overall, however, the regimen was tolerated quite well.

After high‑dose melphalan and ASCT, the CR rate increased from 41% to 64% and the MRD negativity rate increased from 30% to 56% with, again, no differences observed between high-risk and ultrahigh -risk patients. It is important to mention that peripheral blood stem cell mobilization after cycle 4 of induction was very successful; in fact, with only granulocyte-colony stimulating factor, a successful harvest was achieved in 93% of patients, and only 7% of patients required plerixafor.

After consolidation and 1 year of maintenance, which has now been completed in 77 of the 90 patients, response rates are even higher. Indeed, the CR rate increased to 75% with consolidation and 81% after maintenance and the MRD negativity rate increased to 65% with consolidation and it is sustained in 62% or patients with maintenance. With a median follow‑up of 35 months, PFS is 92% and OS is 96%. Three patients have died and only one was considered a treatment‑related death.

Taken together with the data from the E3A06 trial with lenalidomide and the QuiRedex trial with lenalidomide/dexamethasone, these data from the GEM-CEASER trial suggest that early treatment for patients with high-risk smoldering MM may positively affect patient outcomes. However, the question of what should be the goal of early treatment remains: Is the goal to prevent end organ damage and accordingly use an approach such as single agent lenalidomide or is the goal to cure the disease and in such case treat with more intensive therapy? In any case, for patients with high risk smoldering MM early treatment is something that I will discuss with my patients with each of these trial approaches in mind.

Newly Diagnosed Active MM: ASCT Eligible

GRIFFIN
The GRIFFIN study is a multicenter, open-label, randomized phase II study that is comparing one of the standards of care—bortezomib/lenalidomide/dexamethasone (VRd)—vs the same schedule with the addition of daratumumab (Dara) in transplant-eligible adults with newly diagnosed MM. Patients received 4 induction cycles of either VRd or Dara plus VRd, followed by ASCT plus 2 consolidation cycles of either VRd or Dara plus VRd, and then maintenance with either lenalidomide or Dara plus lenalidomide. The primary endpoint is stringent CR by the end of consolidation. The median age in both study arms was similar at 59 years in the Dara arm and 61 years in the control arm. Approximately 13% to 14% of the patients in both study arms have ISS stage III disease and approximately 15% of patients in both arms have high‑risk cytogenetics.

Results presented at ASH 2019 showed that the vast majority of patients responded to this treatment; indeed, 99.0% and 91.8% of patients in the Dara plus VRd arm vs VRd arm, respectively, achieved a response and 42.4% and 30% of patients, respectively, achieved the primary endpoint of a stringent CR at the end of consolidation (1-sided P = .068). Encouragingly, MRD negativity was achieved in 51.0% vs 20.4% of patients in the Dara plus VRd arm vs VRd arm, respectively. As this study is still quite immature, neither median PFS nor median OS has been reached, but at 24 months, approximately 90% of the patients are progression free in the VRd arm and 96% of patients are progression free in the Dara plus VRd arm.

CASSIOPET
Another interesting study that was reported at ASH 2019 is CASSIOPET, a substudy of the large, randomized CASSIOPEIA trial that compared bortezomib/thalidomide/dexamethasone (VTd) vs Dara-VTd in more than 1000 patients. The CASSIOPET trial was designed to analyzed the impact of PET/CT and included 268 patients; PET/CT images were interpreted by a blinded independent team of nuclear medicine physician experts.

The median age, the distribution according to clinical age, and the percentage of patients with high‑risk cytogenetics in the CASSIOPET substudy were representative of the patient population in the larger CASSIOPEIA study. In addition, at baseline, most of the patients were PET positive (80%) and had focal lesions (67% of patients). Bone marrow diffuse uptake was positive in 48.0% of patients, 17.5% of patients had paramedullary disease, and only 7.8% of patients had extramedullary disease.

Following consolidation, the PET response was very high: 89.6% of patients were PET/CT negative. PET/CT CR was observed in 64.1% of patients and PET unconfirmed CR was observed in 25.5% of patients. Of interest, there seemed to be a low concordance between PET/CT and MRD. In fact, of 157 patients who were PET/CT negative after consolidation, 55 patients remained MRD positive. Furthermore, more patients receiving Dara‑VTd achieved PET/CT and MRD double negativity post consolidation compared with VTd alone (66.7% vs 47.5%, respectively).

Regarding the correlation of PET/CT with outcome, the investigators analyzed the impact of both baseline PET/CT negativity and information from PET/CT obtained post consolidation. PET/CT negativity either at baseline or post consolidation was associated with more favorable PFS prognosis. In addition, treatment with Dara‑VTd was associated with a more favorable PFS prognosis vs treatment with VTd. Finally, the investigators have analyzed which PET/CT parameters have more impact on outcome and found that the presence of focal lesions, the presence of paramedullary disease, and the presence of extramedullary disease were all associated with less favorable PFS in a univariate analysis. However, the presence of paramedullary disease at baseline was the only independent factor associated with less favorable PFS in a multivariate analysis.

Based on these results from GRIFFIN and CASSIOPET and other recent data for patients with newly diagnosed MM who are candidates for ASCT, my preferred treatment option will be quad-based therapy with a monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, and dexamethasone.

Newly Diagnosed Active MM: ASCT Ineligible

ALCYONE
Now, let’s discuss trials for patients with newly diagnosed MM who are not eligible for ASCT. An update of the ALCYONE study comparing Dara plus bortezomib/melphalan/prednisone (VMP) vs VMP alone in 706 ASCT-ineligible patients with newly diagnosed MM was presented at ASH. In this trial, patients were randomized to receive 9 cycles of VMP alone or 9 cycles of Dara-VMP with Dara followed by Dara maintenance therapy until progression. The primary endpoint was PFS and secondary endpoints included response rates, OS, and safety. Overall, baseline characteristics were very well balanced between the study arms; the median age of patients was 71 years and 30% of patients in both arms were older than 75 years of age. Approximately 40% of patients had ISS stage III disease and 60% of patients had high-risk cytogenetics.

With a median follow-up of 40.1 months, PFS was significantly longer in the Dara‑VMP arm vs the VMP arm at 36.4 months vs 19.3 months, respectively (HR: 0.42; 95% CI: 0.34-0.51; P < .0001). Dara‑VMP also conferred a benefit in terms of PFS2 (time from randomization to disease progression on first subsequent anticancer therapy or death) vs VMP (estimated 42-month PFS2: 68% vs 50%, respectively; HR: 0.55; 95% CI: 0.43-0.71; P < .0001).

When comparing with the primary analysis, which had a median follow-up of 16 months, the depth of response increased slightly after a follow-up of 40 months. The rate of stringent CR with Dara‑VMP increased from 18% in the primary analysis to 23% in the current analysis, while no meaningful increases were observed in the VMP arm. Similarly, MRD negativity increased from 22% at the primary analysis to 28% in the current analysis in patients receiving Dara‑VMP, but no meaningful increases were observed in patients receiving VMP alone. This increase in response at longer follow-up may be due to the use of maintenance Dara in the Dara‑VMP arm.

In addition, the rate of sustained MRD negativity for ≥ 6 months was 16% with Dara‑VMP vs 5% with VMP  and the rate of sustained MRD negativity for ≥ 12 months was 14% vs 3%, respectively. The increased depth of response, defined by MRD or sustained MRD negativity, with Dara-VMP translated to a clear impact on PFS. In an analysis of PFS by MRD (10^-5) status, patients who were MRD negative achieved significantly longer median PFS than those who remained MRD positive. This was true for patients who received either VMP or Dara‑VMP, but those patients who received Dara-VMP were more likely to achieve MRD negativity.

At 40.1 months of median follow-up, there is a significant OS benefit for patients receiving Dara‑VMP. Indeed, the estimated 42-month OS rate is 75% with Dara‑VMP vs 62% of patients with VMP (HR: 0.60; 95% CI: 0.46-0.80; P = .0003). An analysis of the impact of MRD status on OS shows that MRD negativity and sustained MRD negativity was associated with a significant benefit in OS, independent of the treatment received.

An analysis of the safety profile reveals that the incidence of pneumonia and hypertension was higher with Dara-VMP vs VMP at 13.0% vs 4.2% for pneumonia and 5.5% vs 1.7% for hypertension. Dara maintenance treatment was well tolerated, with only 4.3% of patients developing grade 3/4 anemia and 3.6% of patients developing grade 3/4 pneumonia during the maintenance phase.

In light of these data, going forward in my practice, I will likely recommend a quad regimen, consisting of a proteasome inhibitor, an immunomodulatory drug, a monoclonal antibody, and dexamethasone for patients who are not candidates for ASCT if they are able to tolerate a more intensive regimen. For more frail patients, a triplet regimen may be better tolerated, with dose reductions as necessary.

Relapsed/Refractory MM

CANDOR
A late-breaking abstract at ASH presented the results from the phase III CANDOR trial, which studied carfilzomib/dexamethasone (Kd) vs Kd plus Dara (DKd) in 466 patients with relapsed/refractory MM. Approximately one half of the patients enrolled on this study were relatively young (aged 64 years or younger) and only 9% to 14% of patients were older than 75 years of age. Approximately 15% to 16% of patients had high-risk cytogenetics, which is similar to the rate we see in clinical practice. However, the proportion of patients who were refractory to bortezomib and/or lenalidomide was relatively low at just over 30% of patients.

The study showed a significantly prolonged PFS with DKd vs Kd. Indeed, the PFS was not reached for patients receiving DKd and was 15.8 months for Kd (HR: 0.63; 95% CI: 0.46-0.85; P =.0014). A subgroup analysis of PFS based on various disease characteristics showed some interesting data. When assessing age, younger patients benefited more from DKd vs Kd (HR: 0.57) than patients who were 65-74 years of age (HR: 0.72) or 75 years or older (HR: 0.97). Patients who were refractory to lenalidomide were also more likely to benefit from DKd (HR: 0.45) compared with those who were not refractory (HR: 0.85). However, the opposite was true for patients refractory to bortezomib (HR: 0.83) compared with those who were not (HR: 0.59). Of interest, there was no difference in PFS benefit for those with high-risk or standard-risk cytogenetics (HR: 0.58 vs 0.55). The median OS has not yet been reached in either arm of the study, although there is a trend toward prolonged OS with the addition of Dara (HR: 0.75; 95% CI: 0.49-1.13; P = .0836).

These benefits in PFS and OS are supported by the differences in response rates. Indeed, 69.2% vs 48.7% of patients achieved a VGPR or better with DKd vs Kd, respectively. In addition, 28.5% vs 10.4% of patients achieved a CR or better with DKd vs Kd, respectively, and 17.6% vs 3.9% were MRD negative at 12 months (10^-5 threshold) with DKd vs Kd, respectively.

Regarding common treatment-emergent adverse events, grade ≥ 3 thrombocytopenia, neutropenia, and pneumonia were more common with DKd (24.4%, 8.4%, and 13.3%) vs Kd (16.3%, 5.9%, and 8.5%). By contrast, the incidence of other adverse events of interest, such as acute renal failure and cardiac failure, were lower with DKd (2.9% and 3.9%) vs Kd (6.5% and 8.5%).

CARTITUDE-1
There was a lot of attention given to various treatment modalities targeting BCMA at ASH 2019. First, I will discuss some of the new and updated trial results for BCMA-targeted CAR T-cell therapy. The CARTITUDE‑1 study is an important phase Ib/II trial conducted in the United States that examined the CAR T-cell construct  JNJ-4528 in 29 patients with heavily pretreated relapsed/refractory MM. JNJ-4528 contains 2 BCMA-targeting single-domain antibodies designed to confer more avidity for the antigen and a 4-1BB costimulatory domain. 

This study was conducted to confirm the exciting data that were initially reported in Chinese patients in the LEGEND-2 study, with LCAR-B38M, an identical CAR to JNJ-4528. Patients in the CARTITUDE-1 study had a median of 5 previous lines of therapy, 86% of the patients had received a previous ASCT, and 86% of patients were triple refractory to proteasome inhibitors, immunomodulatory agents, and anti‑CD38. In addition, 14% of patients had extramedullary disease.

The safety profile reported in this study was as expected for this population. Although grade 3 cytokine-release syndrome (CRS) was observed in only 7% of patients, the vast majority—93%—of patients developed some level of CRS. Tocilizumab was required in 76% of patients and anakinra was required in 21% of patients. Neurotoxicity occurred in 3 patients, and one of these patients had grade ≥ 3 neurotoxicity at the same time as grade 3 CRS.

All 29 patients responded to treatment, with 69% of them achieving ≥ CR. In addition, all 17 patients analyzed achieved MRD negativity, with over half of them (n = 9) at the level of 10^-6. Although follow-up is still very short at a median of only 6 months, 27 out of the 29 patients included in the study remained progression free. When examining CAR T-cell expansion and persistence, we can see that the median time to peak expansion was 13 days post infusion, with a preferential expansion of the CD8+ central memory phenotype cells. The detection of CD3+ CAR T-cells did not correlate with continued deepening of the response.

LEGEND-2
In addition to CARTITUDE-1, long-term follow-up data from the LEGEND-2 trial were presented at ASH 2019. As mentioned previously, this trial assessed the CAR T-cell therapy LCAR-B38M in 4 sites in China. This follow-up included 57 patients from one of the sites, with a median follow-up of 25 months. Of note, patients in this study were less heavily pretreated than in CARTITUDE1 and had received a median of 3 lines of previous therapy, 18% of the patients had received previous ASCT, 44% of the patients had received previous lenalidomide, and 68% of the patients had received previous bortezomib.

Similar to what was reported in the US CARTITUDE-1 study, grade 3 CRS was observed in 7% of patients whereas the majority of patients experienced lower-grade CRS (grade 1: 47%, grade 2: 35%). The median time to the onset of CRS was 9 days. CRS was managed with tocilizumab in 46% of patients, and the remainder received either oxygen, a vasopressor, or intubation.

In this analysis with a longer follow-up, the ORR was 87.7%, with 74.0% of patients achieving CR and 68.0% of patients achieving MRD negativity. The median overall PFS was 19.9 months, and a median PFS of 28.2 months was seen in patients achieving a CR. The median OS is 36.1 months; this endpoint has not yet been reached for those patients achieving a CR; while it was rather short, 7.5 months, in those patients who did not achieve a CR.

CC-93269
The phase I CC-93269 study garnered significant interest at ASH 2019. CC-93269 is a humanized, IgG1 bispecific T-cell engager (BiTE) that binds BCMA on MM cells with CD3ε on T-cells. It includes a bivalent anti‑BCMA antibody in a 2+1 format that likely produces better potency, better tumor targeting, and better retention.

This study was based on a dose-escalation phase (part A), including 2 stages. Stage 1 included dose escalation with fixed doses in individual patients, started with a very low dose CC-93269 (0.15 mg) and increased up to 10 mg. In stage 2, interpatient dose escalation was allowed on cycle 1 of Day 18. The BiTE was given weekly in cycles 1-3, every other week in cycles 4-6, and then every month at cycle 7 onward. Part B of the study included a cohort expansion.

Most patients enrolled on this trial were heavily pretreated, with a median of 5 previous lines of therapy. Most patients had been previously exposed to a proteasome inhibitor, an immunomodulatory drug, and/or a CD38 antibody, and 67% of patients had been exposed to all 3 drug classes. In addition, 30% of patients had high‑risk cytogenetics and 30% of patients had derived ISS stage III.

Regarding safety, all-grade CRS was observed in 76.7% of patients, while grade ≥ 3 CRS was present in 3.3% of patients. In addition, 30% of patients developed grade ≥ 3 infections, and grade ≥ 3 neutropenia and anemia were observed in approximately 40% of patients. Four deaths during the treatment period were observed; 1 death was due to CRS and was possibly related to CC-93269, and the other 3, due to sepsis, heart attack, and MM progression, were deemed unrelated to CC-93269.

The preliminary efficacy has generated much attention. Indeed, although the ORR in all patients was only 43.3%, many of these patients were receiving suboptimal doses. At ≤ 3 mg, the response rate was 0%, but this increased to 35.7% in patients who received > 3-6 mg and increased further to 88.9% in patients who received > 6-10 mg. In addition, 44% of patients receiving > 6-10 mg achieved a stringent CR or CR. Finally, of the 13 responding patients, 92% of them achieved MRD negativity in the bone marrow by cycle 4. These data suggest that this treatment approach may be very effective and is on par with what we have seen with CAR T-cell therapy.

Venetoclax Plus Dexamethasone in t(11;14) in Relapsed/Refractory MM
Venetoclax, a selective oral inhibitor of BCL-2, is a targeted therapy in development for patients with MM and has been most effective in patients with the t(11;14) translocation. There has been some question about the safety of this agent in patients with MM after reports from the phase III BELLINI study with venetoclax/bortezomib/dexamethasone vs bortezomib/dexamethasone. In initial reports from this study, there was particularly a high rate of infections and early deaths due to infection in patients who received venetoclax in an unselected population. However, in a subgroup analysis of BELLINI at ASH 2019, the addition of venetoclax significantly improves PFS in t(11;14) or BCL-2^high populations and OS was similar to that of the control group; by contrast, in non–t(11;14) or BCL-2^low populations, PFS not significantly improved with venetoclax and OS favored placebo. These data suggest that venetoclax therapy is clearly beneficial for patients with t(11;14), but venetoclax does not provide benefit and might be detrimental to patients without t(11;14).

A phase I/II study presented at ASH analyzed the efficacy of venetoclax plus dexamethasone in patients with relapsed/refractory MM and t(11;14). During the phase I portion, patients who were previously treated with a proteasome inhibitor and an immunomodulatory drug were included in a dose escalation/safety expansion cohort. In the phase II portion, patients also previously exposed to Dara were included. Most patients were refractory to proteasome inhibitors (65% in phase I and 87% in phase II) and immunomodulatory drugs (90% in phase I and 87% in phase II). Although most patients in phase II were refractory to Dara (87%), a smaller proportion was refractory to Dara in phase I (20%).

In this study of patients with t(11;14) who were heavily pretreated and refractory to multiple agents, 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 phase of study), but only 1 patient died due to infection during the first month of treatment.

In the phase I expansion cohort (where 20% of patients were refractory to Dara), the ORR was 60%, and in the phase II cohort (where 87% of patients were refractory to Dara), the ORR was 48%. The median time to progression was 12.4 months in the phase I cohort and 10.8 months in the phase II cohort. I think these data are interesting and may reflect a role for venetoclax plus dexamethasone in patients with t(11;14) who have already experienced disease progression after available treatment options and require additional therapy.

Venetoclax/Dara/Dexamethasone With or Without Bortezomib in Relapsed/Refractory Multiple Myeloma
Another interesting study to mention is a phase I/II dose escalation and expansion trial that examined the possibility of adding Dara to venetoclax. In this study reported at ASH, 2 populations of patients were treated with 2 different regimens. In cohort 1, patients with t(11;14) and relapsed/refractory MM after ≥ 1 previous therapy including a proteasome inhibitor and an immunomodulatory drug received venetoclax/Dara/dexamethasone, and in cohort 2, patients with relapsed/refractory MM after progression on 1-3 lines of previous therapy but who were not refractory to proteasome inhibitors received venetoclax/Dara/dexamethasone plus bortezomib. Patients in cohort 2 did not have to have a t(11;14) translocation.

The results indicate that, in patients with relapsed/refractory MM, venetoclax/Dara/dexamethasone, with or without bortezomib, is associated with high response rates. Indeed, 96% of the 24 patients in cohort 1 with t(11;14) achieved a VGPR or better with venetoclax/Dara/dexamethasone and 79% of the 24 patients in cohort 2—with or without t(11;14)—achieved a VGPR or better with venetoclax/Dara/dexamethasone/bortezomib. Of note, there were no major toxicities observed, and serious infections occurred in 17% of patients. Only 1 patient death, in cohort 2, occurred. This study is continuing to evaluate venetoclax/Dara/dexamethasone/bortezomib in this population of heavily pretreated relapsed/refractory MM particularly in those with t(11;14).

In my opinion, the following are the most exciting 4 advancements for patients with relapsed/refractory MM from ASH 2019:

1. Data from the CANDOR study showed high response rates with DKd, even in high‑risk patients, a patient population with difficult-to-treat disease.
2. Overall, CAR T-cell therapy targeting BCMA continues to demonstrate promising efficacy and  suggests that early intervention with CAR T-cell therapy may be beneficial.
3. We now have an alternative to CAR T-cell therapy with the BiTEs (along with other anti-BCMA targeted agents, such as antibody drug conjugates) that may allow for expanded access to this class of agents.
4. Finally, we have an effective, targeted therapy for patients with t(11;14) with venetoclax/dexamethasone; the addition of Dara may result in higher and deeper response rates, but more data are needed for this combination.

Your Thoughts?
What are your thoughts on the new data in MM presented at ASH 2019? I encourage you to answer the polling question and join the conversation in the discussion box below.