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International Myeloma Society Annual Meeting

Adding the CD38-directed monoclonal antibody isatuximab in combination with pomalidomide (Pomalyst) and dexamethasone improved progression-free survival (PFS) in both standard-risk patients with relapsed/refractory multiple myeloma and those with high-risk cytogenetics, according to subgroup findings from the phase III ICARIA-MM study that were presented at the 17th International Myeloma Workshop (IMW) Scientific Program.

In the analysis, high cytogenetic risk was defined as ≥1 for del(17p), t(4;14), or t(14;16) abnormalities and was performed by central laboratory at study entry. Cut-offs for del(17p), t(4;14), and t(14;16) were 50%, 30%, and 30%, respectively.

Overall response rate (ORR) benefit was maintained regardless of the high-risk cytogenetic cut-off definition used. Further, PFS benefit was observed in patients with standard- and high-risk cytogenetic risk. The median PFS for patients at high-risk who received the isatuximab regimen was 7.5 months versus 3.7 months in patients who received pomalidomide/dexamethasone alone (HR, 0.66; 95% CI, 0.30-1.28). In standard-risk patients, the median PFS was 11.6 months in the combination arm versus 7.4 months in the monotherapy arm.

In July 2019, the FDA accepted a biologics license application for isatuximab for the treatment of patients with relapsed/refractory multiple myeloma, based on the overall ICARIA-MM data.

 during the 17th IMW Scientific Program, Simon J. Harrison, MBBS, PhD, hematologist and disease group lead: myeloma, Peter MacCallum Cancer Centre, discussed the subgroup findings from the ICARIA-MM study in relapsed/refractory multiple myeloma.

: What benefits were observed with the isatuximab triplet in the high-risk cytogenetic population? 

: In the high-risk cytogenetic population, we saw a significant increase in response rate—up to about 50% compared with 20%. The majority of that benefit was an increase in very good partial response (VGPR) rate, which was around 30% compared with around 3% in the control arm of the study. [This means that] isatuximab is increasing the depth of response as well as the ORR.

What do these outcomes mean for patients with high-risk cytogenetics?

Patients with high-risk mutations across the board do less well, in terms of achieving a response but also in maintaining that response. The addition of isatuximab to pomalidomide and dexamethasone improves both response rate and duration of response. Therefore, a response that lasts for 5 minutes is not that helpful, whereas if you maintain that response for much longer, then clearly that’s an important marker to suggest that the overall survival (OS) will follow that when the analysis is complete in the future.

Patients with high-risk cytogenetic abnormalities benefit at least as much as standard-risk patients from the addition of isatuximab to pomalidomide/dexamethasone, so there is no reason not to offer that therapy to these patients. If you look at the odds ratio, in terms of the response, it seems that those patients with high-risk abnormalities benefit even more than the standard-risk patients.

It doesn’t overcome the overall negative impact of the high-risk abnormality, but it’s a step along the way to help the patients in that area of need achieve better outcomes.

What are some of the unique features of isatuximab?

This molecule, isatuximab, uses a different epitope. It has a different adverse event profile, particularly in terms of reduced infusion reactions. Therefore, it has better tolerance for patients, so it offers a new alternative to daratumumab (Darzalex) in the clinic.

It may be because of the slightly different mechanism of action that it may be more effective in certain subgroups, particularly in those patients with high-risk cytogenetic abnormalities.

What else should be noted about the activity in those with high-risk abnormalities?

High-risk cytogenetics were defined in the study as del(17p), t(4;14), and t(14;16). The individual numbers of each of those abnormalities in the study was relatively small, so it’s hard to say what the overall impact of those abnormalities was across the study population. However, it seems to be that all of the high-risk populations benefitted similarly compared with the overall study population. The magnitude of the difference seems to be maintained.

One of the interesting findings from the study was that in patients with t(4;14), if they had a higher percentage of tumor cells expressing that cytogenetic abnormality, then those treated with isatuximab derived a greater benefit. However, again, the numbers are small and it is hard to say “Absolutely,” but it seems to be that high-risk patients seem to derive the same benefit as standard-risk patients across the board.

How could the use of subcutaneous daratumumab impact clinical practice?

It seems to be subcutaneous antibodies across the board are associated with less toxicity while maintaining efficacy. So it’s simpler, easier to administer, and patients aren’t having the same reactions. Interesting thing though is that isatuximab doesn’t bind as strong as daratumumab and that seems to be the explanation for its fewer infusion-related reactions. Clearly there are ongoing studies looking at shorter duration infusions with isatuximab that appear to be safe. However, subcutaneous isatuximab will be investigated as well.

There has been a lot of focus during the 17th IMW Scientific Program on the high-risk population. Where does this leave the standard-risk population?

The high-risk patients are a reasonable percentage of the population. Up to one-third of patients with myeloma have high-risk cytogenetic abnormalities; they have lagged behind in terms of their outcomes and it still remains an area of need, particularly the double-hit or the ultra—high-risk patients with myeloma still have dismal outcomes.

On saying that, the biggest improvements have been in patients with standard risk. If we are ever going to cure anybody, then it’s going to be standard-risk patients. If we’re aiming for cure, then we still need to focus on the standard-risk patients and also not forget about the high-risk patients.

We probably need better studies designed to specifically accrue high-risk patients to address their specific needs, and it’s an area where we need more international collaboration with studies looking at that population to improve their outcomes.

Harrison SJ, Richardson PG, Alegre A, et al. Efficacy of isatuximab/pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA-MM high-risk cytogenetics subgroup analysis. Presented at: International Myeloma Workshop Scientific Program; September 12 to 16, 2019; Boston, MA. Abstract OAB-048.

Adding the CD38-directed monoclonal antibody isatuximab in combination with pomalidomide and dexamethasone improved progression-free survival in both standard-risk patients with relapsed/refractory multiple myeloma and those with high-risk cytogenetics.

Isatuximab Triplet Showcases Encouraging PFS in High-Risk Multiple Myeloma

A quadruplet regimen combining the anti-CD38 monoclonal antibody isatuximab with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (I-KRd) was safe and had a 100% response rate among 10 patients enrolled in the safety run-in cohort of the phase II, multicenter GMMG-CONCEPT trial.

The 10-patient safety run-in phase was designed to evaluate dose-limiting toxicities during the initial 2 cycles of I-KRd treatment. Following cycle 2, there were 6 patients with a very good partial response (VGPR) and 4 patients with a complete response (CR). Efficacy was also assessed after cycle 6, at which point there were 7 patients with a CR, 2 patients with a VGPR, and 1 patient with progressive disease.

"The GMMG-CONCEPT trial is the first trial introducing quadruplet treatment solely for high-risk multiple myeloma including both transplant-eligible and transplant ineligible patients," said Katja Weisel, MD, Department of Hematology, Oncology and Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany, who presented the results at the 17th International Myeloma Workshop.

All 10 patients experienced treatment-emergent adverse events (TEAEs). Most grade ≥3 toxicities were hematologic, including neutropenia (n = 6), leukopenia (n = 5 ), lymphopenia (n = 2), anemia (n = 2), and thrombocytopenia (n = 1). Nonhematologic grade ≥3 TEAEs included cerebral vascular disorders in 2 patients (n = 2), self-limiting ventricular tachycardia (n = 1), and diarrhea (n = 1). Three patients experienced grade 2 infusion reaction during the first infusion of isatuximab.

There were 5 serious adverse events (SAEs), including 2 infections (1 febrile neutropenia) and the incidents of cerebral ischemia and self-limiting ventricular tachycardia. The 2 cerebral events were classified as non—treatment related due to a preexisting comorbidity. Grade 1/2 infusion reactions occurred in 3 patients during the first isatuximab infusion. There were no deaths due to SAEs or discontinuations due to an adverse event.

"The overall safety profile of I-KRd was favorable and manageable, with no unexpected toxicities and the combination is effective in this setting," added Weisel.

GMMG-CONCEPT is enrolling patients with newly diagnosed multiple myeloma and high-risk disease defined as deletion 17p or t(4;14) or t(14;16) or >3 copies of +1q21; all patients had to be International Staging System stage 2 or 3. Patients could have received 1 cycle (4 weeks) of any treatment for multiple myeloma. Patients are being stratified by transplant eligibility (Arm A, eligible and age ≤70 years) or non-eligibility (Arm B ineligible or age >70 years).

At the meeting, Weisel presented results for the safety run-in cohort of the first 10 patients in Arm A of GMMG-CONCEPT. Nine of the 10 patients had completed 6 cycles of induction therapy. The median age was 56 years (range, 42-67), 4 were male, 6 had del 17p, 2 had t(4;14), and 5 had >3 copies of +1q21.

The primary objective is minimal residual disease (MRD) negativity by flow cytometry to a sensitivity of 10-5. The secondary objectives is progression-free survival. Additional objectives include overall response rate, survival, duration of MRD-negativity, time to next treatment, time to response, and quality of life. Experimental objectives include the best method for defining MRD-negativity (flow, next-generation sequencing, PCR, or imaging) and evaluation of immunologic reconstitution during maintenance.

In the original study design, Arm A was to receive 6 cycles of I-KRd followed by cyclophosphamide-based stem cell mobilization, HD melphalan and ASCT, a second HD melphalan and SCT if the response to the first was not a CR or near CR, consolidation with 4 cycles of I-KRd, and maintenance with I-KR. Arm B was to receive I-KRd for up to 12 cycles, followed by I-KR maintenance. As of September 10, 2019, 112 of the 153 planned patients (117 for Arm A and 36 for Arm B) have been enrolled.

All 10 patients in the safety run-in received cyclophosphamide-based stem cell mobilization with a median stem cell yield of 5 (4-9) × 10

 CD34+ cells/kg. Of these, 3 patients required plerixafor for collection; sufficient stem cells could not be collected from 3 patients. Therefore, the study was amended so that stem cell mobilization would take place after the 3rd rather than the 6th induction cycle.

With regard to the difficulties in stem cell collection after 6 cycles of I-KRd induction, Weisel said, “We were surprised we couldn’t collect stem cells. I think this is a real finding and we have to look at this in other quadruplets.”

In her concluding remarks, Weisel said that the results overall are encouraging and data on additional patients will be reported soon.

Weisel K, Asemissen AM, Schieferdecker A, et al. Isatuximab, carfilzomib, lenalidomide and dexamethasone (I-KRd) in front-line treatment of high-risk multiple myeloma: results of the safety run-in cohort in the phase II, multicenter GMMG-CONCEPT trial. Presented at: The 17th International Myeloma Workshop; Sept. 12-15, 2019; Boston. Abstract 362.

A quadruplet regimen combining the anti-CD38 monoclonal antibody isatuximab with carfilzomib, lenalidomide, and dexamethasone was safe and had a 100% response rate among 10 patients enrolled in the safety run-in cohort of the phase II, multicenter GMMG-CONCEPT trial.

Isatuximab Quadruplet Active in High-Risk, Newly Diagnosed Myeloma

Habte A. Yimer, MD, of Texas Oncology, discusses a real-world study evaluating the long-term use of proteasome inhibition in patients with multiple myeloma, and transitioning from bortezomib (Velcade) to ixazomib (Ninlaro).

View more from the 17th International Myeloma Workshop

Dr. Yimer on Long-Term Proteasome Inhibition in Newly Diagnosed Myeloma

Katja Weisel, MD, myeloma specialist at the University of Tübingen, discusses an analysis of the INSIGHT MM study evaluating fixed-duration versus continuous therapy for patients with multiple myeloma.

Dr. Weisel on INSIGHT MM Analysis of Duration of Therapy in Myeloma

The regimen of daratumumab (Darzalex), bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (D-VTd) demonstrated an improvement in minimal residual disease (MRD) negativity rates and progression-free survival (PFS) compared with VTd alone in patients with high-risk multiple myeloma, according to a subgroup analysis of the phase III CASSIOPEIA trial.

The phase III CASSIOPEIA trial randomized 1085 treatment-naïve, transplant-eligible patients with multiple myeloma who were transplant eligible to receive the daratumumab regimen or VTd alone.

The trial was divided into 2 parts, an induction and consolidation phase, followed by a maintenance treatment with daratumumab or observation. Findings for part 1 of the study demonstrated a 53% reduction in the risk of progression or death in the D-VTd arm versus VTd alone (HR, 0.47; 95% CI, 0.33-0.67; 

The subgroup analysis data, which were presented at the 17th International Myeloma Workshop, showed that D-VTd led to a 34% reduction in the risk of disease progression or death compared with VTd alone in those with International Staging System (ISS) Stage III disease (HR, 0.66; 95% CI, 0.32-1.39). In patients with high-risk cytogenetics of del(17p) or t(4;14), the daratumumab regimen reduced the risk of disease progression or death by 33% (HR, 0.67; 95% CI, 0.35-1.30).

However, a benefit with stringent complete response rate was not observed with D-VTd over VTD alone in those with ISS Stage III disease (

In May 2019, the FDA granted a priority review designation to a supplemental biologics license application for D-VTd for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant, based on part 1 of the phase III CASSIOPEIA trial. The FDA is scheduled to make a decision on the application on or before September 26, 2019.

 during the 17th International Myeloma Workshop, lead author Pieter Sonneveld, MD, PhD, professor of hematology and head of the Department of Hematology at Erasmus MC Cancer Institute in The Netherlands, discussed the significance of the subgroup analysis.

: Could you discuss the results of your subgroups analysis?

: We presented a subgroup analysis, which was a planned analysis, for the outcomes in patients with high-risk disease. This is for patients with ISS Stage III or with high-risk cytogenetics: del(17p) and t(4;14). Of course, this is a small subgroup. However, we were able to analyze the data and the results indicate that the response rate is the same in these high-risk cytogenetics and ISS Stage III as compared with the intent-to-treat population—so the full population.

Of 1085 patients randomized to D-VTd or VTd, 15.5% had a high-risk cytogenetic abnormality. ISS staging was 39.8%, 45.0%, and 15.2% for stage I, II, and III, with more patients classified as stage II in D-VTd versus VTd and similar patients classified as stage III in D-VTd versus VTd.

Another issue fully addressed in this trial was the MRD negativity. For the first time, in a frontline trial in transplant-eligible patients, we conducted a full analysis of MRD using flow cytometry. The results are published, but it’s important to note that MRD negativity was achieved in about 64% of patients with D-VTd. This is a significant increase of MRD negativity.

The MRD-negative rate was higher for D-VTd versus VTd, including in high-risk cytogenetic and ISS stage III subgroups. We also looked at PFS. With a follow-up time of only 18 months, we see the curves are going to separate and that there is significant benefit for D-VTd in this high-risk subgroup.

How would you define the significance of the data in terms of cytogenetic risk and ISS stage?

For patients who were ISS Stage III or had high-risk cytogenetics, we see a benefit for D-VTd over VTd alone. These smaller number of patients represent less than 10% of total patients. We can’t draw firm conclusions right now, but we can see that response rate, the level of MRD negativity, and PFS are of the same order of magnitude as in the intent-to-treat population.

How do these findings inform current thinking about treating patients with multiple myeloma?

We think that not only for the high-risk patients, but for the whole group of patients who are transplant-eligible and newly diagnosed with myeloma, that there will be a new standard in the future coming from VTd, or the regimen of bortezomib, lenalidomide (Revlimid), dexamethasone (VRd), or other triple-drug combinations going to a 4-drug regimen, including daratumumab, will eventually become the new standard of treatment.

It’s too early to do that right now because we are waiting for the results of the second randomized part of the study that involves daratumumab as a maintenance therapy. However, based on the first part of the trial, we have submitted data to the regulatory bodies. My assumption is that, like in the older patients, adding daratumumab will become a standard for the initial treatment of patients.

What impact could the combination of daratumumab and VTd have on the community oncologist if it is approved?

The big question is whether we will have approval to use daratumumab in the first-line setting, not only in the elderly, but also in the transplant-eligible patients.

Once the combination [is approved] it offers the unique opportunity for a high response rate, for long-term PFS. Therefore, I expect that it will be popular in the community setting. Patients will enjoy a long disease-free period, with a good quality of life—maybe going back to work and enjoying life&mdash;which is important. Daratumumab adds to the common standard of treatment.

Did the study findings strengthen the case for finding the right combination of treatments?

This is one of the new options. Currently, we are running another study in the European Myeloma Network of D-VRd, which is highly comparable with the CASSIOPEIA trial. However, VRd is a more effective regimen than VTd. We consider this an upgrade of the original treatment with daratumumab.

Also, other combinations are undergoing investigation including isatuximab, which is another CD38-directed antibody [in] the ICARIA-MM study in the relapsed setting.

We probably have a new standard here, from diagnosis through the different stages of the disease and treatment.

We need to look closer at the issue of retreatment. If we treat patients upfront with daratumumab, at a certain stage they will stop their treatment. If they progress or relapse, can we treat them again with daratumumab to the full benefit of the drug? Or, should we switch to another antibody like isatuximab or elotuzumab (Empliciti)? There are many others.

Then, the important issue is that we treat as many patients [as we can] with daratumumab in the first-line setting. This is the priority. The relapsed setting is also a valuable place for daratumumab, but it should not be our first goal. What we don’t know yet is how this treatment compares with other [monoclonal antibodies] and if we can combine with other [monoclonal antibodies].

Sonneveld P, Attal M, Perrot A, et al. Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (NDMM): subgroup analysis of high-risk patients (Pts) in CASSIOPEIA. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract OAB-003.

Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. 

. 2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.

Pieter Sonneveld, MD, PhD, discusses the significance of the subgroup analysis of the phase III CASSIOPEIA trial evaluating the regimen of daratumumab, bortezomib, thalidomide, and dexamethasone in patients with high-risk multiple myeloma.

International Myeloma Society Annual Meeting | Conference

Isatuximab Triplet Showcases Encouraging PFS in High-Risk Multiple Myeloma

Isatuximab Quadruplet Active in High-Risk, Newly Diagnosed Myeloma

Dr. Yimer on Long-Term Proteasome Inhibition in Newly Diagnosed Myeloma

Dr. Weisel on INSIGHT MM Analysis of Duration of Therapy in Myeloma

Daratumumab-VTd Regimen Shows Benefit in Newly Diagnosed High-Risk Multiple Myeloma