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Isatuximab is a monoclonal antibody therapy targeting a unique epitope of CD38. CD38 is a cell-surface antigen which is abundantly expressed on plasma cells, and thus presents an attractive target in the treatment of multiple myeloma.1
In March 2020, isatuximab received FDA approval for use in combination with pomalidomide and dexamethasone for the treatment of adult patients with relapsed or refractory (R/R) multiple myeloma who have received at least two prior lines of therapy including lenalidomide and a proteasome inhibitor. This approval was based on the findings of the ICARIA-MM trial (NCT02990338).2 More recently, in March 2021, isatuximab was approved by the US FDA for use in combination with carfilzomib and dexamethasone for patients with R/R myeloma who have received between one and three prior lines of therapy. This approval was based on the results of the IKEMA trial (NCT03275285).3
In this video, Enrique Ocio, MD, PhD, of Marqués de Valdecilla University Hospital, Santander, Spain, shares updated data from Part B of a Phase I trial investigating isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for patients with newly diagnosed multiple myeloma who are transplant-ineligible or have no intent to receive transplant.4
In Part A of the study, a weight-based infusion of isatuximab plus VRd (isa-VRd) was found to be effective and well-tolerated, with a median infusion duration at first infusion of 3.7 hours. 5 Part B of the trial is exploring isatuximab administered as a fixed-volume infusion with standard doses of VRd.
Dr Ocio reports that in Part B, the median duration of isatuximab infusion decreased significantly, from two hours for the second infusion to one hour and 20 minutes for subsequent infusions. The study reported an overall response rate of 97.8%, with a stringent complete response rate of 35.6% and a very good partial response rate of 55.6%. 51.1% of response-evaluable patients were measurable residual disease (MRD) negative.
“With this quadruplet, with this new method of infusion of isatuximab, we have a combination which is convenient for patients, it’s safe for them, and I think, quite effective,” says Dr Ocio.
Measurable residual disease (MRD) has become increasingly prominent in multiple myeloma research over the least few years, with building evidence demonstrating the potential benefits of its use in guiding treatment. Although multiple myeloma remains incurable, overall survival has dramatically increased, primarily due to the approvals of novel therapies such as lenalidomide and daratumumab, with a growing number of patients achieving deep responses. As a result, MRD is now being used for response assessment in clinical trials due to its ability to detect extremely low levels of residual disease after therapy, and is also being assessed in adaptive therapy strategies.6
In this video, Luciano Costa, MD, PhD, of the University of Alabama at Birmingham, Birmingham, AL, discusses the findings of the Phase II MASTER trial (NCT03224507). The MASTER trial is investigating the safety and efficacy of induction therapy using daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), followed by autologous stem cell transplant (ASCT) and Dara-KRd consolidation in patients with newly diagnosed multiple myeloma. The duration of therapy is being guided by MRD, assessed using next-generation sequencing, with patients who become MRD-negative discontinuing maintenance therapy and being monitored for resurgence of MRD or relapse.
Dr Costa reports that of 123 patients enrolled in the study at data cut-off, at a median follow-up of 25.1 months, 80% of patients had achieved MRD negativity. MRD negativity was reached in 38% of patients after induction therapy, in 65% of patients after ASCT, and in 80% of patients after MRD-directed consolidation. 71% of patients reached confirmed MRD negativity and have entered MRD-SURE, an MRD surveillance program.7 “From this study we can conclude that yes, you can do MRD response-adaptive therapy in a multi-institutional setting,” commented Dr Costa.
Research into chimeric antigen receptor T-cell (CAR-T) therapy has been rapidly progressing in the field of multiple myeloma, with idecabtagene vicleucel becoming the first CAR-T therapy to be granted FDA approval for myeloma in March 2021, based on results from the Phase II KarMMa trial (NCT03361748).8
At the 18th International Myeloma Workshop in 2021, Hermann Einsele, MD, FRCP, of the University of Würzburg, Würzburg, Germany, shared initial results from the Phase II CARTITUDE-2 trial (NCT04133636) studying ciltacabtagene autoleucel (cilta-cel) for the treatment of multiple myeloma.
Cilta-cel is an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy. It was initially assessed in multiple myeloma in the Phase Ib/II CARTITUDE-1 trial (NCT03548207), which enrolled patients with relapsed or refractory myeloma. At a median follow-up of 12.4 months, the trial reported an overall response rate of 97%, with 67% of patients achieving a stringent complete response.9
Unfortunately, treatment-related adverse events (TRAEs) were common in the CARTITUDE-1 trial, with 95% of patients experiencing cytokine release syndrome, 4% of which was grade three or four, and neurotoxicity occurring in 21% of patients, with 9% being grade three or four. Six deaths occurred in the study due to TRAEs.9
In the CARTITUDE-2 study, risk assessment and early monitoring was introduced to detect late onset neurotoxicity. “So, what they found from the data from the CARTITUDE-1 trial is that patients that had a high tumor load, that had a CRS or ICANS before, then had a high CAR T-cell expansion and good CAR T-cell persistence, that these were the patients that were at a high risk of developing this late neurotoxicity,” explains Prof. Einsele.
For those detected as high risk for developing neurotoxicity, bridging therapy was intensified to lower tumour burden at the time of CAR-T infusion. “With risk assessment and the more intensified bridging therapy, and with the early monitoring for neurotoxicity, this late-onset neurotoxicity with neurocognitive or Parkinsonian-like syndromes was completely abolished or prevented in the CARTITUDE-2 trial,” Prof. Einsele reports.10
At the 18th International Myeloma Workshop in 2021, Elena Zamagni, MD, PhD, of the University of Bologna, Bologna, Italy, discusses updated data from high-risk patients with multiple myeloma enrolled in the Phase II FORTE trial (NCT02203643). The FORTE trial is testing carfilzomib-based induction or consolidation with or without autologous stem cell transplant (ASCT), followed by maintenance with carfilzomib plus lenalidomide (KR) or lenalidomide alone.
In standard-risk patients, the FORTE trial demonstrated that carfilzomib-lenalidomide-dexamethasone (KRd) with ASCT significantly improved progression-free survival (PFS) in comparison to KRd without ASCT or carfilzomib-cyclophosphamide-dexamethasone (KCd). KR maintenance was also shown to improve PFS in comparison to lenalidomide alone.
Out of 474 patients enrolled in the study, 243 were found to be high-risk, defined as the presence of one or more high-risk chromosomal abnormalities, including del117p, t(4;14), t(14;16), del11p and 1q gain or amp1q. 105 patients were double hit, defined as the presence of two of more high-risk chromosomal abnormalities.11
The study reported that the 4-year progression free survival (PFS) rate for high-risk patients who received KRd-ASCT was highest, at 62%, versus 45% for both KRd without ASCT and KCd-ASCT. This PFS advantage was also observed in double-hit patients, with those who received KRd-ASCT having a PFS of 55% versus 31% and 33% for KRd without ASCT and KCd-ASCT respectively.11 “The addition of transplant is particularly useful in high-risk patients,” comments Dr Zamagni. “For standard-risk patients, maybe the triplet is enough because the rate of MRD negativity can be achieved the same. But for patients at high risk of early relapse, the addition of transplant is worthwhile.”
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