CONFERENCE UPDATE: NDF 2021
The evolving treatment landscape of high-risk MM
With major advances in the management of multiple myeloma (MM), next-generation proteasome inhibitors, immunomodulatory drugs and anti-CD38 monoclonal antibodies were approved for the treatment of relapsed/refractory MM (rrMM).1 However, Prof. Chim, Chor-Sang James noted that most patients who developed advanced rrMM are refractory to many treatment agents, and anti-CD38 monoclonal antibodies and other immunotherapies are the most important treatment options left for these patients.
Where the anti-CD38 antibody isatuximab is currently under study, other emergent treatment options that target the B-cell maturation antigen (BCMA) have yielded deep responses in rrMM.1 Importantly, BCMA is a cell surface protein that is universally expressed on malignant plasma cells, enabling a highly selective treatment target specifically for MM treatment.2 As such, BCMA-targeting antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE) and chimeric antigen receptor T-cell (CAR-T) therapy are being developed to address the unmet needs of rrMM patients. Of the BCMA-targeting treatment options, the phase 1 dose-escalation CRB-401 study showed that a sufficient amount (≥150x106 cells) of the anti-BCMA CAR-T therapy, idecabtagene (bb2121), induced a dose-dependent response with a median progression-free survival (PFS) of 11.8 months in patients who had very advanced disease and a median of 8 prior regimens.3 In the follow-up phase 2 KarMMa study, idecabtagene also showed a dose-dependent survival benefit with a median overall survival (OS) of 19.4 months in heavily pre-treated patients.4
Similarly, the phase 1b/2 CARTITUDE-1 study showed that another anti-BCMA CAR-T, LCAR-B38M/JNJ-4528, was able to achieve a 6-month PFS in 93% of patients who had a median of 5 prior lines of therapy (86% and 31% of patients are triple and penta-refractory, respectively).5 Importantly, an impressive objective response rate (ORR) of 100% was achieved, with 76% of patients achieving stringent complete response and 21% achieving very good partial response.5
From a safety perspective, Prof. Chim noted that while cytokine release syndrome (CRS) is an expected side effect of CAR-T in MM patients due to its mechanism of action, multiple studies showed that MM patients have a comparatively better safety profile than those with B-cell acute lymphoblastic leukemia (ALL), diffuse large- B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). In the ZUMA-1 study, 11% and 32% of large B-cell lymphoma patients have experienced ≥grade 3 CRS and neurological events, respectively, after receiving the anti-CD19 CAR-T axicabtagene ciloleucel (KTE-C19).6 Comparatively, MM patients in the CRB-401 study had a much lower rate of ≥grade 3 CRS and neurological events of 6% and 3%, respectively.3 In the CARTITUDE-1 study, 93% of patients had experienced CRS, yet only 7% of these patients experienced ≥grade 3 CRS.5 “Compared to other forms of blood cancer receiving CAR-T, MM is a privileged entity with a low rate of severe CRS or neurotoxicity,” commented Prof. Chim.
As CAR-T is a potentially highly effective yet toxic treatment for MM, Prof. Chim urged that high-risk MM patients should be identified to assess whether upfront CAR-T therapy is warranted. To identify these patients, Prof. Chim recommended the inclusion of a cytogenetic scoring system (CSS) that can identify patients who had an OS of <3 years despite bortezomib-based induction therapy and hence warrant a clinical trial with upfront CAR-T. Under this scoring system, high-risk patients with a CSS score of >1 can be enrolled into clinical trials and receive induction with anti-CD38 antibodies. Allogeneic hematopoietic stem-cell transplantation (HSCT) can then be given in tandem for patients with del(17p) according to the mSMART guidelines, and CAR-T can be given to patients as consolidation.
An equally efficacious and safe alternative: The once-weekly carfilzomib-based therapy
Multiple myeloma (MM) is an incurable hematological disease with a global incidence of 160,000 cases in 2018.1,2 Since treatment failure among patients with relapsed/ refractory multiple myeloma (rrMM) was common with conventional therapies, additional treatment options are urgently needed to improve the survivals of these patients.2,3 At the recently held Annual Scientific Meeting of Hong Kong Society of Myeloma, Dr. Keith Stewart revealed the merits of carfilzomib, a second-generation proteasome inhibitor, as a combination therapy to manage rrMM and highlighted the results of ARROW - the first randomized phase 3 trial comparing the efficacy and safety of twice-weekly carfilzomib + dexamethasone (Kd) regimen with the once-weekly Kd regimen.
Evaluating efficacy and safety of D-RVd induction therapy for NDMM patients: An update of post 24 months of maintenance
A triplet combination induction therapy of lenalidomide, bortezomib and dexamethasone (RVd), followed by autologous stem cell transplantation (ASCT), and the lenalidomide (R) maintenance therapy, is the standard frontline regimen for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM).1 Although the standard induction therapy may be efficient to a certain extent, novel strategies with higher efficacy and lesser toxicity are needed.
GRIFFIN is a randomized phase 2 study examining the efficacy and safety of daratumumab (DARA) + RVd (D-RVd) as an induction therapy, with the aim of improving the stringent complete response (sCR), minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS) in transplant-eligible NDMM patients.1 The patients received 4 D-RVd or RVd induction cycles (21-cycles), 2 D-RVd or RVd consolidation cycles following a high-dose therapy with ASCT, and R maintenance therapy with lenalidomide (28-cycles) alone or with DARA.1
The subgroup analysis of patients indicated that a treatment regimen integrating D-RVd during induction, consolidation and R maintenance, when combining with ASCT, was clinically effective.1 An improved depth of response was evident through sCR rates and MRD negativity rates.1 Although results showed a certain favorability towards D-RVd, larger studies with more patients may be required to obtain conclusive data.
The real-world use of ixazomib achieved stable disease for nearly 3 years, longer than in clinical trial
Multiple myeloma (MM) is the second most common hematological malignancy and is associated with significant morbidity due to its end-organ destruction.1 Despite significant treatment advances in the past couple decades, MM remains an incurable malignancy with most patients eventually experience rela
Real-world analysis found ixazomib triple therapy effective in the management of relapsed/refractory multiple myeloma
Although the median overall survival (OS) of patients with multiple myeloma (MM) has significantly improved over the past two decades, MM remains an incurable malignancy with most patients experiencing relapse and requiring additional therapy.1 Among these patients, the presence of clonal heterogeni
Belantamab mafodotin-blmf: A potential new candidate in combination treatment for patients with relapsed or refractory multiple myeloma
In the recent DREAMM-2 study, single-agent belantamab mafodotin-blmf has demonstrated anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.1 Based on this result, the United
The use of daratumumab in multiple myeloma: Developing novel immunotherapy strategies to prolong survival
Multiple myeloma (MM) is a type of clonal neoplasm with substantial morbidity and mortality. With the development of better therapies, MM has transformed from untreatable to still incurable but treatable.1
New ‘KdD’ triple drug combination enhances clinical efficacy in the treatment of relapsed/refractory myeloma
There has been a shift in the treatment paradigm for relapsed/refractory (R/R) multiple myeloma (MM) over the last decade due to the emergence of novel drugs and combination regimens. At the recent American Society of Hematology (ASH) Annual Meeting 2019,
Management of multiple myeloma in Hong Kong
Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies.1 In Hong Kong, the majority of MM patients are older than 65-years-old. Management of these patients needs special consideration due to age-related comorbidities.