The evolving treatment landscape of high-risk MM

07 Jul 2021

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.

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