Clinical efficacy of sequencing CD38 targeting monoclonal antibodies in relapsed refractory multiple myeloma: A multi‐institutional experience

Mohan, Meera; Becnel, Melody; Shah, Urvi; Dong, Huaying; Gundarlapalli, Sravani; Peterson, Timothy E.; Orozco, Jennifer; Horowitz, Sandra B.; Chhabra, Saurabh; Dhakal, Binod; Thanendrarajan, Sharmilan; Radhakrishnan, Sabarinath Venniyil; Hadidi, Samer Al; Tan, Carlyn; Mailankody, Sham; Hultcrantz, Malin; Korde, Neha; Hassoun, Hani; Lesokhin, Alexander M.; Thomas, Sheeba K.; Patel, Krina; Manasanch, Elisabet E.; Weber, Donna M.; Szabó, Anikó; Kaufman, Gregory P.; Lee, Hans C.; Zangari, Maurizio; Rhee, F. Van; Usmani, Saad Z.; D’Souza, Anita; Orłowski, Robert Z.; Schinke, Carolina

doi:10.1002/ajh.26580

Cited by 5 publications

(3 citation statements)

References 13 publications

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“…This extends what had been shown previously in prospective and retrospective clinical studies. 26 , 27 , 28 , 29 , 30 Based on these results, re-treatment with anti-CD38 antibodies in patients refractory to daratumumab before CAR-T is likely to be of limited benefit and may be restricted to bridging therapy to a more definitive option, such as CAR-T or bispecific antibodies. Interestingly, My-DST with a more stringent cutoff for sensitivity was predictive of clinical partial response.…”

Section: Discussionmentioning

confidence: 99%

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CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies

Perez de Acha,

Reiman,

Jayabalan

et al. 2023

Blood Advances

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Monoclonal antibodies targeting CD38 are important treatment in both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with FDA-approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether or not patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for > 1 year showed greater sensitivity than those with < 1 year, although they still were less sensitivity than those that were daratumumab naïve. CD38 expression on MM cells gradually recovered, although again not to the level of anti-CD38 antibody-naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response, but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had < 6 months of clinical benefit, but one patient for who was daratumumab-exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting one year before CD38 antibody re-challenge, but this approach may be best used as a bridge to, or after, CAR-T.

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Section: Discussionmentioning

confidence: 99%

“… 27 , 28 Similar results have been found for patients previously treated with isatuximab. 29 , 30 Taken together, there can be benefit from re-treatment with CD38 antibodies, but it remains unknown how much time off is optimal to improve outcomes.…”

Section: Introductionmentioning

confidence: 99%

CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies

Perez de Acha,

Reiman,

Jayabalan

et al. 2023

Blood Advances

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“…However, not all MM cells are eliminated, and resistance develops with CD38 downregulation after prolonged treatment [4,5]. The effectiveness of later retreatment with CD38-targeting antibodies after the development of resistance has been limited [6][7][8]. Recently, the FDA approved of two chimeric antigen T (CAR-T) cell therapies and one bispecific antibody (bsAb) that targets B cell maturation antigen (BCMA) [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts

VanWyngarden,

Walker,

et al. 2023

Cancers

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An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46–ADC or the nonbinding control–ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46–ADC treatment showed significantly decreased engraftment compared to control–ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity.

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Real-world experience with isatuximab in the treatment of relapsed-refractory multiple myeloma: a case series from the Grand Duchy of Luxembourg

2023

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Clinical efficacy of sequencing CD38 targeting monoclonal antibodies in relapsed refractory multiple myeloma: A multi‐institutional experience

Cited by 5 publications

References 13 publications

CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies

CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies

CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts

Real-world experience with isatuximab in the treatment of relapsed-refractory multiple myeloma: a case series from the Grand Duchy of Luxembourg

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