Clinical efficacy of sequencing CD38 targeting monoclonal antibodies in relapsed refractory multiple myeloma: A multi‐institutional experience
Authors: Meera Mohan, Melody Renee Becnel, Urvi A. Shah, Huaying Dong, Sravani Gundarlapalli, Timothy Peterson, Jennifer S. Orozco, Sandra Horowitz, Saurabh Chhabra, Binod Dhakal, Sharmilan Thanendrarajan, Sabarinath Venniyil Radhakrishnan, Samer Al Hadidi, Carlyn Tan, Sham Mailankody, Malin Hultcrantz, Neha Korde, Hani Hassoun, Alexander M. Lesokhin, Sheeba K. Thomas, Krina K. Patel, Elisabet E. Manasanch, Donna M. Weber, Aniko Szabo, Gregory P. Kaufman, Hans C. Lee, Maurizio Zangari, Frits van Rhee, Saad Z. Usmani, Anita D'Souza, Robert Z. Orlowski, Carolina Schinke
Journal: American Journal of Hematology (2022)

To the Editor: Multiple Myeloma (MM) remains largely incurable with a small proportion of patients attaining long-term disease control. Monoclonal antibodies (MoAbs) targeting plasma cell surface antigens play an increasing role in improving outcomes.1 Among these, the CD38-targeted MoAbs daratumumab (Dara) and isatuximab (Isa) are widely used for relapsed MM Isa differs from Dara in its mechanism of action with more antibody-dependent rather than complement-mediated cytotoxicity and relatively less reliance on Fc receptor-mediated crosslinking for induction of apoptosis. In addition, Isa uniquely inhibits the CD38 enzymatic activity via allosteric inhibition unlike the other CD38 targeting MoAb.2 This suggests the possibility that Isa3-5 may retain efficacy in patients whose disease has progressed on prior Dara-based therapy, and such information could aid clinicians in appropriately sequencing these regimens. In an effort to examine the possible efficacy of retreatment with one anti-CD38 MoAb after MM progression on a prior agent in this same class, we present our data from four academic institutions (Medical College of Wisconsin, University of Arkansas for Medical Sciences, Memorial Sloan Kettering Cancer Center, and MD Anderson Cancer Center) which includes patients with relapsed refractory (RR) MM who received at least one cycle of Dara-based therapy and subsequently received Isa-based therapy. The risk was assessed according to the international staging system (ISS), revised ISS criteria, gene expression profiling (GEP70 for patients from the University of Arkansas for Medical Sciences) and PET-CT defined focal lesions (FL) ≥ 3, as previously described. High risk cytogenetics were defined as presence of t (4;14), t (14;16), t (14:20), 1q21 abnormalities ≥3 copies or del 17p.6, 7 Clinical Benefit Rate (CBR) is defined as percentage of patients who achieved a sCR, CR, VGPR, PR, and MR. Augmentation of response was defined as the proportion of patients achieving a higher level of response at the end of treatment from what they had at start of Isa therapy (e.g., PD to SD, SD to PR; PR to VGPR) using the IMWG uniform response criteria. Data cut off was September 30th, 2021. Baseline characteristics are summarized in Table S1. Fifty-nine patients were included in the analysis and median age was 66 (range 42–86) years at the time of start of Isa-based therapy. Deletion 17p and chromosome 1q21 abnormalities were observed in 14.5% (n = 8) and 29.1% (n = 16) of patients, respectively. GEP 70 data was available on 12 patients, with high-risk disease noted in 7 patients. PET CT defined bony focal lesions were noted in 61% (n = 25) patients with majority having ≥3 PET FL (92.5%) on the last imaging study prior to Isa therapy. Extramedullary disease was present in 22% (n = 13) of patients. Most patients (80%) had at least one prior high dose chemotherapy and autologous stem cell transplantation (ASCT) and the median prior lines of therapy before Isa-based therapy were 6 (range 1 = 18). Most patients had previously been treated with at least two IMiDs (lenalidomide [96.6%, n = 57], pomalidomide [72.9%; n = 43]) and two PIs (bortezomib [94.9%; n = 56], and carfilzomib [79.7%; n = 47]). Dara was mostly combined with pomalidomide and dexamethasone, Pd (47.5%, n = 28) with 20.3% (n = 12) receiving more than one line of Dara. The median time to Isa after discontinuation of Dara therapy was 13.2 (range 1–47) months and there was an interval of >6 months between therapies in majority of patients (64.4%, n = 38). The median number of cycles of Isa therapy was 2 (<1–13) and most often used in combination therapy (98.3%) with pomalidomide and dexamethasone (Pd) (93.1%; n = 54). An CBR of 44% (n = 26), Figure 1A, was attained with Isa-based combinations on sequencing after Dara-based therapies. The most common best responses were SD (15/59; 25%) and PR (15/59; 25%) although 31% (18/59) patients experienced PD, while 5 patients had ≥VGPR to Isa therapy. The distribution of baseline high risk features such as unfavorable metaphase cytogenetics, high risk FISH lesions, GEP 70 HR score were not different between responders and non-responders. There was no difference in response rates when patients are stratified by prior exposure to pomalidomide (43.8% vs. 41.9%). A higher CBR was noted in the patients who received Isa more than 6 months after Dara compared to those who were treated within 6 months (57.9% vs. 19%; p = 0.004). Prior response of ≥ VGPR to Dara was not predictive of response to Isa (Isa responders 31.3 vs. Isa non responders 68.8%; p = 0.226). On multivariate analysis, the effect of a longer treatment wash-out period between therapy was independently associated with a response to Isa (OR 0.23, 95% CI 0.06–0.88; p = 0.032). As most patients had interim treatment for disease progression between Dara and Isa, augmentation of disease response was subsequently investigated. Most patients had PD (n = 28; 49%) going into Isa therapy and with an augmentation of response attained in 75% of patients (n = 21). Among the patients with SD (n = 8; 14%) at start of Isa therapy, 37.5% (n = 3) had a response to treatment. Overall, augmentation of response while on Isa-based therapy was observed in 42.4% (n = 25) of patients. While baseline patient and treatment characteristics were not predictive of augmentation to Isa, a prior response of ≥ VGPR to Dara was associated with lower rates of response augmentation (18.8% vs. 81.3%; p = 0.025). On multivariate analysis, high risk FISH (OR 2.22, 95% 0.70–6.62; p = 0.20) and longer interval group between Dara discontinuation and Isa therapy (OR 1.86,95% 0.59–6.09; p = 0.31) was not associated with augmentation of response, while ≥VGPR to prior Dara had a trend to overall poor augmentation of disease response to Isa therapy (OR, 3.4, 95% 0.96–15; p = 0.085). Notably, the CBR and augmentation of disease response in patients with a longer wash out period (>6 months) between therapy was 57.9% and 36.8%, respectively. When looking at the 5 patients who achieved at least a VGPR with Isa based therapy, it was noted that all patients had received interim therapy with an alkylating agent, either high dose melphalan (2 patients with salvage ASCT) or cyclophosphamide (as part of high dose therapy or conditioning for CAR-T cell therapy). The median duration of Isa therapy in these patients was 8 (range 0.7–16) months, with 3 patients eventually terminating therapy due to disease progression (n = 2) and one patient developing pneumocystis pneumonia. The median duration of therapy for the entire patient cohort was 3 (range 1.8–4) months with 10 patients having ongoing responses as of the last follow up, Figure 1B. Specifically, patients treated with Isa >6 months after Dara had a median of duration of therapy 3 (range 0.2–8.7) months compared to those who had a shorter interval between therapy 2.3 (range 0.5–11.2) months (Figure S1). About 10% of patients in this analysis continued to remain on Isa therapy as of last follow up. There were 2 deaths attributed to a cardiac event presumably unrelated to treatment or infectious complications. The median OS was 12 (range 9.1-NR) months, Figure 1C. The median survival stratified by interval between therapy favored the patients who had a longer gap between therapy (Figure S1). Resistance to Dara is a mounting concern and optimal management is largely unclear. Existing data on sequencing or retreatment strategies with alternative CD38 targeting molecules are largely limited.8-11 Several lines of evidence suggest that Dara failure is mediated by an impaired effector cell function and increasing the effector cell to target ratio could plausibly enhance anti-tumor activity.12 Recently, a phase I/II study reported absence of objective response in Dara refractory RRMM patients treated with Isa. The majority (60%) of treated patients in the study were exposed to Dara within 6 months of Isa therapy.9 The longer gap (median 13.2 months) between treatments in patients included in the current series could have influenced the CBR of 44%. The re-establishment of ≥VGPR with Isa in Dara refractory patients was noted in the current series following immune re-constitution after an interim ASCT or CAR T between the therapies. In addition, cyclophosphamide modulated tumor immunity by selective depletion of immunosuppressive regulatory T cell (T reg) and enhancing effector T cell function has been described previously and can explain the durable CR to IsaPd after Dara failure in one patient who received interim cyclophosphamide therapy. While this needs further confirmation, our study provides proof of concept of re-establishment of disease response using drugs targeting the same antigen possibly in the setting of a reinvigorated immune system. The preferential selection of Dara resistant clones in patients with prior deep responses (≥VGPR) before disease progression on Dara based therapy could have abrogated the benefit of Isa in this group of patients even after modulation of the bone marrow microenvironment. The relatively small number of patients in the current report precluded any definite conclusions. Another critical question is the role of rechallenging with Dara following Dara-refractory disease. Current literature suggests a median PFS with rechallenge of Dara Pd in patients who were refractory to both the agents is 3.3 months.13 It is plausible that retreatment with an alternative naked MoAb, including re-challenging with Dara, could have yielded the same results observed here. Other factors that need to be considered when choosing CD38 MoAb include the logistics of administration of these agents, patient preferences, and overall health care economics. Future studies need to explore the role of sequencing other targeted therapies such as antibody drug conjugates and bispecifics in patients previously exposed to MoAbs targeting the same antigen. We acknowledge several limitations of our study including the retrospective nature, sample size, inability to control for the companion drugs and isolate the response specific to individual drugs used in Isa-based combination regimens. In conclusion, this large multi-institutional series of heavily pre-treated MM patients receiving Isa following Dara failure provide real world evidence of clinical efficacy, albeit modest, particularly if sequencing can be sufficiently spaced out. Urvi A. Shah has received grants and research support from Celgene/Bristol Myers Squibb, Janssen paid to the institution, personal fees from Janssen, and honorariums for continuing medical education activity from MJH Life Sciences, ACCC, MashUpMD, all outside of the submitted work. Malin Hultcrantz reports research funding from GSK, outside the submitted work. Hani Hassoun reports grants from Celgene, Takeda, and Janssen, outside the submitted work. Neha Korde reports research funding through Amgen and participates in advisory board with Medimmune and honorariums for continuing medical education activity from MJH Life Sciences, outside of the submitted work. Alexander M. Lesokhin reports grants from Novartis, during the conduct of the study; grants from Bristol Myers Squibb; personal fees from Trillium Therapeutics; grants, personal fees and nonfinancial support from Pfizer; and grants and personal fees from Janssen, outside the submitted work. Alexander M. Lesokhin also has a patent US20150037346A1 with royalties paid. Sham Mailankody reports research funding from Allogene Therapeutics, Juno/Bristol Myers Squibb, Takeda Oncology, and Janssen Oncology; personal fees from Plexus communication, and Physician Education Resource, MJH Life Sciences outside the submitted work. Carlyn Tan reports other from Janssen Research and Development outside the submitted work. Saad Z. Usmani reports grant support from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX and Takeda; personal fees from Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda and TeneoBio; outside the submitted work. All the other co-authors have no relevant conflict of interest. Anita D'Souza reports institutional Research Funding: Abbvie, Takeda, Sanofi, Prothena, Caelum, TeneoBio, Janssen, Regeneron; Ad Board: BMS, Imbrium, Pfizer; Consulting: Janssen, Prothena. Please contact the corresponding author with data request. Figure S1. Kaplan Meier curve showing duration of treatment (2a) and overall survival (2b) in patients stratified by time between Isatuximab and Daratumumab therapy. Table S1. Baseline characteristics of patients. 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