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Multiple myeloma (MM) patients are at higher risk for severe COVID-19. Their mRNA vaccination response against SARS-CoV-2 is unknown. Thus, we analyzed responses to mRNA vaccination against COVID-19 among these patients. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined serum antibody levels prior to immunization and 12–21 and 14–21 days following the first and second vaccinations, respectively, with mRNA-1273 (Moderna) or BNT162b2 (Pfizer/BioNTech) among 103 MM patients (96 and 7 with active and smoldering disease, respectively). We stratified patients into clinically relevant responders (>250 IU/mL), partial responders (50–250 IU/mL, which was above pre-COVID-19 background), and nonresponders ( second line of treatment, and among those not in complete remission. Patients who received mRNA-1273 vaccine had higher anti-spike antibody levels than those who were vaccinated with BNT162b2. Thus, most MM patients have impaired responses to mRNA vaccination against COVID-19, and specific clinical and myeloma-related characteristics predict vaccine responsiveness.

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.

We have reported that IgG antibody responses following two mRNA COVID-19 vaccinations are impaired among patients with multiple myeloma (MM). In the current study, sixty-seven patients with MM were tested for anti-spike IgG antibodies 0-60 days prior to their first vaccination, 14-28 days following the second dose, and both before and 14-28 days after their third dose of the mRNA-1273 or BNT162b2 vaccines. After the first two doses, most patients' (93 %) antibody levels declined to ineffective levels (250 BAU/mL) prior to their third dose (D3). D3 elicited responses in 84 % of patients (61 % full response and 22 % partial response). The third vaccination increased antibody levels (average = 370.4 BAU/mL; range, 1.0-8977.3 BAU/mL) relative to just prior to D3 (average = 25.0 BAU/mL; range, 1.0-683.8 BAU/mL) and achieved higher levels than peak levels after the first two doses (average = 144.8 BAU/mL; range, 1.0-4,284.1 BAU/mL). D3 response positively correlated with mRNA-1273, a 10-fold change from baseline for the two-dose series, switching from BNT162b2 to mRNA-1273 for D3, and treatment with elotuzumab and an immunomodulatory agent. Lower antibody levels prior to D3, poorer overall response to first two doses, and ruxolitinib or anti-CD38 monoclonal antibody treatment negatively correlated with D3 response. Our results show encouraging activity of the third vaccine, even among patients who failed to respond to the first two vaccinations. The finding of specific factors that predict COVID-19 antibody levels will help advise patients and healthcare professionals on the likelihood of responses to further vaccinations.

Background Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. Methods A receiver operating characteristic curve was used to establish a definition for high risk baseline sBCMA. Mantel Byar analysis was used to examine if high risk sBCMA was correlated with shorter time to transformation, and a time dependent cox proportional hazard was used to determine if it is independent of other risk factors. A z-test for proportions was used to compare the percentage of patients that progressed among high risk versus low risk sBCMA patients. Results A baseline sBCMA level ≥ 137.5 ng/mL was found to be the optimal cut off between high and low risk SMM patients. Patients with high risk sBCMA levels had a shorter time to transformation (p = 0.000332). sBCMA was also higher at the time of transformation than baseline levels (p = 0.0116). sBCMA was the only variable found to be significantly predictive of time to transformation, and additionally was found to be independent of other risk factors. Conclusions In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

Introduction: Amid the current COVID-19 pandemic, the highest mortality rates are among the elderly and immunocompromised. Multiple myeloma (MM) patients are immunocompromised and often are elderly. Not only do MM patients develop more frequent infections, but it is one of the leading causes of death for these patients. This population develops more severe COVID-19 due to various mechanisms that impair their ability to fight infection. This also reduces their ability to generate immunity from vaccination, as has been demonstrated by their diminished responses to vaccines for various respiratory illnesses. It follows that while phase III trial results for mRNA1273 and BNT162b2 COVID-19 vaccines showed an efficacy of 94-95% against even mild infection with this virus, the efficacy has been shown to be lower among MM patients. We recently evaluated patients' antibody responses to vaccination for COVID-19 by measuring anti-spike IgG levels in patient serum from before vaccination (baseline) and two weeks after dose 2 (D2W2) of vaccination with mRNA-1273 or BNT162b2, and found that most MM patients have impaired responses (Stampfer et al., Leukemia 2021). Patients who received mRNA-1273 vaccine had higher antibody levels than those who were vaccinated with BNT162b2, and specific clinical and myeloma-related characteristics predicted vaccine responsiveness. In the current study, we are monitoring anti-spike IgG antibody levels at Dose 2 Week 8 (D2W8) and Dose 2 Week 16 (D2W16) post-mRNA vaccination among these patients and in age-matched healthy controls to investigate antibody decay. Methods: Participants in the trial included MM patients (n=91) at the Berenson Cancer Center, and age-matched healthy controls (n=27). Healthy subjects were not known to be immunocompromised or currently receiving immunosuppressive therapy. Vaccination was done outside of the clinic and subjects provided copies of their CDC-issued COVID-19 vaccination cards to confirm dosing dates. Sera from vaccinated individuals were drawn at baseline (0-60 days prior to first vaccine dose) and at intervals following their second dose (14-21, 56-70, and 112-126 days post-vaccination). Background levels were determined from the clinic's serum bank of healthy subjects drawn pre-April 2019. Using an ELISA-based assay that detects IgG antibodies to SARS-CoV-2 spike protein, we determined Anti-SARS-CoV-2 spike ectodomain serum antibody levels and quantified them in IU/mL based on the WHO International Standard 20/136. Results: We analyzed the patient and control populations, and specifically for those classified as responders from our original published study (D2W2 >50 IU/mL). All controls but only 70% of patients (64/91) were classified as responders, so this responder-specific analysis was only relevant for patients. There was a significant decline in anti-SARS-CoV-2 spike antibodies from D2W2 to D2W8 for both patients and controls; D2W16 results are pending. Median values dropped from 283.1 IU/mL to 90.9 IU/mL among patients, and 893.6 IU/mL to 354.4 IU/mL among controls. Median antibody levels among patients classified as responders dropped from 482.9 IU/mL to 145.5 IU/mL (p Conclusions: The markedly lower anti-spike antibody levels among MM patients compared to healthy controls at week 8 post-vaccination indicate that they remain at high risk for breakthrough infections. Combined with their rapid decline in anti-spike antibody levels over only a 6-week period, this indicates that even MM patients who responded initially to vaccination are likely to require boosters sooner than healthy individuals. This immunocompromised population remains at high risk even following vaccination and should continue to maintain social distancing precautions during periods of high local SARS-CoV-2 transmission. Disclosures No relevant conflicts of interest to declare.

Background: Anti-CD38 monoclonal antibodies have become a standard treatment option for patients with either relapsed/refractory (RR) or newly diagnosed multiple myeloma (MM). There are two approved drugs in this class, daratumumab and isatuximab. These agents have become a mainstay of myeloma treatment being used in a variety of combination approaches. Although they are widely used, very little has been reported regarding the benefit they provide if they are used again in subsequent lines of therapy among patients that have already been treated with prior anti-CD38 containing regimens. Methods: MM patients that were treated at the Berenson Cancer Center and previously received either daratumumab or isatuximab and were treated with another anti-CD38-containing combination were retrospectively analyzed. Response to each anti-CD38 regimen was evaluated for responses according to the International Myeloma Working Group (IMWG) criteria. We used Kaplan-Meier curves to determine progression free survival (PFS) and overall survival (OS). Results: There were 49 patients identified as having received > 2 anti-CD38 containing regimens. Among these patients, 40, 1, and 8 received only daratumumab, only isatuximab, or a combination of both anti-CD38 regimens. 17, 19, 8, and 41 received an IMiD, PI, a combination of both, or other combinations. Overall, the median PFS was 3.9, 3.2, 2.6, 1.9, and 1.5 months for the first (n=49), second (n=49), third (n=23), fourth (n=15), and fifth (n=8) exposures, respectively. For their first anti-CD38 containing regimen (n=49), the clinical benefit rate (CBR) and overall response rate (ORR) were 44.9% and 38.8%, respectively (7.7% MR, 34.7% PR, and 4.1% CR), and 36.7% showed SD. During their second exposure (n=49), the CBR and ORR were 42.9% and 40.8%, respectively (2.0% MR, 36.7% PR, 12.0% VGPR, and 2.0% CR) and 36.7% showed SD. The PFS among patients who were exposed to a second regimen and discontinued therapy without disease progression to their first anti-CD38 containing regimen was 5.9 months compared with only 3.0 months for those who progressed during their first regimen. OS from the start of anti-CD38 treatment was a median of 36.5 months (range, 1.8-56.5). OS was longer among patients who did not progress on first exposure with a median of 26.2 months (range, 1.8-56.5) compared to patients who progressed during their first regimen (median not yet reached; range, 7.6-54.5). PFS among patients treated with a proteasome inhibitor (PI)-containing combination in their first exposure was 8.7 months versus 4.5 months among patients who were treated with an immunomodulatory agent (IMiD)-containing treatment. Additionally, the PFS among patients treated with a PI versus an IMiD with their second exposure to an anti-CD38 containing regimen was 5.9 and 2.8 months, respectively. Conclusions: Our retrospective study suggests that RRMM patients who are retreated with another anti-CD38 containing regimens can continue to respond after multiple exposures to this drug class. The ORR differs little during the first two exposures to these agents for RRMM patients. To our knowledge, this study provides support for retreatment of RRMM patients with anti-CD38 containing regimens. Additional studies are planned to further investigate this patient population. Disclosures Vescio: Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; GlaxoSnithKlein: Speakers Bureau; Amgen: Speakers Bureau.