Prospective Observational Study of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma: Microbiota Profiling and Cytokine Expression.

PURPOSE: Define incidence and risk factors of osteonecrosis of the jaw (ONJ) and explore oral microbial signatures and host immune response as reflected by cytokine changes in saliva and serum in multiple myeloma (MM) patients on bisphosphate (BP) therapy. PATIENTS AND METHODS: A single center observational prospective study of MM patients (n = 110) on >2 years of BP, none had ONJ at enrollment. Patients were followed every 3 months for 18 months with clinical/dental examination and serial measurements of inflammatory cytokines, bone turnover markers, and angiogenic growth factors. Oral microbiota was characterized by sequencing of 16S rRNA gene from saliva. RESULTS: Over the study period 14 patients (13%) developed BRONJ, at a median of 5.7 years (95% CI: 1.9-12.0) from MM diagnosis. Chronic periodontal disease was the main clinically observed risk factor. Oral microbial profiling revealed lower bacterial richness/diversity in BRONJ. Streptococcus intermedius, S. mutans, and S. perioris were abundant in controls; S. sonstellatus and S anginosus were prevalent in BRONJ. In the saliva, at baseline patients who developed BRONJ had higher levels of MIP-1ß; TNF-α and IL-6 compared to those without BRONJ, cytokine profile consistent with M-1 macrophage activation. In the serum, patients with BRONJ have significantly lower levels of TGF beta and VEGF over the study period. CONCLUSION: Periodontal disease associated with low microbial diversity and predominance of invasive species with a proinflammatory cytokine profile leading to tissue damage and alteration of immunity seems to be the main culprit in pathogenesis of BRONJ.

Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma.

Programmed death 1 (PD-1) receptor and its ligand (PD-L1) facilitate immune evasion in multiple myeloma (MM). We hypothesized that pembrolizumab, PD-1-antibody, can enhance antimyeloma cellular immunity generated by pomalidomide, leading to improved clinical responses. In this single-center, phase 2 study, 48 patients with relapsed/refractory MM (RRMM) received 28-day cycles of pembrolizumab, 200 mg IV every 2 weeks, pomalidomide 4 mg daily for 21 days, and dexamethasone 40 mg weekly. Patients had a median of 3 (range: 2-5) lines of therapy, median age 64 (range: 35-83) years, and had received both an immune modulatory drug (IMiD) and proteasome inhibitor: (35 [73%] of 48) were refractory to both; (31 [70%]) had received an autologous transplant, and (30 [62%]) had high-risk cytogenetics. Adverse events grade 3 to 4 occurred in (19 [40%] of 48 patients), including hematologic toxicities (19 [40%]), hyperglycemia (12 [25%]), and pneumonia (7 [15%]). Autoimmune events included pneumonitis (6 [13%]) and hypothyroidism (5 [10%]), mostly ≤ grade 2. Objective responses occurred in (29 [60%] of 48) patients, including stringent complete response/complete response (4 [8%]), very good partial response (9 [19%]), and partial response (16 [33%]); median duration of response was 14.7 months. At median follow-up of 15.6 months, progression-free survival (PFS) was 17.4 months and overall survival was not reached. Analyses of pretreatment marrow samples revealed a trend for increased expression of PD-L1 in responding patients and longer PFS with increased T-lymphocyte infiltrates, irrespective of PD-1 expression. Pembrolizumab, pomalidomide, and low-dose dexamethasone have acceptable safety and durable responses in RRMM patients. This trial was registered at www.clincialtrials.gov as #NCT02289222.

Disparities in black and white patients with multiple myeloma referred for autologous hematopoietic transplantation: a single center study.

BACKGROUND: Racial disparity in the incidence of multiple myeloma is well established; however, to the authors' knowledge, little is known regarding the impact of racial differences on disease characteristics, response to therapy, and clinical outcome. METHODS: The authors studied 453 patients (174 of whom were black and 279 of whom were white) who underwent transplant between 2000 and 2013. The median follow-up was 4.4 years. RESULTS: Black patients were significantly younger than white patients (median age, 54 years vs 59 years; P<.0001), more frequently presented with anemia (P = .04), had more of the immunoglobulin G isotype (P<.001), and had a borderline favorable cytogenetic risk (P = .06). Overall response to induction was similar, but deeper responses were observed in more white patients compared with black patients receiving immunomodulatory drug-based induction (P = .02). Referral for transplant was significantly delayed in black individuals (median, 1.3 years vs 0.9 years; P = .003). Overall survival from the time of transplant was similar for black and white patients, with medians of 6.2 years and 5.7 years, respectively, but survival from the time of diagnosis was significantly longer among black individuals (median, 7.7 years vs 6.1 years; P = .03). Maintenance therapy was found to positively impact progression-free survival but not overall survival, irrespective of race. CONCLUSIONS: The results of the current study confirm ethnic differences in age, referral patterns, response to therapy, and overall survival. Future validation of these disparities is urgently needed.

Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells.

PURPOSE: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells. EXPERIMENTAL DESIGN: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant. RESULTS: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%). CONCLUSIONS: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.

Evaluation of chemotherapy-induced peripheral neuropathy using current perception threshold and clinical evaluations.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is increasing with introduction of new and combination cancer pharmacotherapies. This study evaluated associations between clinical and self-report measurements and current perception threshold (CPT), a neuroselective measure of sensory nerve function that may detect asymptomatic CIPN damage. METHODS: Data for this secondary analysis were from a prospective, observational study using CPT to evaluate CIPN. Bivariate mixed models, accounting for the intraclass correlation between repeated patient assessments, were used to assess the relationship between CPT at each frequency (5, 250, and 2,000 Hz) and each subjective measure (Neuropathic Pain Scale, FACT-GOGntx) and objective measurement (quantitative sensory testing, deep tendon reflexes, and grip strength). RESULTS: A total of 29 chemotherapy-naïve subjects with various cancer types had a mean age of 56.7 (SD 10.4); nine subjects developed CIPN grade >1 using NCI CTC-AE criteria. Cold detection thresholds were inversely associated with CPT 5 [b(95 % CI) = -2.5(-4.5, -0.5)] and CPT 2,000 [-7.5(-11.8, -3.3)] frequencies. FACT GOG-ntx quality of life (QoL) scale and neurotoxicity and function subscales were inversely associated with CPT 2,000 [-1.8 (-3.5, -0.05), -2.2 (-4.2, -0.2), and -5.4 (-9.8, -0.9), respectively], indicating worsening QoL, impairment, and function as hypoesthesia increases. CONCLUSIONS: CPT 2,000 may identify impending worsening of patient-reported outcomes such as QoL.

Subcutaneous administration of bortezomib: strategies to reduce injection site reactions.

Bortezomib (Velcade) is approved by the FDA for IV or SC injection in select patients with multiple myeloma or mantle cell lymphoma. The SC route functions as an alternative to IV administration for patients with poor IV access. Learn about effective strategies used to reduce injection site reactions that can occur with SC delivery.

Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma.

In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.

Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells.

PURPOSE: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant. EXPERIMENTAL DESIGN: In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26). RESULTS: The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients). CONCLUSIONS: Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.