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Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.

Background: Peripheral neuropathy occurs in 20-25% of patients with an IgM paraprotein and 40-50% of patients with an IgM monoclonal gammopathy have a detectable anti-myelin associated glycoprotein (MAG) antibody. The presence of an anti-MAG antibody is often associated with a chronic, progressive symmetric demyelinating polyneuropathy that can lead to sensory deficits and gait dysfunction, significantly altering a patient’s quality of life. Prior clinical trials have failed to demonstrate an effective long-term therapy for anti-MAG neuropathy. Additionally, the best manner to assess the evolution of this type of neuropathy has not been elucidated. We designed this clinical trial to evaluate a potential therapy for anti-MAG related neuropathy based on previous reports of subjective improvement in patients with anti-MAG neuropathy treated with rituximab or Bruton’s tyrosine kinase inhibitors. We included multiple neurologic outcome measures so their responsiveness and performance could be assessed in a clinical trial setting. Methods: This is a single-arm open-label phase II trial investigating the use of acalabrutinib and an anti-CD20 monoclonal antibody for the treatment of an IgM-associated anti-MAG mediated neuropathy. Eligible patients must have positive anti-MAG antibody titers with an IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia (WM). Patients must have a predominantly sensory neuropathy characterized by demyelinating features in nerve conduction studies with a modified Rankin score of ≥1 with progressive symptoms or a modified Rankin score of ≥2. The ECOG performance status must be ≤2. Acceptable organ and marrow function are required. Prior exposure to chemotherapy, Bruton Tyrosine Kinase inhibitors, or other therapies for WM are not permitted except for steroids, IVIg, or an anti-CD20 monoclonal antibody given at least 90 days before study drug initiation. Approximately 33 patients will be enrolled in this study. Patients will be treated with acalabrutinib 100 mg orally twice daily on days 1-28 of each cycle and treatment will be administered until disease progression or unacceptable toxicity. Rituximab (or a biosimilar) will be administered on days 1, 8, 15, and 22 of cycles 1 and 4. The primary endpoint of this trial is to evaluate the overall hematologic response rate (defined as ≥25% reduction in serum IgM) associated with the treatment. The key secondary endpoint is to evaluate the proportion of patients that achieve improvement or stability in neuropathic symptoms based on the Inflammatory Rasch-built Overall Disability Scale (I-RODS) patient-reported disability scale. Additional secondary neurologic endpoints include the INCAT disability score, exam-based outcomes (the MRC distal sum score and INCAT-ISS), measures of function (10-meter walk test, 9-hole peg test), a pain scale, a fatigue scale (FSS), and a neuropathy-specific quality of life scale (IN-QOL). Additional secondary endpoints include time to next treatment, overall survival, hematologic response based on MYD88 and CXCR4 mutational status, change in bone marrow disease burden, and proportion of adverse events associated with treatment. This study is currently open and accruing patients. Clinical trial information: NCT05065554 Sponsor: AstraZeneca Citation Format: Shayna Sarosiek, Christopher T. Doughty, Andrew Branagan, Catherine A. Flynn, Kirsten Meid, Timothy P. White, Megan Little, Carly Leventoff, Steven P. Treon, Jorge J. Castillo. Phase II study of acalabrutinib and an anti-CD20 monoclonal antibody in patients with anti-MAG mediated neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT550.

Multiple myeloma is a malignant plasma cell neoplasm that is incurable despite significant progress in treatment over the past several decades. The incorporation of novel agents and combinations into the MM treatment paradigm has resulted in improved survival and tolerability, as well as deeper responses including achieving a minimal residual disease negative state. The addition of new treatment options and combinations has added complexity in treatment selection for myeloma patients. The current strategy for newly diagnosed myeloma involves induction, consolidation, and maintenance therapy. However, nearly all myeloma patients will develop refractory disease. This highlights the need for more effective therapies targeting the myeloma cells and their microenvironment. In this article, we summarize current management of transplant eligible and ineligible newly diagnosed patients in both the upfront and relapsed refractory setting, highlighting risk adapted strategies. We also summarize emerging therapies, such as immune and targeted approaches, as well as drugs with novel mechanisms of action. Emerging strategies offer individualized treatment options and may ultimately offer the possibility of a cure for myeloma patients.

Fludarabine and rituximab are commonly used in combination in the treatment of Waldenstrom’s macroglobulinemia (WM), though long term outcome of this regimen remains to be defined. We therefore examined the outcome of 43 WM patients treated on a clinical trial whose eligibility included < 2 prior therapies, and no previous nucleoside analogue or rituximab treatment. Therapy consisted of 6 cycles (25 mg/m2/day for 5 days) of fludarabine and 8 infusions (375 mg/m2/week) of rituximab over 31 weeks. 43 patients were enrolled with a median age of 61, and median prior therapies of 0. Responses were: CR (n=2); VGPR (n=14); PR (n=21); MR (n=4); for an overall and major response rate of 95.3% and 86.0%, respectively. At best response, median bone marrow disease involvement declined from 55% to 5% (p88.3 vs. 36.9 months; p=0.049). Grade ≥ 3 toxicities included neutropenia (n=27); thrombocytopenia (n=7); pneumonia (n=6), including two patients who succumbed to non-PCP interstitial pneumonia; peripheral neuropathy (n=2); limbic encephalitis (n=1); hemolytic anemia (n=1). With a median follow-up of 40.3 months, we observed transformation to aggressive lymphoma (n=3); myelodysplasia (n=1); acute myelogenous leukemia (n=2); bladder carcinoma (n=1); and carcinoma of unknown primary (n=1) among 8 patients. The results of this study demonstrate that fludarabine and rituximab is an active regimen in WM, though short and long term toxicities need to be carefully weighed against other available treatment options.

Waldenstrom’s macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, we have observed unusual response activity in five WM patients which appears related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, while four other patients demonstrated less dramatic, but also unexpected responses associated with sildenafil used at doses of 25–50 mg once to twice a week. In view of these observations, we next evaluated sildenafil for its ability to induce apoptosis of lymphoplasmacytic cells obtained from WM patients. All patients provided written consent for this study which was approved by our institutional review board. Sorted (CD19+, light chain restricted) bone marrow lymphoplasmacytic cells obtained from 6 WM patients were cultured in media alone or with sildenafil (kindly provided by Pfizer Pharmaceuticals, Inc.) at 0.01 ug/ml for 24 hours. These studies demonstrated a mean 2.1 (range 1.24–4.8) fold increase in sildenafil specific/spontaneous apoptosis in lymphoplasmacytic cells from 5 of 5 patients, which included those from a patient who demonstrated a clinical response to sildenafil. Importantly, the concentrations at which apoptosis was observed in these studies is within pharmacologically achievable levels for sildenafil. The results of these studies, along with those recently reported by Sarfati et al (Blood 101:265) who demonstrated caspase mediated apoptosis of B-chronic lymphocytic leukemia (CLL) cells by sildenafil, provide the framework for investigation of sildenafil and related phosphodiesterase inhibitors in the treatment of WM and other B-cell malignancies.

Rituximab and thalidomide are active agents in Waldenstrom’s macroglobulinemia (WM) producing major response rates of 25–50%. Moreover, as previously shown by us, thalidomide enhances rituximab mediated ADCC killing of lymphoplasmacytic cells (Blood 100:314b). As such, we conducted this phase II study using combination rituximab and thalidomide in WM patients who previously had not received rituximab or thalidomide. Intended therapy was as follows: Weeks 1–52 Thalidomide (200 mg po qhs for 2 weeks, then 400 mg po qhs) Weeks 2–5 Rituximab (375 mg/m2/week) Weeks 13–16 Rituximab (375 mg/m2/week) Patients were evaluated at week 12, and if they had at least stable disease (SD) were eligible for further therapy and for response evaluation. Dose modifications, delay, and/or discontinuation of thalidomide were permitted for toxicities. Twenty-five patients have been enrolled, 20 of whom were previously untreated. Six patients are off study, 4 because of no response and 2 because of deaths unrelated to protocol therapy. Grade 3/4 toxicities to thalidomide included neuropathy (n=15); somnolence or confusion (n=12); rash (n=7); tremors (n=2); bradycardia (n=2); other (n=3); and led to its eventual discontinuation in 11/19 patients. All evaluable patients received the intended rituximab therapy. Paradoxical IgM spikes following rituximab occurred during both courses of therapy and were observed in 12/25 (48%) patients similar to those spikes which we reported with rituximab monotherapy (ASH2003; 102:690a). Responses to date among the 23 evaluable patients are as follows: CR (n=1); PR (n=12); MR (n=2); SD (n=4). Four patients had no response to therapy. No patients with stable disease or better have progressed with a median follow-up of 10 months (range 6–13 months). Response to therapy is associated with cumulative dose of thalidomide. Patients who responded to therapy received a median thalidomide cumulative dose of 37,600 (range 5700–74,500) mg as compared to 5,650 (range 2100–21,000) mg among non-responding or stable disease patients. These studies demonstrate that thalidomide in combination with rituximab is active in WM, and associated with the cumulative dose of thalidomide. In view of the encouraging response rates obtained with this combination and the potential for improved toxicity profile, a phase II study examining the thalidomide analogue CC-5013 (Revlimid) plus rituximab is planned.