Retreatment of Multiple Myeloma with Previously Refractory Drugs [Retrospective study]

Highlight(s): Retreatment with previously refractory drugs is a viable option for late-line relapsed/refractory multiple myeloma (RRMM). Patients with a longer gap between the initial line of therapy with index drug and retreatment had superior outcomes with retreatment.

In this retrospective study, the authors describe 315 patients with RRMM  who were retreated with a drug that the disease had been previously refractory to. Subsequent retreatment was most frequently with lenalidomide (n= 143, 45%), followed by bortezomib (n= 95, 30%), pomalidomide (n= 36, 11%), daratumumab (n= 19, 6%), ixazomib (n= 7, 2%), and carfilzomib (n=5,2%). The remaining 10 patients (3%) were retreated with cyclophosphamide, thalidomide, or selinexor.

They found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS 16.9 months vs. 8.1 months, p<0.001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had a better PFS with retreatment (28.2 vs. 8.9 months, p=0.016).

Prognostic risk and survival of asymptomatic IgM monoclonal gammopathy: Results from a Spanish Multicenter Registry [Retrospective study]

Highlight(s): Here, the authors describe the risk of progression of patients with asymptomatic IgM gammopathy and propose a prognostic model for patients with or without a bone marrow (BM) evaluation, highlighting the presence of a very low‐risk group. In addition, they demonstrated that the relative mortality of these patients was different from that of those with symptomatic Waldenström macroglobulinemia (WM). 

Here, the authors assessed the risk of progression and the mortality of 956 patients with asymptomatic IgM gammopathy across 25 Spanish centres. After a median follow‐up of 5.7 years, 156 patients progressed, most of them to symptomatic WM. The cumulative incidence of progression was 13% and 20% at 5 and 10 years, respectively. The serum IgM ≥10 g/L, BM infiltration ≥20%, β2‐microglobulin ≥3 mg/L, and albumin <4 g/dL (abbreviated to the “10‐20‐3‐4” model, relating to numbers from the cutoff values for each biomarker) were the most potent predictors of disease progression in a multivariate Cox regression model, allowing the identification of three risk categories. The probability of progression to symptomatic disease at 5 years was 4.5%, 15.7%, and 42.8% for low‐, intermediate‐, and high‐risk groups, respectively. In patients without a BM evaluation, presence of none or 1 risk factor and 2 or 3 risk factors conferred a progression risk of 6% and 27% at 5 years, respectively. The model was independent of the presence of MYD88 L265P mutation, which conferred a negative impact only in asymptomatic WM patients. The relative survival (RS) ratio at 5 years of asymptomatic patients was similar to the Spanish population, which contrasted with the 0.76 5‐year RS of symptomatic WM patients. After fitting a logistic regression model to evaluate the discrimination between the Dana Farber Cancer Institute risk model versus this, they observed that the ROC area was 0.76 versus 0.79 (p = 0.025) at 5 years of follow‐up, respectively.

How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms [Review]

Cytoreductive and antithrombotic drugs are two complementary levers to reduce thrombotic risk. The long-term antithrombotic strategy will be tailored to the specific type of initial thrombosis, the underlying type of myeloproliferative neoplasm (MPN), and the individual bleeding risk.

The figures in the original article summarise practically the antithrombotic therapeutic approach as follows:

Cytoreductive treatment goals:

●      In essential thrombocythemia and pre-primary myelofibrosis patients: Platelets <400 x 10^9/L

●      In polycythemia vera patients: Hematocrit <45%

●      In primary myelofibrosis patients: Platelets <400 x 10^9/L and Hematocrit <45%

●       

Scenarios:

1.  How we manage arterial thrombosis in an MPN patient who has already been treated by cytoreductive therapy and aspirin

●      Ischemic stroke or transient ischemic attack:

         -      0 to 3 months: Discuss single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) per neurology guidelines.

         -      More than 3 months: Indefinite low-dose aspirin

●      Acute coronary syndrome:

         -      0 to 12 months: Start DAPT (aspirin + P2Y12 inhibitor)

         -      More than 12 months: Indefinite low-dose aspirin

●      Peripheral arterial disease with acute limb ischemia:

         -      0 to 6 months: Multidisciplinary consultation to assess the need for revascularization and evaluate antithrombotic treatment

         -     More than 6 months: Indefinite low-dose aspirin

2. How we manage venous thrombosis in a newly diagnosed MPN patient (outside splanchnic vein thrombosis).

●      Superficial venous thrombosis: 

         -      0 to 45 days: Fondaparinux 2.5 mg daily; if cell blood counts are uncontrolled, continue for 3 months.

         -      More than 3 months: Indefinite low-dose aspirin

●      Distal deep vein thrombosis:

         -     0 to 6 months: therapeutic dose anticoagulation.

         -      More than 6 months: Indefinite low-dose aspirin

●      Proximal deep vein thrombosis and pulmonary embolism (PE):

         -      0 to 6 months:  Therapeutic dose anticoagulation

         -      More than 6 months: MPN controlled?

                  *     Yes: evaluate the bleeding risk:

                           +     Bleeding symptoms or patient at high risk of bleeding: Discuss low-dose direct oral anticoagulant (DOAC) or indefinite low-dose aspirin.

                           +      No bleeding symptoms and patient without risk factors for bleeding: Therapeutic dose anticoagulation. Low-dose DOAC should be evaluated in prospective clinical trials.

                 *      No: therapeutic dose anticoagulation until the disease is controlled.

●      Life-threatening PE:

         -      0 to 6 months:  Therapeutic dose anticoagulation

         -      More than 6 months: Long-term therapeutic dose anticoagulation.

3. How we manage thrombosis (with exclusion of splanchnic vein thrombosis) in an MPN patient who has already been treated by cytoreductive therapy and aspirin

●      Arterial thrombosis: 

        -      Screen for an occult cancer

        -      Multidisciplinary consultation to evaluate the need for antithrombotic strategy modification

        -      Potential options:

                 *      Switch to another antiplatelet agent.

                 *      DAPT

                 *      SAPT and low-dose DOAC

●      Venous thrombosis:

        -      Screen for an occult cancer

        -      Stop aspirin and start therapeutic anticoagulation (Low-molecular-weight heparin/vitamin K antagonist  or DOAC) for 6 months.

        -      Life-threatening PE?

                *      Yes: Long-term therapeutic dose anticoagulation.

                *      No:  Was MPN controlled at the time of thrombosis?

                         +      Yes: Long-term therapeutic dose anticoagulation.

                         +      No: If MPN is controlled after 6 months of anticoagulation, evaluate the bleeding risk and discuss antithrombotic treatment (see Figure 2 in Review Article).

JAK2-mutant clonal hematopoiesis is associated with venous thromboembolism [Retrospective study]

Highlight(s): JAK2-mutant clonal hematopoiesis is associated with substantial risk of venous thromboembolism (VTE). JAK2-mutant clonal hematopoiesis of indeterminate potential (CHIP) confers a greater risk of VTE than heterozygous thrombophilia but is present at a lower frequency in the general population.

The authors evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400,000 samples from the UK Biobank.  CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1.17 (95% confidence interval [CI], 1.09-1.3; P= 0.002) but was not significantly associated with prevalent VTE with an odds ratio (OR) of 1.02 (95% CI, 0.81-1.23; P = 0.81). TET2-mutant CHIP was associated with incident VTE with an HR of 1.33 (95% CI, 1.05-1.69; P = 0.02). JAK2 mutations were highly associated with both prevalent and incident VTE risk, with an OR of 6.58 (95% CI, 2.65-16.29; P = 4.7 x 10^–5) and an HR of 4.2 (95% CI, 2.18-8.08; P = 1.7 x 10^-5), respectively, consistent with the thrombophilia associated with JAK2-mutant MPN.  The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed MPN based on laboratory parameters. JAK2-mutant CHIP was more strongly associated with VTE but was less common than VTE associated with heterozygous factor V Leiden and heterozygous prothrombin gene mutation. The prevalence of JAK2-mutant CHIP in this study was 0.02%. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but individuals with JAK2-mutant CHIP have a significantly elevated risk of developing VTE. Individuals with JAK2-mutant CHIP may have VTE events in unusual locations, such as splanchnic vein thrombosis, based on data from the UK Biobank.

Prevention and Treatment of Cancer-Related Infections, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology [Guideline]

This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to chimeric antigen receptor (CAR) T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

CAR T-cell products confer a risk of potentially life-threatening immunologic toxicities, like neutropenia, lymphopenia, and hypogammaglobulinemia, and thus may increase the risk of infection in patients. The highest risk for infection occurs within the first 30 days of administration of CAR T-cell therapy, and bacterial infections predominate during this period. Opportunistic infections can be expected, and prophylaxis, particularly for the prevention of Pneumocystis jirovecii pneumonia (PJP), herpes simplex virus (HSV), and varicella zoster virus (VZV), is warranted until immune reconstitution.

Preinfusion risk factors for infection include certain underlying malignancies, prior lines of therapy with or without autologous/allogeneic hematopoietic cell transplantation, antecedent infection, and neutropenia. Risk factors post-infusion may include prolonged neutropenia, cytokine release syndrome/immune effector cell associated neurotoxicity syndrome and associated treatment (e.g., high-dose steroids, IL-6 inhibitors), lymphopenia, and hypogammaglobulinemia. Beyond day +30, respiratory viral infections predominate. Fungal infection risk remains low but may vary based on prior therapies, degree of immunosuppression, and other relevant risk factors.

Relevant serologic screening for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus is recommended. Moreover, cytomegalovirus and additional screening may be considered based on epidemiologic risks. Antibacterial and antifungal prophylaxis can be considered for neutropenic patients. PJP and HSV/VZV prophylaxis are recommended.

See Figure 1 in the original paper