Cellectar Biosciences Announces EMA Eligibility for Conditional Marketing Authorization of Iopofosine I 131 for Refractory Waldenstrom Macroglobulinemia
Cellectar Biosciences announced that the European Medicines Agency (EMA) has confirmed the eligibility to file for Conditional Marketing Authorization...
Breakthrough Clinical Results
Cellectar Biosciences announced that the European Medicines Agency (EMA) has confirmed the eligibility to file for Conditional Marketing Authorization (CMA) for iopofosine I 131 as a treatment for post-BTKi refractory Waldenstrom macroglobulinemia (WM). The submission of the CMA application is expected in early 2026, with potential approval and commercial launch in Europe in 2027. Iopofosine I 131 has been granted PRIME designation from the EMA for the treatment of patients with WM who received at least two prior lines of therapy. The decision follows advice from the Scientific Advice Working Party (SAWP) of the EMA, based on the CLOVER WaM Phase 2 study results.
Key Highlights
- EMA confirms eligibility to file for Conditional Marketing Authorization (CMA) for iopofosine I 131 for post-BTKi refractory Waldenstrom macroglobulinemia (WM).
- CMA application submission expected in early 2026, with potential European approval and commercial launch in 2027.
- Iopofosine I 131 has been granted PRIME designation from the EMA for WM patients who received at least two prior lines of therapy.
- CLOVER WaM study demonstrated an overall response rate (ORR) of 83.6% and a major response rate (MRR) of 58.2%.
Incidence and Prevalence
Latest Estimates of Waldenstrom Macroglobulinemia Incidence and Prevalence
The most recent data on Waldenstrom Macroglobulinemia (WM) comes from a 2021 study using a national population-based database in Korea. This study provides valuable insights into the epidemiology of this rare condition, particularly in Asian populations.
Incidence and Prevalence in Korea
The incidence of WM in Korea increased from 0.03 to 0.10 per 10 between 2003 and 2016, showing a rising trend over this period. The prevalence was measured at 0.42 per 10 in 2016.
During the study period, 427 patients were newly diagnosed with WM, with a notable male-to-female ratio of 3.2:1, indicating a significant gender disparity in disease occurrence.
Mortality and Survival
The study reported that 217 patients with WM died during the study period, with a standardized mortality ratio of 7.57. The overall survival rate was 47.5%. Older age was identified as a significant factor associated with worse overall survival (P < 0.0001) in multivariate analysis.
WM was the most common cause of death among these patients (n = 102, 48.6%), followed by other malignant neoplasms (n = 82, 39.0%).
Geographic and Ethnic Variations
A key finding from this research is that the national incidence of WM in Korea, described as "a racially homogeneous country in Asia," was lower than that in previous reports from other countries, highlighting ethnic disparities in WM occurrence.
Despite the lower incidence, researchers noted that "the incidence increased, and mortality was the highest ever reported," emphasizing "the need for greater awareness of WM, particularly in Asian countries."
Global Context
The study suggests significant geographic and ethnic variations in WM epidemiology globally. While specific global estimates beyond Korea were not provided, the research highlighted that WM incidence appears to be lower in Asian populations compared to other regions.
This data contributes to our understanding of the global distribution of WM and underscores the importance of considering ethnic factors in the epidemiology of this rare condition.
Key Unmet Needs and Target Populations for Waldenstrom Macroglobulinemia
Based on recent research, several unmet needs exist in the management of Waldenstrom Macroglobulinemia (WM):
- Current treatment options do not result in cure
- For symptomatic Waldenstrom's disease, the primary goal of treatment is to keep the disease under control for as long as possible without impairing the patient's quality of life
- Evidence-based treatment decisions in Waldenstrom's macroglobulinemia currently rely mainly on small-scale, single-armed trials
- Patients with this disease should be treated in the setting of a clinical trial whenever possible
- There is a need for trials aimed at improving the quality of treatment for other IgM-associated diseases, such as IgM neuropathies and cold agglutinin disease
The limited evidence base from large-scale clinical trials represents a significant challenge in optimizing care for WM patients. The focus on maintaining disease control while preserving quality of life highlights the chronic nature of this condition and the importance of treatment approaches that balance efficacy with tolerability.
The recommendation for treatment within clinical trials underscores the ongoing need for research to develop more effective therapies. Additionally, the recognition of related IgM disorders indicates the potential benefit of broader research approaches that address the spectrum of IgM-associated conditions.
Study Design Parameters
Study Design Parameters and Endpoints in Key Waldenstrom Macroglobulinemia Trials
Major Clinical Trials
iNNOVATE Trial
- Double-blind, randomized, placebo-controlled phase III study
- Compared ibrutinib-rituximab versus placebo-rituximab
- Enrolled patients with confirmed symptomatic WM, either previously untreated or previously treated
- Randomized to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n=75 per arm)
- Primary endpoint: progression-free survival (PFS)
- Secondary endpoints: response rate, time to next treatment, hemoglobin improvement, overall survival, and safety
- Median follow-up of 50 months
ASPEN Phase III Study
- Included 201 patients with MYD88-mutant WM in cohort 1 (102 receiving zanubrutinib, 99 receiving ibrutinib)
- Cohort 2 included 28 patients with MYD88 wild-type WM
- Primary endpoint: sum of very good partial response (VGPR) + complete response (CR) rates
Acalabrutinib Trial
- Single-arm, multicenter, phase 2 trial conducted in 19 European and 8 US academic centers
- Included both treatment-naive patients and relapsed/refractory patients
- Primary endpoint: investigator-assessed overall response (at least a minor response)
Atacicept Trial
- Open-label phase-I study with 16 patients (12 MM, 4 WM) with advanced disease
- Treatment: one cycle of five once-weekly subcutaneous injections of atacicept
- Endpoints: safety, tolerability, and disease progression
Orelabrutinib Trial
- Evaluated in 47 eligible patients with relapsed/refractory WM
- Primary endpoint: major response rate (MRR) assessed by Independent Review Committee
- Median follow-up of 16.4 months
Response Criteria and Endpoints
Common Primary Endpoints
- Progression-free survival (PFS)
- Overall response rate (ORR)
- Major response rate (MRR)
- Very good partial response (VGPR) + complete response (CR) rates
Secondary Endpoints
- Time to next treatment
- Hemoglobin improvement
- Overall survival
- Safety outcomes
- Response duration
Safety Assessment
- Adverse events grading
- Specific toxicities: atrial fibrillation, neutropenia, bleeding events
- Serious adverse events
Prognostic Factors and Stratification
Genetic Factors
- MYD88 and CXCR4 mutation status impact response rates
- Different MRRs observed: 84.6% for MYD88+/CXCR4-, 100% for MYD88+/CXCR4+, and 25.0% for MYD88-/CXCR4-
Prognostic Scoring Systems
- International Prognostic Scoring System for WM (ISSWM) identifies five adverse covariates
- Modified Staging System for WM (MSS-WM) uses age, albumin, and LDH to stratify patients
Treatment Approaches
- BTK inhibitors (ibrutinib, zanubrutinib, acalabrutinib) show overall response rates higher than 90%
- Ibrutinib was the first BTK inhibitor to receive FDA approval for WM in 2015
- Zanubrutinib is the most recently FDA-approved therapy with comparable efficacy but improved side effect profile
- Standard-of-care options include bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC)
