Activity of CAR T-cells and bispecific antibodies in multiple myeloma with extramedullary involvement [Retrospective study]

Highlights:

●      Extramedullary multiple myeloma (EMD) is associated with low response rates, short progression-free survival, and poor prognosis.

●      Chimeric antigen receptor (CAR) T cells and bispecific antibodies (bsABs) have shown efficacy in relapsed myeloma, but it remains uncertain whether one T cell redirection strategy should be preferred.

●      With significantly higher response rates, deeper remissions, and longer median progression-free survival (mPFS), these retrospective data suggest CAR T cells may provide a meaningful benefit in EMD.

The authors retrospectively analyzed data from 80 patients with EMD not adjacent to the bone treated with ide-cel, cilta-cel, teclistamab, or talquetamab at three academic centers in Germany. All patients were heavily pretreated, and a high-risk cytogenetic profile was prevalent in >41% of patients. All cohorts had a median of 5 to 7 prior lines of therapy. The vast majority of patients receiving cilta-cel, ide-cel, or teclistamab were BCMA-naive (>88%). Response rates after CAR T cell infusion were significantly higher (100% with cilta-cel, 82% with ide-cel) than with bsABs (29% for talquetamab, 36% for teclistamab). Complete resolution of EMD was more frequent after CAR T cell therapies (50% and 41%) than after bsABs (16% and 14%). With a median follow-up of 12.2 months, median PFS was not reached in patients that had received cilta-cel; mPFS was 7.3 months after ide-cel and significantly longer for both CAR T cell products compared to talquetamab or teclistamab (mPFS 4.0 and 2.6 months). Effective debulking therapy prolonged remissions after CAR T cell infusion compared to no debulking or no response to debulking.

Defining Bloodstream and Central Venous Catheter-Related Infections in Patients Following Haematopoietic Cell Transplantation: Position Paper of the EBMT  Infectious Diseases Working Party and Practice Harmonization and Guidelines Committee [Consensus]

Key points: See Table 2 in original article.

●      Definite bloodstream infection (BSI):

○      One positive blood culture or non-culture based microbiologic testing (NCT) with non-commensal. 

○      Two separate positive blood cultures with commensal pathogens (same genus and species; such as coagulase-negative staphylococci (coagulase-negative staphylococci [CoNS], Bacillus spp., Micrococcus spp. or Propionibacterium spp.) with the same susceptibility profile if tested in the presence of any sign of deterioration in patient clinical condition that can be compatible with infection, or increase in inflammation markers (per local protocol).

●      Probable BSI: One positive blood culture with viridans group streptococci (VGS) in the presence of any sign of clinical or laboratory deterioration compatible with infection.

●      Definite BSI of presumed mucosal barrier injury (MBI) source:

○      One positive culture or NCT with intestinal pathogen (the following pathogens are excluded as primary bloodstream infection pathogens as they are eligible for use in secondary BSI determinations: Campylobacter, Salmonella, Shigella, Listeria, Vibrio and Yersinia as well as C. difficile, Enterohemorrhagic E. coli, and Enteropathogenic E. coli) in a patient with appropriate clinical context.

■     Appropriate clinical context includes at least one among:

1) Allogeneic stem cell transplantation with gastro-intestinal graft-versus-host disease (GVHD) grade III-IV OR ≥1 liter diarrhea in a 24-hour period with onset on or within the 7 calendar days before the date the positive blood specimen was collected.

■     To address the rare situations when the severe GVHD is present more than one year after hematopoietic stem cell transplantation (e.g. secondary GVHD following donor lymphocyte infusion), the authors suggest removing the cutoff "≤1 year" from the definition of the MBI.

■     2) Neutropenia: 2 separate days with <500 cells/mm³ within 3 calendar days before and the 3 calendar days after sample collection.

○      2 or more positive blood cultures with VGS and/or Rothia spp. in the presence of any clinical or laboratory sign compatible with infection in patients with an appropriate clinical context.

●      Probable BSI of presumed MBI source: One positive blood culture with VGS in the presence of any sign of clinical or laboratory deterioration compatible with infection in patients with an appropriate clinical context.

●      Definite catheter-related BSI (CRBSI):

○      Pathogen grows from a culture of the catheter tip AND same pathogen (genus and species) from at least 1 percutaneous blood culture + in vitro susceptibility testing results in the same resistance pattern (if done in both isolates).

○      If semiquantitative or quantitative cultures were performed – they shall meet criteria: semiquantitative (>15 colony forming units [CFU] per catheter segment) or quantitative (>10² CFU per catheter segment).

○      2 blood cultures (from a catheter hub and percutaneous) with the same pathogen. If quantitative criteria with a ratio of >3:1 CFU/mL of blood (catheter vs. percutaneous) OR if meet differential time to positivity (DTTP) criteria  (growth in a culture of blood obtained through a catheter hub is detected by an automated blood culture system at least 2 hours earlier than a culture of simultaneously drawn peripheral blood of equal volume).

●      Probable CRBSI:

○      2 blood cultures (from a catheter hub and percutaneous) with the same pathogen: CoNS, S. aureus, Candida parapsilosis, Bacillus spp., Micrococcus spp., or Propionibacterium spp.

AND do not meet quantitative/DTTP criteria (or not performed)

AND other sources excluded.

○      Pathogen detected in blood cultures (catheter only or percutaneous only if drawing blood cultures from central catheter is impossible) that typically causes CRBSI:

■      At least two positive blood cultures for the same genus and species CoNS, Bacillus spp., Micrococcus spp., or Propionibacterium spp. cultures (same genus and species) with the same susceptibility profile if identified in both.

■      Single positive blood culture with S. aureus and Candida parapsilosis with the absence of another plausible source.

Management recommendations for kidney transplantation in patients with plasma cell dyscrasia [Opinion-based recommendations]

Key points: See Table 1 in original article.

●      Pre-kidney transplant requirement:

○      Confirm candidacy based on selection criteria:

■      High risk, interphase fluorescence in situ hybridization and minimal residual disease positive: no kidney transplant (see Figure 2 in original article).

○      Avoid positive crossmatch and ABO incompatible transplant if possible

○      Living donor kidney transplant (LDKTx): Bone marrow (BM) assessment within 3 months and serum free light chain (sFLC) within 4 weeks of transplant

○      Deceased donor kidney transplant (DDKTx): BM assessment within 6 months and sFLC within 3 months of transplant

○      Hematological assessment (sFLC, serum protein electrophoresis [SPEP]/immunofixationI [IFx]) every 3 months while on waitlist

○      Hold Immunomodulatory drugs (IMiD) 4 weeks and Proteasome Inhibitors (PI)/Daratumumab 2 weeks prior to transplantation if possible

●      Post-kidney transplant management:

○      Induction therapy as per transplant centers

○      Consider thromboprophylaxis (e.g. starting aspirin as early as post-operative day 2) for patients on IMiD receiving deceased kidney transplant

○      Maintenance immunosuppression as per transplant centers

○      Maintenance therapy for multiple myeloma (MM): Initiate maintenance as indicated. Typically 2-3 weeks after kidney transplant.

○      MM surveillance with SPEP and sFLC: every 3 months. Protocol allograft biopsy not required but could be considered

○      Recurrence or relapse of MM: Salvage therapy by hematology team

Consider reducing antimetabolite dose by 50% at the time of introduction of MM maintenance therapy and in case of cytopenia

How I treat patients with CLL after prior treatment with covalent BTK inhibitor and BCL-2 inhibitor  [Review]

Key points: See Figure 1 in original article.

●      Patients with chronic lymphocytic leukemia (CLL) who are double-refractory (covalent BTK inhibitors [cBTKis] and BCL-2 inhibitors [BCL-2is]), having progressed following exposure to both classes face limited options and poor outcomes.

●      For patients with intolerance to cBTKis, second-generation agents may remain effective (zanubritinib, acalabrutinib). Similarly, retreatment with venetoclax can be considered after prior fixed-duration use.

●      In double-refractory disease, the non-covalent BTKi (e.g., pirtobrutinib) and CD19-directed chimeric antigen receptor (CAR) T-cell therapy (lisocabtagene maraleucel) are available standard-of-care options.

○      Pirtobrutinib provides rapid disease control but often with limited durability, emphasizing the importance of early planning for consolidation with CAR T-cells or allogeneic stem cell transplant.

●      Persistent disease after CAR T-cell therapy warrants close follow-up and timely referral for transplant evaluation in eligible patients. While PI3K [phosphoinositide 3-kinase] inhibitors are also available, their role is limited due to toxicity and modest efficacy.

●      Investigational agents (including BTK degraders, bispecific antibodies, and novel cellular therapies) offer promise for the future.

New book in hematology: American Society of Hematology Self-Assessment Program, Ninth Edition

“The American Society of Hematology Self-Assessment Program (ASH-SAP), Ninth Edition is the most comprehensive edition to date, encompassing both adult and pediatric hematology, including classical and malignant disorders. With 49 chapters, many newly rendered illustrations, and 254 multiple-choice questions, ASH-SAP is designed for self-directed learning and review with case studies, key points, graphics, animation, and a glossary”

Update clinical trial BRUIN CLL-314

“Lilly's Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, met its primary endpoint in a head-to-head Phase 3 trial versus Imbruvica (ibrutinib) in CLL/SLL: Pirtobrutinib met the primary endpoint of response rate non-inferiority, favoring pirtobrutinib with a nominal P-value for superiority < 0.05”

IACH Friends and Members Corner

Summer Greetings from the IACH

As the holiday season unfolds, the International Academy for Clinical Hematology (IACH) would like to extend its warmest wishes to you and your loved ones.

May this summer bring you well-deserved rest, joyful moments, and renewed energy. Whether you are spending time with family, exploring new places, or simply enjoying some peace and quiet, we hope it will be a time of inspiration and balance.

Thank you for your continued dedication to advancing the field of hematology. We look forward to reconnecting soon for an exciting season of scientific exchange and educational innovation.

With our warmest regards,

The IACH Team

This corner is yours! Please send us any information you would like to share with the IACH community (Upcoming event, congratulations message, award announcement, call for a grant, new important appointment, vacant position, etc) to info@clinical-hematology.org.