PHD 2022: In the treatment of multiple myeloma we have achieved significant progress, confirm real-world data

3 new standards of care

Updated national guidelines for MM are expected to be released in the 4th quarter of 2022. Last year, the International Myeloma Working Group's recommended guidelines for the treatment of relapsed/refractory MM (RRMM) and the European Hematology Association/European Society for Clinical Oncology (EHA-ESMO) clinical practice guidelines on diagnosis, treatment, and monitoring of MM were published.

For patients with newly diagnosed MM (NDMM) who are not candidates for autologous stem cell transplantation (ASCT), there are 3 new standards of care: daratumumab (dara) + bortezomib (V) + melphalan (M) + prednisone (P) (daraVMP; based on the Alcyone study), dara + lenalidomide (R) + dexamethasone (d) (daraRd; MAIA study), or VRd (SWOG study). The choice of 1st line treatment can of course subsequently influence the therapeutic approach in later lines. The combination RVd (Rd) appears to be a viable option if daratumumab-based regimens are not yet available.

Currently, there are many effective new treatment triplets, although they can be economically demanding. In Central and Eastern European countries, usual challenges in access to treatment persist: availability, economic situation, unrealistic requirements or expectations, and additional criteria from the State Institute for Drug Control (SÚKL) beyond those indicated by the European Medicines Agency (EMA), etc.

Real-world data

According to the speaker, the best data can be obtained from several phase III studies, meta-analyses, and confirming real-world findings. A study based on data from the USA registry revealed that 53–75% of RRMM patients in routine practice in the USA did not meet eligibility criteria for inclusion in randomized controlled trials.

The only validated MM registry in the EU is the Registry of Monoclonal Gammopathies (RMG), which in 2021 (after 14 years of operation) includes over 14,000 patients from the Czech Republic, Slovakia, and Austria. Regarding MM treatment, data from the RMG show an increasing proportion of NDMM patients in our country who are suitable for transplantation (22% in 2009, 33% in 2016), with transplant-related mortality calculated within 100 days of the procedure being 0.7%. According to data from 792 NDMM patients suitable for transplantation, the median progression-free survival (mPFS) and overall survival (mOS) at standard risk is 29.5 months and 93.2 months, respectively, and at high risk 18.3 months and 55.3 months, respectively.

Quick reflections on rapid progress

The current topic in MM treatment is immunotherapy – the speaker even used the term “immunotsunami.” He discussed the following modalities targeting the B-cell maturation antigen (BCMA):

• Antibody-drug conjugate (belantamab mafodotin).
• T-cell activating strategies: CAR T-cell therapies – idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel); bispecific antibodies – teclistamab, AMG701).

CAR T-cell therapies achieve promising responses in patients who had previously used proteasome inhibitors (PI), immunomodulatory drugs, and anti-CD38 antibodies, thus having been exposed to 3 drug classes (triple-class exposed). In the single-arm open-label phase Ib/II CARTITUDE-1 study (Jaganath et al., IMW 2021), the use of cilta-cel in these patients achieved an mPFS of 23 months, with an overall 18-month PFS of 66% and overall 18-month OS of 80.9%.

The following phase III randomized studies are set to start:

• EMN28/CARTITUDE-6 focuses on NDMM patients, comparing daraVRd + cilta-cel vs. daraVRd + ASCT; it will enroll 750 patients over 2 years.
• EMN30/MajesTEC-4 will address NDMM patients on maintenance therapy post-ASCT, comparing adding teclistamab to lenalidomide vs. lenalidomide alone, aiming to enroll 1000 patients over 2 years.

New indicators and biomarkers

A new surrogate marker for clinical trials is sustained minimal residual disease (MRD) negativity. The primary indicator in clinical trials is PFS. The sum of PFS medians in the 1st–3rd treatment lines could, thanks to modern therapy options, amount to 10 years:

dara-Rd (1st line) – mPFS > 60 months → pomalidomide-carfilzomib (2nd line) – mPFS 36 months → other regimens (3rd line) – mPFS 24 months

For the future, the strategy of a “therapy-free window” is being discussed (critical is the MRD negativity status).

Importance of circulating plasma cell levels

During ASH 2021 in Atlanta, a Czech study examining circulating plasma cells (cPC) as a strong prognostic marker in non-transplant eligible MM was presented orally, highlighting the importance of a 2% cPC concentration as a new cut-off regarding PFS outcomes: in a cohort of 395 patients, the mPFS was 3 months for cPC ≥ 2%, but 17.9 months for cPC < 2%; the median OS was 14.6 months for cPC ≥ 2%, but 33.6 months for cPC < 2%. Patients with cPC ≥ 2% represent an extremely high-risk NDMM population, with a prognosis similar to that of primary plasma cell leukemia (PCL) – they are hidden PCL patients. Circulating plasma cells appear to be a strong independent prognostic biomarker also in NDMM patients ineligible for transplant.

The paradigm of diagnostic criteria for PCL based on the proportion of circulating plasma cells in peripheral blood has already changed, from ≥ 20% (Kyle et al., 1974) to ≥ 5% (Fernández de Larrea, 2021). Garces et al. in 2021 stated that cPCs are detected in 92% of MM patients using next generation flow cytometry (NGF). Jelínek et al. in 2022 reported that 2% cPC in MM has the same prognosis as PCL. According to Prof. Hájek, it is therefore a question whether the diagnosis of PCL should be abandoned.

Eva Srbová
MeDitorial editorial team

Source: Hájek R. Heřmanský's lecture: Multiple myeloma: a quick reflection on the fast progress. 22nd Prague Hematology Days – Hematology 2022 – Post-ASH, 20. 1. 2022.