Current and Emerging Therapies for Patients With Multiple Myeloma

Multiple myeloma (MM) is a malignant disease of the bone marrow characterized by clonal expansion of plasma cells (1, 2). Current guidelines recommend that newly diagnosed transplant-eligible patients with multiple myeloma (NDMMTE) need to undergo several courses of induction, followed by one or two courses high-dose melphalan, followed by autologous stem cell transfusion (ASCT) (3, 4). 

With the introduction of new drugs, the prognosis of patients with multiple myeloma has considerably improved over time. Currently, induction therapy schemes usually consist of an immunomodulator (such as Thalidomid© or Revlimid©), a CD38-targeting antibody, a proteasome inhibitor, and dexamethasone (please see Onkopedia guidelines (5) and (6)). The induction therapy is then followed by stem cell mobilization and subsequently one or two courses of high-dose melphalan chemotherapy based on the initial cytogenetic findings of the malignant plasma cells and the initial stage of the disease. Current guidelines recommend two rounds of high-dose melphalan therapy followed by ASCT in case of the following initial findings: presence of cytogenetic translocations, such as (4;14), (14;16), (14;20) or deletion 17p (del17p), determined by fluorescence in situ hybridization (FISH). In addition, the Revised International Staging system (R-ISS vIII) recommends two rounds of high-dose melphalan (4, 5). Furthermore, if the patient does not achieve partial responses after the first round of high-dose melphalan, as described by the International Myeloma Working Group (IMWG) recommendations (7), a second course of high-dose melphalan therapy should be administered. Subsequently, patients treated outside clinical trials typically receive either 2-3 rounds of consolidation therapy followed by Revlimid© (usually 10 or 15 mg on a daily basis) or proceed directly to a Revlimid©-based maintenance therapy until progression or intolerable toxicity. Essentially, all NDMMTE patients undergo at least one round of high-dose chemotherapy, which is associated with high morbidity, including acute toxicities (e.g. cytopenia, infection), long-term effects (e.g. myelodysplastic disease [MDS]), secondary malignancies and rarely death. 

Based on preliminary data and published reports, exposure to high doses of the genotoxic agent melphalan might render the residual malignant myeloma cells into more aggressive clones, accelerating relapse (8, 9) by potentially altering the stroma (10, 11). Finally, exposure to melphalan is well known to increase the possibility of secondary malignant disease development (12, 13). In patients with MM, high-dose melphalan therapy improves overall survival (OS) and progression-free survival (PFS) if patients from all risk groups are taken in consideration. Yet, it remains to be unraveled whether also low-risk patients have an additional benefit from high-dose melphalan therapy or whether, for these patients, a less toxic regime would be similarly sufficient with regard to PFS and OS. Thus, one challenge remains, whether for low-risk myeloma patients, a treatment without high-dose melphalan would be sufficient. This is the aim of a number of planned trials. 

On the other hand, high-risk patients (e.g. patients with del17p) often relapse within a short time after first-line treatment with high-dose melphalan. Instead of Revlimid©, a number of publications examined the use of bortezomib in a maintenance setting. However, this has not fully improved prognosis. Hence, the questions remain whether treatment for these patient cohorts should be escalated by incorporating either chimeric antigen receptor (CAR)-T cells or novel immunotherapeutic approaches, such as bispecific antibodies or new immune conjugates, as a new consolidation approach after high-dose melphalan therapy. Evaluating such alternative is associated with significantly higher costs. Until the present moment, despite all clinical developments, no cure has been achieved for MM. With the emergence of new therapeutic approaches, new hope arises that cure could be achieved. 

In addition to new therapeutic approaches, the diagnosis and monitoring of myeloma has also improved, with novel detection methods such as flow cytometry and next-generation sequencing used in addition to electrophoresis and that allow earlier detection of relapse or a deep response (14). This also opens to the possibility to either escalating or deescalating therapy, based on the individual response of the patient. Incorporation of measurable residual disease (MRD) negativity is a hallmark of clinical trials in the field of myeloma, but is less commonly performed in a routine setting. If established, it could help deescalate therapy or switch to another therapy, based on response. 

The novel aforementioned methods can be supplemented by positron emission tomography-computerized tomography (PET-CT) examination. Patients who are MRD negative and have no active PET-positive sites after onset of therapy, have a particular excellent prognosis regarding OS and PFS (15, 16). 

Noteworthy, in addition to established risk factors such as cytogenetic aberrations, the gene expression patterns of the malignant cells can also help to better predict prognosis. These tools have been validated retrospectively and some are currently commercially available to support the decisions of physicians and patients to either (de)escalate the therapy on an individual basis. Studies are presently ongoing to test their ability to tailor therapy in a prospective manner. 

Major new challenges 

A major obstacle to apply MRD negativity or gene expression pattern tools is the fact that, at presentation or at first relapse, the disease might still be quite homogenous; however, with the higher number of relapses, the clonal diversity might increase and the genetic composition of the myeloma cells can be rather different at different sites where biopsies or samples are taken from (9). In clinical trials, new methods, such as evaluation of circulating tumor cells, are examined to at least partially take into consideration the clonal heterogeneity of myeloma cells. 

References 

1. Gerecke C, Fuhrmann S, Strifler S, Schmidt-Hieber M, Einsele H, Knop S. The Diagnosis and Treatment of Multiple Myeloma. Dtsch Arztebl Int. 2016;113(27-28):470-6. 
2. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009;374(9686):324-39. 
3. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905. 
4. Engelhardt M, Terpos E, Kleber M, Gay F, Wasch R, Morgan G, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014;99(2):232-42. 
5. Bernhard Wörmann CD, Hermann Einsele, Hartmut Goldschmidt, Eberhard Gunsilius, Martin Kortüm, Nicolaus Kröger, Heinz Ludwig, Lars-Olof Mügge, Ralph Naumann, Ron Pritzkuleit, Christoph Röllig, Christof Scheid, Christian Taverna, Katja Weisel, Florian Weißinger. Multiples Myelom 2018 [Available from: https://www.onkopedia.com/de/onkopedia/guidelines/multiples-myelom/@@guideline/html/index.html. 
6. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. 
7. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-73. 
8. Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016;128(13):1735-44. 
9. Landau HJ, Yellapantula V, Diamond BT, Rustad EH, Maclachlan KH, Gundem G, et al. Accelerated single cell seeding in relapsed multiple myeloma. Nat Commun. 2020;11(1):3617. 
10. Rellick SL, Piktel D, Walton C, Hall B, Petros W, Fortney JE, et al. Melphalan exposure induces an interleukin-6 deficit in bone marrow stromal cells and osteoblasts. Cytokine. 2012;58(2):245-52. 
11. Rellick SL, O'Leary H, Piktel D, Walton C, Fortney JE, Akers SM, et al. Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. 
12. Musto P, Anderson KC, Attal M, Richardson PG, Badros A, Hou J, et al. Second primary malignancies in multiple myeloma: an overview and IMWG consensus. Ann Oncol. 2017;28(2):228-45. 
13. Thomas A, Mailankody S, Korde N, Kristinsson SY, Turesson I, Landgren O. Second malignancies after multiple myeloma: from 1960s to 2010s. Blood. 2012;119(12):2731-7. 
14. Lahuerta JJ, Paiva B, Vidriales MB, Cordon L, Cedena MT, Puig N, et al. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials. J Clin Oncol. 2017;35(25):2900-10.
15. Went M, Sud A, Speedy H, Sunter NJ, Forsti A, Law PJ, et al. Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology. Blood Cancer J. 2018;9(1):1. 
16. Moreau P, Attal M, Caillot D, Macro M, Karlin L, Garderet L, et al. Prospective Evaluation of Magnetic Resonance Imaging and [(18)F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study. J Clin Oncol. 2017;35(25):2911-8.