Sequencing of Treatment in MM (Multiple Myeloma)
Introduction
Multiple myeloma (MM) is a haematological malignancy characterised by the clonal expansion of malignant plasma cells in the bone marrow. MM manifests clinically as hypercalcaemia, renal failure, anaemia and bone lesions (known as CRAB features), and is most common in people aged over 65 years. MM affects around 361 people in Ireland each year, 1 and despite advancements in treatments remains incurable in 2022.
Treatment of MM normally consists of a combination of two, three or even four drugs from different classes. With so many drugs available now, it can be difficult for clinicians to decide in which sequence therapies should be given. There is no one-size-fits-all approach to treatment as each patient is different. Treatment approaches vary, depending on patient fitness, co-morbidities, disease features and eligibility for an autologous stem cell transplant (ASCT). Additionally, practice is moving towards trying to personalise therapy options for high-risk patients, however clinically available biomarkers to direct this approach are lacking. High-risk patients are most commonly defined by their cytogenetic profile, with the presence of del(17p), t(4;14), t(14;16), t(14;20), or gain(1q) associated with high-risk disease. Generally, this indicates a predicted overall survival of approximately 3 years. 2 Alternatively, standard-risk patients have an overall survival of 7-10 years and cytogenetic abnormalities associated with this outcome include t(11;14), t(6;14) and trisomies of odd numbered chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. 2
Treatment at diagnosis is focused on getting the patient into a deep remission – measured by a reduction in serum paraprotein, normalisation of the light chain ratio and reduction in the percentage of bone marrow plasma cells. Initial treatment in Ireland at present consists of one of the following National Cancer Control Programme (NCCP) approved regimens; RVD (bortezomib, lenalidomide, dexamethasone), VMP (bortezomib, melphalan, prednisone), CyBorD (cyclophosphamide, bortezomib, dexamethasone), Rd (lenalidomide, dexamethasone) or most recently D-VTD (daratumumab, bortezomib, thalidomide, dexamethasone). Treatment choice is largely guided by patient “fitness” in terms of frailty and co-morbidities, age is a factor, but biological age is more important than numerical age. Regimens like VMP and Rd are preferable for older, frailer patients who are not transplant eligible.
Despite the discovery of effective monoclonal antibodies (daratumumab, isatuximab), immune modulators (lenalidomide) and other therapies, MM remains an incurable disease. Even with successful initial treatment, the disease follows a remitting and relapsing course with accumulation of toxicity and a decline in bone marrow function over time. Treatment at relapse is decided based on disease and patient factors, with resistance to prior therapies being a major issue. There is much debate on whether an aggressive multidrug approach that ensures a better response should be prioritised over a sequential disease control approach that considers quality of life as well as overall survival. 2
In this article, we briefly outline the available therapies for MM and their mechanisms of action. We discuss treatment options at diagnosis followed by treatment at each relapse and how they can be sequenced to aim for optimal outcome. Finally, we also discuss some novel agents in clinical trials for MM and how they are likely to influence the future disease landscape.
Myeloma Therapies
There are various therapies approved by the US Food and Drug Administration (FDA), the European medicines agency (EMA) and the NCCP for the treatment of MM. These can be divided into several main classes: corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory agents (IMiDs), monoclonal antibodies (mAbs), and nuclear export inhibitors (outlined in Table 1). Additionally, at diagnosis, patients who are well enough will be considered for an ASCT.
Corticosteroids and alkylating agents have been available for many decades for MM treatment, with the alkylating agent melphalan and corticosteroid prednisone previously being the most common treatments used. Corticosteroids remain a backbone of MM treatment and are directly toxic to MM cells while also sensitising cells to newer therapies. 3 Corticosteroids work by inhibiting cytokines and NF-κB signalling which is vital for myeloma growth. Alkylating agents are described as DNA intercalating agents causing DNA damage and later cell death.
Proteasome inhibitors have been approved for MM for the last two decades and are largely responsible for the unprecedented improvement in overall survival seen in Ireland in recent data. MM cells rely heavily on proteasome, and proteasome inhibition prevents the degradation of pro-apoptotic proteins, inhibition of NF-κB and ultimately cell death. 4 Bortezomib was the first proteasome inhibitor approved in 2003 for both newly diagnosed and relapsed/refractory MM and since then has been followed by carfilzomib and ixazomib which are currently approved for relapsed/ refractory MM. 3
Thalidomide, lenalidomide and pomalidomide are IMiDs – they alter the immune system, namely the interaction between MM cells and the surrounding bone marrow. Bone marrow microenvironment cells offer MM cells a protective niche – interrupting this relationship has been a major source of breakthroughs in MM therapy. The main target of IMiDs is thought to be cereblon which targets two transcription factors IKZF1 and IKZF2 which are important for MM survival. 2 For many years, there was a lack of effective mAb therapy for MM patients, in contrast to diseases like lymphoma. The discovery of CD38 as a target has changed the treatment landscape in MM and patients now have access to Daratumumab, and isatuximab in the relapsed and clinical trial setting, respectively. 2
More recently the nuclear export inhibitor Selinexor has been FDA approved in the US (not available in Ireland currently) for treatment of relapsed MM. Selinexor inhibits exportin 1 (XPO1) which normally exports tumour suppressor and growth regulatory proteins out of the nucleus. When inhibited this ultimately results in suppression of NF-κB and upregulation of apoptosis. 2
Treatment of Newly Diagnosed Multiple Myeloma
At diagnosis, MM patients can be widely classified as either eligible for an ASCT, or ineligible for an ASCT. The factors considered for eligibility are based on a patient’s ‘fitness’ given the intensive nature of an ASCT, namely existing comorbidities (such as renal failure, cardiovascular disease etc.) and age. Patients over 75 years old are unlikely to be considered eligible due to the higher risk of toxicity and the availability of effective treatments for these patients. Initial treatment will vary depending on if a patient is to receive an ASCT or not.
Transplant-Eligible
Due to superior response rates and greater progression free (PFS) and overall survival (OS) standard of care induction regimens now include both a proteasome inhibitor and an immunomodulatory drug for transplant eligible patients Patients deemed eligible to receive an ASCT will typically receive 4-6 cycles of induction therapy followed by a stem cell harvest. A patient’s stem cells are harvested and stored until they are ready to receive them back as a stem cell transplant. Following treatment for MM, the aim is that malignant cells will have been reduced or completely removed, and are then replaced with the patient’s healthy stem cells which can become new healthy blood cells.
Induction regimens incorporating novel therapies have resulted in median PFS of more than 30 months and 5-year OS rates of more than 70%. 5 Ideally, patients will be treated on a clinical trial which can help to provide the highest standard of care to cancer patients.
There is much international debate regarding timing of ASCT, with some experts favouring to delay ASCT beyond the initial treatment phase due to the success of newer therapies. However, the IFM-2009 trial prospectively confirmed that, combined with novel agent triplet induction, upfront ASCT was associated with a superior PFS (50 vs. 36) months. 6, 7 In Ireland, ASCT is offered as part of induction to patients who are transplant eligible. Studies have also investigated the role of a second, tandem ASCT with results being contradictory as to whether it is beneficial for overall survival. Generally, routine tandem ASCT is not recommended outside of clinical trials, but may be considered for high-risk patients or patients who did not show a complete response after their first ASCT. 2
Transplant-Ineligible
As outlined above, various regimens are approved for the initial treatment of patients who are not transplant eligible. Results from recent clinical trials have shown that the addition of daratumumab can enhance the depth of response at diagnosis and improve outcomes. 2 Generally, induction therapy is administered for 8-12 cycles followed in some cases by maintenance therapy. Maintenance therapy is most commonly lenalidomide, and in frail, elderly patients, a lower dose of lenalidomide may be better tolerated. Maintenance with bortezomib or lenalidomide is recommended for patients with high-risk myeloma, however in some frail patients, this may not be well tolerated and an important consideration is quality of life.
Treatment of Relapsed & Refractory Myeloma
MM remains incurable as patients will eventually become relapsed or refractory to treatment following remission, with treatment being required once a patient is symptomatic. This can occur multiple times and thus adequate sequencing of therapies at this point is carefully considered to ensure the best outcome. The choice of treatment at relapse will depend on which regimen the patient received as their previous line(s) of therapy and their initial response, cytogenetics, aggressiveness of the relapse, and again the patient’s fitness and quality of life (Figure 1). 8, 9 Many MM patients will receive five or more lines of therapy over many years, while other life circumstances and co-morbidities also develop. These patients are ideally treated on a clinical trial, which can provide access to the best standard of care and novel agents for MM.
In Ireland, there are several NCCP approved regimens for treatment of relapsed and refractory myeloma; RVD (bortezomib, lenalidomide and dexamethasone), bortezomib and dexamethasone (VD), CyBorD/cyclophosphamide, VD (bortezomib and dexamethasone), daratumumab monotherapy, pomalidomide and dexamethasone, Kd (carfilzomib and dexamethasone), KRd (carfilzomib, lenalidomide and dexamethasone), DVd (daratumumab, bortezomib and dexamethasone), IRD (ixazomib, lenalidomide and dexamethasone), and lenalidomide and dexamethasone.
At first relapse, generally a triplet regimen is recommended with the incorporation of a therapy the patient has not been exposed to in the recent past. 2, 8 Treatment is continued until progression unless the patient cannot tolerate the regimen. If a patient received first line bortezomib-based therapy, they can receive a lenalidomide based regimen at relapse. Vice versa, if a patient becomes refractory during continuous lenalidomide maintenance, a patient may receive a bortezomib based regimen. 10
Future Treatment of Myeloma
Treatment of MM is changing rapidly and there are now several clinical trials internationally, which are exploring the utility of entirely new mechanisms of killing MM cells. This includes chimeric antigen receptor-T (CAR-T) cell therapy which is likely to change the life expectancy and treatment approach for MM patients drastically in the near future. In brief, this immunologic approach uses T-cells harvested from the patient, which are then genetically engineered to make them target MM cells and kill those cells. These T-cells are then re-infused back to the patient where they specifically home to and kill MM cells. CARs are hybrid molecules that contain both an antigen recognition domain and T-cell activation domains. T- (11). Most CAR-T therapies, in trial, target BCMA, but SLAMF7, CD19 and CD38 CAR-T approaches are also used in clinical trials for MM.
Most of these therapies are being trialled in relapsed refractory patients, and research should aim to determine at what point receiving these therapies is most beneficial. It is possible in the future that CAR-T cells will replace ASCT in MM patients. Other targeted approaches in clinical development aim to focus on specific subgroups of MM patients who have individual genetic signatures, in a more personalised approach. Venetoclax is an inhibitor of anti-apoptotic protein BCL-2 which has shown promise specifically in patients with a t(11;14) translocation. 12 There are several trials investigating this, focusing on this subgroup of patients at relapse, and venetoclax has potential to become one of the first genetically targeted drug for MM patients. Bispecific antibodies are another emerging immunologic approach, these can bind both plasma myeloma cells and T-cells simultaneously to target plasma cells for T-cell mediated death. Several trials are investigating bispecific antibodies that bind B-cell maturation antigen (BCMA) which is specifically expressed on plasma cells, and CD3 expressed on T-cells. 2 Teclistamab and Elranatamab are both BCMA targeting bispecific antibodies in trial, which may be accessed in Ireland through managed access programs. Both of these have shown clinical efficacy in relapsed refractory MM. Additionally, novel mAb Belantamab can also be accessed through such trials and also targets BCMA.
Conclusion
The number of therapies available for MM has rapidly increased in recent decades with 5-year survival rates now approaching 70%. Whilst this is undoubtedly a major success, it can be challenging for clinicians to decide on the most appropriate treatment sequence. Since MM is a complex disease and each patient responds differently, treatment at diagnosis is initially based on whether a patient is deemed eligible for an ASCT or not. At relapse, the sequence of treatment becomes more complex and largely depends on a patient’s previous response and which therapies they have already been exposed to. There is no doubt that within the next decade even more MM therapies will become available and therefore it is important that clinical trials answer questions about the timing of treatment. It is also important to emphasise that many MM patients have a lower risk and a more indolent disease course, and may benefit from less treatment or time off therapy. Biomarkers which can be used to decide in advance, which patients might benefit from a more intensive or less intensive approach are now even more essential.
References available on request
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