Relapsed/refractory patients

Clinical Advances in Myeloma 2018 | Treatments for newly diagnosed and relapsed patients

The MM Hub were delighted to attend Clinical Advances in Myeloma on 31 January 2018, at the Hallam Conference Centre, London, UK. This was a small conference with approximately 40 attendees and gave us an opportunity to chat informally with local clinicians. The major topics discussed are summarized in an overview article that can be read here. Below is a summary of two talks from the second session of the day that addressed current and emerging treatments, in particular, those for Newly Diagnosed Multiple Myeloma (NDMM) and Relapsed and Refractory (RR) MM. Slides from some of the presentations can be viewed here.

Current treatments for newly diagnosed myeloma

The first talk in this session was given by Jamie Cavenagh, from St Bartholomew’s Hospital, London, UK on the topic of Current treatments for Newly Diagnosed Myeloma. He introduced his talk by explaining that MM remains an incurable disease and that current treatments can only prolong life and improve the quality of life, although acknowledged the dramatic improvement in survival due to the appearance of novel agents. To illustrate this, data from a raft of clinical trials were presented, including FIRST, SWOG SO777, UPFRONT, ELOQUENT 2, CASTOR, ALCYONE, POLLUX, IFM 2009 and TEAMM.

Using the FIRST trial as an example, the concept of continuous therapy was discussed. In this trial, lenalidomide plus low-dose dexamethasone (Rd) was given continuously until disease progression, or for a defined period of only 18 months, and these regimens were compared with melphalan, prednisone, and thalidomide (MPT). The superiority of continuous Rd was found to lie within a subset of MM patients that still respond to lenalidomide in the longer term. Hence, this finding contributes to the belief that continuous therapy is a preferential treatment modality for all MM patients. However, Professor Cavenagh also explained that the meaning of continuous therapy needs to be clearly defined as continuation until tumor cells have acquired resistance to the therapy. He also highlighted the importance of Treatment Free Intervals (TFIs) and that a patient’s best response usually follows the line of therapy.

The SWOG SO777 trial to assess the combination of bortezomib, lenalidomide, and dexamethasone (VRD) was mentioned with emphasis on the high Overall Survival (OS) and Progression Free Survival (PFS) achieved in previously untreated patients. Professor Cavenagh stressed the importance of using multiple therapies with different modes of action to decrease the likelihood of a patient developing resistance.

Data from the UPFRONT trial was also presented. This is a US-community based study, in which three frontline bortezomib-based regimens were compared in transplant-ineligible patients. The results of this study did not show significant differences between patients treated with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-melphalan-prednisone (VMP) in terms of OS and PFS. Interestingly, the recent phase III ALCYONE study showed that the addition of daratumumab to bortezomib, melphalan, and prednisone (VMP) in non-transplant eligible NDMM patients led to a reduction in the risk of disease progression or death by 50%, in comparison to those who did not receive daratumumab. Professor Cavenagh said, ‘the inclusion of daratumumab as part of first-line therapy for patients eligible for transplant and the ones who are non-eligible, will be a key clinical question’, stating that, ‘daramatumumab is now a game changer in MM’.

The topic of precision medicine was then briefly addressed, with reference to the t(11;14) genetic aberration, for which targeting with venetoclax monotherapy has shown significant improvement, with an ORR of 21% for all patients and 40% for patients with t(11;14). Combining bortezomib, dexamethasone and venetoclax gave an ORR of 97% for patients not refractory to bortezomib. Approximately 10-15% of patients with MM have the t(11;14) aberration, along with cyclin D1 upregulation, but its association with increased BCL-2 expression is unclear. Recent data, however, has suggested that patients with the t(11;14) aberration should be re-classified, as they have a worse outcome than standard risk patients. Professor Jonathan Kaufman spoke about this study and success in treating these patients with venetoclax as at ASH 2017 – listen here, and to read the original study, read more here.

Briefly, the role of Autologous Stem Cell Transplantation (ASCT) in the modern drug era was discussed, with data from the IFM 2009 clinical trial highlighted – read here. This study showed that the OS was not different between patients who were treated with bortezomib, lenalidomide and dexamethasone (RVD) alone, and those that received ASCT plus RVD. However, patients that underwent transplant had a longer treatment-free survival.

Professor Cavenagh also highlighted the fact that due to a longer survival rate, MM patients are accumulating significantly more skeletal disease than before, and that this is something that clinicians treating MM need to be on the lookout for. Another increasing issue is the occurrence of secondary malignancies, which are associated with poor prognosis.

Finally, Professor Cavenagh spoke about the role of supportive care. The TEAMM (Tackling Early Morbidity and Mortality in Myeloma) study is an important trial that assessed the use of antibiotic prophylaxis in the first 12 weeks of diagnosis and treatment of NDMM, due to the concern that clinicians were withholding antibiotic prophylaxis for fear of healthcare-associated infections (HCAI). The study recruited 977 patients from the UK who were randomized to receive either levofloxacin or a placebo. The study showed that levofloxacin significantly reduces the incidence of febrile episodes and death. It was pointed out, however, that in many instances, cotrimoxazole has superior benefit compared to levofloxacin.

Emerging treatments for relapsed myeloma

The second talk was presented by Rakesh Popat, from the University College London Hospitals, who spoke about the latest treatments for relapsed MM. Dr Popat explained that relapse is an inevitable part of the course in MM and that patients will continue to relapse until eventually, they succumb to drug toxicity, complications or refractory disease. Treating RRMM is, therefore, a challenge and management of patient care is also important as patients are subject to recurrent infections. However, a case study was then presented to illustrate how different novel treatments can now be used to successfully overcome sequential relapse, resulting in deep and durable responses even late into the disease.

Dr Popat then presented data from a number of pivotal clinical trials. The ENDEAVOR trial was outlined as this data led to the approval of carfilzomib. A 7-month improvement was observed for patients who treated with carfilzomib and dexamethasone (Cd) in comparison to the control arm, bortezomib and dexamethasone (Vd), with the greatest PFS observed for those who had only one prior line of treatment. Additionally, the lack of prior bortezomib exposure resulted in the median OS not being reached compared to 42.2 months (Vd) with HR = 0.75, 95% Cl;0.55–1.04. This finding has therefore shaped the current indication for carfilzomib - its use in combination with lenalidomide and dexamethasone, to treat MM patients that have had 1-3 prior lines of therapy and no prior bortezomib exposure. Practical points for the use of carfilzomib were outlined, in particular, careful patient selection based on frailty and pre-defined heart conditions; ECHO is worth doing pre-dose and treatment during an infection should be avoided. Bi-weekly IV dosing was recommended, with pre- and post- hydration, as well as close monitoring of both blood pressure and renal function.

The TOURMALINE MM-1, which recruited patients at first relapse to assess the efficacy of ixazomib plus lenalidomide and dexamethasone, was then described. The primary endpoint was met with an improvement of 20.6 months with the addition of ixazomib in comparison to 14.7 months for the control arm. Dr Popat suggested that maintaining the intensity of ixazomib up until a year could help drive depth of response. Results also showed that ixozomib, unlike other agents, has a significant effect in patients with either the del(17) and t(4;4) genetic aberrations, and therefore it would be interesting to investigate this agent in patients with a double-hit genetic abnormality.

Data from the phase Ib trial for venetoclax, bortezomib and dexamethasone (VD) treatment in RRMM patients was then described. This trial, conducted by Philippe Moreau and published in Blood, resulted in a particularly high ORR in patients with high ratio for Bcl:Bcl xl and the t(11:14) abnormality. The study also revealed that patients with the t(11:14) aberration are more sensitive to low doses of venetoclax,  compared to patients with other genetic markers. In addition to this, the combination of venetoclax and bortezomib led to NOXA stabilization, which alters MCL-1 expression and enables patients to be resensitized to venetoclax.

The use of monoclonal antibodies (mAb) in RRMM was then presented. To date, the most advanced target is CD38, with daratumumab at the most advanced stage of development. Daratumumab is now available on the NHS via the Cancer Drug Fund (CDF) for use as a fourth line monotherapy. This follows data from the Phase II trial (MMY2002) in which a 31% increase in ORR was observed in a heavily pre-treated population. One of the benefits for patients is the short two-hours infusion, which can be administered as an outpatient. Real world data for daratumumab from a study conducted at UCLH, was shown to illustrate how the infusion time could be decreased following the first infusion, and the infusion-related reactions (IRR) were limited to the first dose. It was noted that isatuximab, another anti-CD38 mAb, is currently being assessed in combination with pomalidomide/dexamethasone in RRMM patients in a phase Ib clinical trial, which is eagerly awaited.

Success with daratumumab plus lenalidomide and dexamethasone in the relapsed setting was further illustrated with data from the POLLUX trial,  which showed a significant improvement in PFS for those receiving daratumumab. It is noteworthy that high-risk patients did worse in both arms. Likewise, data from the CASTOR trial of daratumumab plus bortezomib and dexamethasone (VD) in the relapsed setting was also shown; high-risk patients fared better compared to those who only received VD. The trial also showed that a longer duration of treatment seemed useful.

The data from a phase II trial with selinexor was then discussed. The STORM trial showed an ORR of around 20% in heavily pre-treated MM patients refractory to their most recent regimen when treated with selinexor plus low-dose dexamethasone (Sd). Further investigation of selinexor is ongoing and of particular interest will be the phase III BOSTON trial, in which the combo of selinexor, bortezomib and dexamethasone will be tested.

A short overview of the DREAMM-1 trial, in which RRMM patients received GSK2857916 monotherapy (an antibody-drug conjugate against B-Cell Maturation Antigen (BCMA)), was given. The majority of patients tested in this study were refractory to both IMiDs and daratumumab. GSK2857916 was well tolerated and administered successfully with a short infusion time of less than an hour, and importantly an ORR of 60% was observed. The development of new IMiDs and CelMODS targeting the cereblon was discussed, with several possible drugs in the pipeline. 

Dr Popat concluded with an overview of the UK NHS treatment pathways, which are summarized in the table below:

 

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