Dr Kumar: The combination of bortezomib， lenalidomide and dexamethasone (VRd) is currently considered as the standard initial treatment for patients with newly diagnosed multiple myeloma (NDMM). This is based on improved overall survival from the prior phase III trial that showed that VRd is better than Rd. There had been study results that suggest that carfilzomib may be a more effective proteasome inhibitor when combined with lenalidomide and dexamethasone (KRd)， based on studies in both relapsed disease and in the newly diagnosed setting， though in the newly diagnosed setting these were phase II trials. So， we wanted to see in a phase III trial if KRd is better than VRd for induction therapy. We designed this phase III trial to compare the progression-free survival and response rates between KRd and VRd. In addition to progression-free survival， we also wanted to look at the differences in response rate， overall survival， minimal residual disease (MRD)-negativity rate， duration of response， as well as time to next treatment. We also looked at some quality-of-life metrics.

 

Oncology Frontier：In some studies， carfilzomib is considered to have an advantage over bortezomib in the del(17p) patient subgroup. The Mayo Clinic recommends four-drug combination therapy for high-risk patients. For high-risk patients who are not suitable for four-drug therapy， is KRd better than VRd?

 

Dr Kumar: This clinical trial excluded patients with high-risk disease. We only allowed patients with translocation (4;14) from the group with high-risk disease. Patients with t(14;16)， t(14;20)， deletion 17p， high LDH， and plasma cell leukemia were all excluded from the current clinical trial. So， the results of the trial cannot be extrapolated for deciding whether VRd or KRd is a better regimen for high-risk myeloma. Similarly， this trial was only designed for patients who are not planning to do an upfront autologous stem cell transplant. So， if you are thinking about induction therapy for an autologous stem cell transplant， the relative efficacy of VRd or KRd in that setting is unanswered in this clinical trial.

 

Oncology Frontier：：How do you think of carfilzomib in bortezomib-resistant patients?

 

Prof. Hou：For the treatment of myeloma refractory to bortezomib， we would first consider choosing drugs with different mechanisms， such as lenalidomide or daratumumab. If these drugs are unsuitable for patients because of resistance to previous treatment， or not being available， or too toxic， carfilzomib should be considered for inclusion in the regimen for these patients. Although bortezomib and carfilzomib are both proteasome inhibitors， they have different structures and slightly different mechanisms of action. The randomized， phase III， open-label， multicenter ENDEAVOR study for relapsed and refractory multiple myeloma compared carfilzomib and dexamethasone versus bortezomib and dexamethasone. This study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival for carfilzomib and dexamethasone (Kd56) versus bortezomib and dexamethasone (Vd) in relapsed and refractory multiple myeloma. Subgroup analyses show that in refractory and relapsed multiple myeloma， outcomes are improved using carfilzomib compared with bortezomib， regardless of the number of previous lines of treatment， or previous exposure to bortezomib or lenalidomide， or renal function. Overall survival was also longer with Kd56 versus Vd across age and cytogenetic subgroups， and according to the number of previous lines of therapy， previous bortezomib exposure， previous lenalidomide exposure and lenalidomide-refractory status. Several points should be emphasized when interpreting the results with carfilzomib in this clinical trial. Firstly， in the ENDEAVOR study of refractory and relapsed multiple myeloma， the dosage of carfilzomib was 56 mg/m2. In both the Korean and ENDURANCE studies， the carfilzomib dosage was 36mg/m2， so， it is under investigation what the best dosage of carfilzomib is for refractory and relapsed multiple myeloma.

 

Dr Kumar: This would mostly be in the setting of relapsed disease I presume， because in the newly diagnosed setting， the proportion of patients who don’t get a response to a triplet drug is 10-15%， which we saw in this trial as well. For that group of patients， we certainly can switch to another class of drug， likely a monoclonal antibody. That would be an appropriate combination. Similarly， in the setting of relapsed disease， where a patient is refractory to bortezomib and carfilzomib， then we should think about using a combination that includes a monoclonal antibody with an immunomodulatory drug， like lenalidomide or pomalidomide， depending on the situation.

 

Oncology Frontier：There was a long history of bortezomib in the therapeutic evolution of MM. And bortezomib is considered as one of the cornerstones of induction therapy. Since the first-line maintenance recommendation is lenalidomide， how do you think of the value of bortezomib in maintenance? In which subgroups of patients may it have advantages? 

 

Prof. Hou: There are two main reasons for recommending lenalidomide as first-line maintenance therapy in multiple myeloma. One is prolonging PFS and OS. The other is its durability. There has been a lot of data supporting the role of bortezomib in maintenance therapy for multiple myeloma. In our daily clinical practice， we use bortezomib as maintenance therapy in patients with renal insufficiency or with high-risk cytogenetic abnormalities， in particular， those with double-hit or triple-hit disease; also for those patients who are not tolerant of lenalidomide， or those where the response is poor. For example， if a patient demonstrates only a partial response to lenalidomide maintenance， we can add bortezomib to the maintenance regimen.

 

Dr Kumar: Bortezomib as a maintenance therapy has been studied in a handful of trials. There have not been any randomized trials looking at bortezomib maintenance versus a non-bortezomib maintenance or no maintenance. Based on the data that we have from these studies， our recommendation is currently to use a bortezomib-based maintenance in patients with high-risk disease， such as those with deletion 17p， t(4;14)， and so on. For those patients， it would be preferred， if possible， to do maintenance with a combination of a proteasome inhibitor and an immunomodulatory drug (IMiD). So， in our practice， patients with deletion 17p are currently kept on a combination of bortezomib， lenalidomide and dexamethasone until disease progression.

 

Prof. Hou: Dr Kumar， may I ask a question? There are a lot of guidelines concerning multiple myeloma in different countries. From the US， both the NCCN Guidelines and the mSMART consensus are well known. Many Chinese doctors consider them like the Bible in their management of multiple myeloma. Do you have any comment on the differences between these two guidelines? How should doctors follow them in their daily practice?

 

Prof.Kumar: Prof Hou， That is a important question. They both serve very different roles in terms of their purpose. The mSMART algorithm was designed to reflect the consensus recommendation from the Mayo Clinic group which suggest a limited set of choices for management of newly diagnosed and relapsed myeloma， primarily in the context of risk stratification and based on our assessment of currently available data. in contrast， The NCCN guidelines typically reflects a consensus opinion of myeloma experts from nearly 30 different institutions that are part of  NCCN and includes majority of regimens that have data supporting their use and are currently used in the practice settings in the US. The NCCN guidelines do not direct the physicians to a specific regimen but rather provides a set of choices， which are ranked based on the strength of available evidence and the consensus opinion of the members. The insurance companies in the US often use the NCCN guidelines to decide on reimbursement of a variety of different therapies that we use for myeloma.