With respect to those drugs that are currently available, the anti-CD38 antibodies still have a very big role and there have been multiple trials performed with different partners such as with proteasome inhibitors and immunomodulatory drugs, particularly with pomalidomide. The reason for mentioning them first is that many patients are now becoming refractory to lenalidomide and so these types of combinations with anti-CD38 antibodies certainly have a role. The current developments in terms of using many of the powerful drugs in first and early lines is that many patients are now becoming refractory to anti-CD38 antibodies relatively early and, to that extent, there are combinations such as carfilzomib and pomalidomide but also new drugs such as the BCMA antibody-drug conjugate which will hopefully provide an additional option for people who are already refractory to anti-CD38 as well as the new cereblon E3 ligase ubiquitin modulators, or CELMoDs, which are basically the derivatives, shall we say, of the IMiDs which are currently in clinical trials. So the hope is that they will also play a role in patients who are becoming more and more refractory.

In patients with relapsed multiple myeloma who are not eligible for TC-directed therapies, what factors do you consider when selecting alternative treatments?

The first thing to say is that in patients who are very refractory, if possible, we would try to use T-cell redirected therapies. The reasons that they may not be eligible, the first important and probably most prevalent reason is access. However, there are patient factors as well, for instance, there are some patients whose performance status is not good enough really for them to sustain the toxicities of T-cell redirected therapies. It’s also important to know that it is also a patient preference sometimes that they do not wish to run the risk of the significant side effects of T-cell redirected therapy.

So those are many of the factors which help us to make the decision with the patient for non-T-cell directed therapies.

What are the key challenges you face in managing side effects and maintaining quality of life for multiple myeloma patients receiving non-TC redirected therapies?

The most prevalent side effect is cytopenias and, in relation to that, infections. It’s got to be said that while the T-cell redirected therapies have a high rate of infections, in particular the bispecifics as well as CAR T, but we tend to pay attention more to the rate in bispecifics. But for non-T-cell directed therapies the later the line of relapse it is, the more susceptible they are to infection. Therefore we obviously monitor them very closely, we use prophylactic antivirals as well as prophylaxis against pneumocystis and we also try our best to ensure that their white blood cells are supported.

I guess my main message is that while infections may not be as up in the concerns, because of the concerns in T-cell redirected therapies, they are as much a worry for non-TC therapies. There are some more unique side effects, in particular with the BCMA antibody-drug conjugate belantamab which affects patients’ eyes. But it is important to be aware that if one does choose to use that in the future, as in the clinical trial, it’s very important to monitor their visual acuity with particular indexes for keratopathy and to make appropriate dose reductions as well as increasing the interval between doses. Certainly the clinical trials have shown that the side effects can be mitigated by these measures.

Given the advances in therapies, what combination or sequencing strategies do you find most effective for patients with relapsed multiple myeloma?

In terms of the issue of transplantation, if I might first address that, because obviously autologous transplant remains a standard of care in transplant eligible patients at first line. So, for instance, there was quite a lot of discussion about whether salvage transplants should be used. Now, I would put it to you that, in my opinion, in jurisdictions where there is reasonable access to the new therapies we are doing less and less salvage transplants. One of the concerns is the fact that the use of melphalan together with lenalidomide maintenance can increase the chances of second malignancy. While that percentage is not high, if you have other options it is appropriate to try to overcome that and avoid that risk.

In terms of sequencing, it would be fair to say that most of the sequencing is predicated upon the availability of drugs but, given that most jurisdictions have daratumumab for non-transplant eligible patients, and that is often used in conjunction with lenalidomide, and lenalidomide is now used very commonly until progression, disease progression. So the majority of patients after the first line are already lenalidomide refractory and may be anti-CD38 refractory.

So the sequencing would be that if a patient is lenalidomide refractory but not anti-CD38 refractory and there’s access to anti-CD38 we would certainly use that in combination in the second line. However, if that is not available then other combinations such as carfilzomib/pomalidomide can be used. Overall, the maxim is that because of the attrition of patients with each successive line, one basically has to use the most powerful therapy at each line.