Real Progress Made in Relapsed/Refractory Multiple Myeloma, But Questions Remain

What are the main disease- and patient-related factors that you consider when selecting from the variety of approved treatment options for patients with relapsed/refractory multiple myeloma?

The good news is that there have been 11 approved novel agents in myeloma as of the beginning of 2020, and more are anticipated later this year. Thus, we have a good number of choices for our patients and these choices continue to increase.
 
In general, there are several factors to take into account when selecting therapy for patients with relapsed and refractory disease. Patient-related factors include how is the patient doing? What is their overall performance status? What type of symptom burden do they have? What are their comorbidities, and, importantly, do they have residual side effects from prior therapy?
 
Conversely, we must also consider how their disease is behaving. Is the disease moving gradually with a less aggressive relapse, or is the patient’s disease taking off and behaving aggressively? This tempo of relapse will influence choices, including the number and type of agents being considered for any combinatorial approach.
 
I approach relapse with the philosophy of “guilty until proven innocent”. With relapse it is important to be proactively monitoring the patient, and preempt worsening progression and end-organ damage if at all possible.

How have recent advances in treatment, in particular the addition of monoclonal antibodies (mAbs) targeting CD38 to standard therapy, changed the treatment landscape for patients with relapsed/refractory multiple myeloma?

The development and use of CD38-targeting mAbs have been true game changers in my opinion. When you think about key drug classes for relapsed/refractory disease, we now have proteasome inhibitors, mAbs, and immunomodulatory drugs, in addition to other small molecule inhibitors, such as histone deacetylase inhibitors and more recently selective inhibitors of nuclear export protein. mAbs have provided a backbone class of drugs that are a real force, in my view, in how they influence outcomes. We are using daratumumab and more recently isatuximab in the relapsed setting, and deploying them earlier than we did several years ago. In fact, and quite remarkably in my view, daratumumab is now approved upfront and being used in newly diagnosed disease. Moreover, with the advent of subcutaneous administration, daratumumab is proving even more convenient to administer. Antibodies are thus becoming much more widely used, with another key agent being elotuzumab, which works differently and in combination as a true immunoadjuvant mAb targeting SLAMF7, again being used primarily in relapsed disease but also elsewhere.

Results from the ICARIA-MM trial led to the recent approval of isatuximab for use in combination with pomalidomide and dexamethasone to treat adults with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor. From your perspective, where does this approval fit within clinical practice and other approved agents?

The ICARIA-MM trial (ClinicalTrials.gov Identifier: NCT02990338) was a large phase 3 trial performed across numerous centers around the world.¹ The trial randomized patients to [receive] pomalidomide and dexamethasone or pomalidomide, dexamethasone, and isatuximab. In this study, we were able to show a doubling of progression-free survival in favor of the 3 drugs vs the 2. There was a survival trend even with early follow up and an effective doubling of response rate was shown. The 3 drugs were also generally well tolerated. We also did quality-of-life studies that showed no loss of quality of life from the triplet compared with the doublet [therapy]. There were also subgroups of patients who were more vulnerable, like those with renal disease, who did better with the 3 drugs vs 2.
 
The approval of isatuximab in relapsed disease is important because it is the first approval of a CD38 mAb combination with pomalidomide from a phase 3 study in advanced disease. It is also a very important addition to the CD38 armamentarium because it is a chimeric mAb, which is qualitatively different from daratumumab. Preclinically as a result isatuximab has different characteristics and clinically it also has differences in my view.
 
Isatuximab is less complement activating, so it doesn’t require as much premedication to be safely given to patients with chronic obstructive pulmonary disease, asthma, or other pulmonary conditions. It is administered weekly for the first month and then every 2 weeks thereafter, which makes its administration less frequent compared to other [drugs], plus its infusion times are shorter as well. With the advent of subcutaneous daratumumab that particular advantage is less pronounced than before, but as daratumumab is increasingly being used earlier in myeloma, isatuximab has become an antibody of choice in later relapse, in my opinion.

What are some of the most commonly observed side effects of treatment in patients with relapsed or refractory multiple myeloma? What strategies do you find to be most successful in managing these side effects?

The side effects of isatuximab are quite limited in my experience. The most important ones are neutropenia and also chest infections that may occur in combination with pomalidomide and dexamethasone. Importantly, isatuximab does not cause significant neuropathy. Apart from the suppression of counts described above, it is generally well tolerated. It can cause fatigue, but it isn’t associated with gastrointestinal side effects and other systemic symptoms that can be challenging with other classes of drugs in the relapsed and refractory setting. It is also not associated with cardiovascular, renal, or other vascular toxicities that can be a challenge with carfilzomib-based therapy.

What recent or ongoing trials are the most exciting from the perspective of future options for patients with relapsed/refractory multiple myeloma? What are the questions that still remain in regards to that research?

Multiple questions remain. In the relapsed/refractory setting we have our immunomodulatory- and proteasome inhibitor–based platforms very well established, with sequencing and combinations key. We target CD38 relatively early now, and if that fails we then reach for B-cell maturation antigen (BCMA)-targeting agents, such as the antibody drug conjugate belantamab mafodotin, various chimeric antigen receptor T platforms and now, excitingly, bispecific mAbs (aka BiTes). Importantly, we also have several other approved agents with novel mechanisms of action, including selinexor and panobinostat, and under study numerous others, such as novel cytotoxic chemotherapy and the very exciting new “CelMoDs”.
 
One approved small molecule inhibitor that is sometimes under-appreciated and I mentioned before is the histone deacetylase inhibitor, panobinostat. Another important addition I also described above is selinexor, which has shown considerable promise, especially with the encouraging results of the recently reported phase 3 BOSTON trial (ClinicalTrials.gov Identifier: NCT03110562). Specifically, its novel mechanism of action by inhibiting nuclear export proteins, which modulate a key pathway for myeloma growth, resistance, and survival, is especially appealing.
 
In terms of other new agents, drugs like venetoclax, which specifically target translocation 11;14, are intriguing. In my experience, our t11;14 patients have done very well with venetoclax. For non-11;14 patients, however, it has been not helpful in the phase 3 setting, and in fact may be harmful. For that reason, in my view, we need to be careful about certain types of targeted approaches in myeloma.
 
Overall, it is important to share that there is continued real progress. As we are targeting BCMA, and after we have targeted CD38, there is also the “stemness of myeloma” that is very important to bear in mind. This stemness reflects the fact that the disease itself is highly complex and very diverse. As you think about BCMA, for example, it is relatively far down the ontogeny of myeloma differentiation, as its full name suggests. In short, BCMA reflects a relatively mature phenotype, with “upstream” cells being less mature and so different as a phenotype. In that regard, it is exciting to have new agents that may be able to target this. One example in development is the novel and selective cytotoxic melflufen, which appears promising in early phase studies for the treatment of not just relapsed and refractory myeloma, but also extra-medullary disease.
 
In that same spirit, I already mentioned that we have been targeting BCMA and we hopefully will have the approval of belantamab mafodotin just around the corner. Here we deliver in an “off the shelf” fashion, an antibody drug conjugate to the tumor targeting BCMA, but because there is immunogenic cell death and consequent collateral damage to surrounding disease, this may in part help address the issue of stemness and do so especially in combination.