A “Surprising” Correlation

The 4 patients in the study were participants in an ongoing clinical trial looking at the safety and efficacy of isatuximab for treating RRMM (ClinicalTrials.org Identifier: NCT02514668). They were the last 4 to enroll at the University of Utah, which is 1 of about 20 sites for the trial across the United States and Europe, and Dr Atanackovic and his colleagues seized the opportunity to examine the patients’ immune responses. The patients had not received prior daratumumab treatment, he noted.

Dr Atanackovic was not familiar with any of the patients’ clinical history, but he went to the clinic where they being treated as soon as he saw that the level of myeloma-associated antibodies for 2 of the patients had been increasing for the entire approximately 1.5-year course of isatuximab treatment, which they received as a single agent.

“I’ll never forget the day I went there and asked them, ‘Who are these 2 cases?’” Dr Atanackovic told Cancer Therapy Advisor. He found out they both had complete responses to the treatment, which at the time of publication had lasted 20 months, whereas the 2 patients who did not have antibody or T-cell responses had either stable or progressive disease. “I [could] have never even hoped for anything like this in my wildest dreams; it was very surprising,” Dr Atanackovic said.

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The researchers ruled out other explanations for the link between immune and clinical responses, such as something like the nonresponders were much older than the responders. (In fact, they were similar in age.) They also found that myeloma cells from nonresponders, like the responders, tested positive (before treatment) for CD38, the target of treatment, along with other myeloma markers.

The findings suggest that “the fitness of the immune system may be more important for the prediction of a clinical response than the characteristics of just [the] tumor cells,” Dr Atanackovic said, although he reiterated these findings are based on only 4 patients.

However, looking at the myeloma-associated antibodies that were present in responders before and during treatment, does not yield any clues about which ones could be predictive of isatuximab response or associated with that response. Whereas 1 patient had antibodies against MAGEB1 and MAGEB3 before treatment and developed antibodies against MAGEC2 during treatment, the other had antibodies against MAGEC1 before treatment and NYESO1 during treatment.

“My hope would be out of all the myeloma antigens … we will be able to identify a subset of 5 to 8 or 10 where patients most commonly show an response,” said Dr Atanackovic. It would be cost-effective and spare patients unnecessary treatment to use such a panel of myeloma-associated antibodies to guide treatment, he added.

Expanding the Study

An ongoing international clinical trial of 109 patients with RRMM is comparing the responses to isatuximab alone and in combination with cemiplimab, a monoclonal antibody against programmed death receptor-1 (PD-1) that is under investigation for the treatment of myeloma, and is investigating the immune response to this combination of agents (ClinicalTrials.gov Identifier: NCT03194867).

Dr Atanackovic, who is one of the researchers involved in this clinical trial, hopes it will help answer the main outstanding questions from the current study: Are there certain antibodies present in patients before receiving isatuximab that could help predict their treatment response — and does an enhanced immune response, in this case an enhanced T-cell response elicited by cemiplimab, improve clinical outcomes? “If the more T cells or [higher] antibody levels against these antigens, the better your clinical response, then you could try to further improve this by giving the patient something to enhance their T-cell–mediated immune system, for example,” he said.

Dr Landgren agrees that it would be important to understand whether T-cell and antibody-mediated immune responses contribute to the efficacy of CD38-targeted therapy. “If you really understood these types of things, then maybe that could unlock mechanisms of resistance and you could maybe identify new drug targets.”

References

  1. van de Donk NWCJ and Usmani SZ. CD38 antibodies in multiple myeloma: mechanisms of action and modes of resistance. Front Immunol. 2018;20(9):2134.
  2. Atanackovic D, Yousef S, Shorter C, et al. In vivo vaccination effect in multiple myeloma patients treated with the monoclonal antibody isatuximab [published online August 13, 2019]. Leukemia. 2019 doi: 10.1038/s41375-019-0536-3