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Review Examines Growing Treatment Options for Heavily Refractory MM


Relapse remains a daunting reality in multiple myeloma, but clinicians have more tools to work with to fight the disease.

The treatment landscape for patients with multiple myeloma (MM) continues to expand, but those advances have not yet changed that most patients will experience a relapse.

In a new review article published in Clinical Lymphoma, Myeloma & Leukemia, investigators outlined the latest treatment options and strategies for patients with late-stage, highly refractory disease.

They began by outlining the poor survival rates in patients. Although MM has an overall 5-year survival rate of 53.9% in the United States, they noted that patients with relapsed MM that is refractory to an immunomodulatory agent and a proteasome inhibitor (PI) have a median survival time of just 13 months from the time resistance emerges.

The authors next reviewed the available treatment options. In some cases, retreatment with the same agent is appropriate, they said, although typically it is preferable to use a different drug class or a second- or third-generation agent in the same class. Delayed, second, or salvage autologous stem cell transplantation is also an option for certain fit patients—even though many patients may not be eligible, they noted.

Pomalyst (pomalidomide) is a next-generation immunomodulatory agent that binds to cereblon and has shown significant promise in patients previously treated with Revlimid (lenalidomide) in combination with PIs or monoclonal antibodies, the authors said. The phase 3 OPTIMISMM trial of pomalidomide in combination with Velcade (bortezomib) and dexamethasone found the regimen extended progression-free survival (PFS) by 4 months, although the authors said that patients in that study were less heavily pretreated than in other similar trials.

Next-generation PIs like Kyprolis (carfilzomib) and Ninlaro (ixazomib) have shown promise in patients who are refractory to lenalidomide. “However, so far there is a relative lack of data on outcomes in patients already refractory to bortezomib,” the authors wrote. “Patients with disease refractory to bortezomib may benefit from combinations with next-generation PIs, especially with agents using different mechanisms of action.”

For instance, the TOURMALINE-MM1 phase 3 study showed that patients receiving ixazomib in combination with lenalidomide and dexamethasone had an improved overall response rate and PFS compared with patients on lenalidomide and dexamethasone. In that study, 12% of patients had previous exposure to lenalidomide.

Monoclonal antibodies like Empliciti (elotuzumab), Darzalex (daratumumab), and Sarclisa (isatuximab) have also become important treatment options, and yet the investigators noted that daratumumab has become more common in earlier lines of therapy, meaning that more patients with relapsed or refractory MM (RRMM) may need different options like elotuzumab due to their prior exposure to daratumumab.

Other novel therapies, like Xpovio (selinexor), a selective inhibitor of nuclear export, and Farydak (panobinostat), a histone deacetylase inhibitor, have also emerged as important treatment options.

With so many options available, the authors wrote that the onus is on physicians to craft therapies based on the particulars of individual cases.

“Selecting among the potential therapeutic options for RRMM depends on prior drug exposure and/or resistance patterns to previous treatment,” they wrote, adding that doctors should seek to take advantage of synergies between different therapies.

“For example, pomalidomide may be best used in combination with immunostimulatory monoclonal antibodies due to the synergistic effects seen with these 2 drug classes on the immune system and in particular effector or natural killer cells,” they wrote.

Factors to consider when making treatment decisions include expected efficacy, toxicities, cytogenetic abnormalities, and patient age, frailty, and quality of life concerns.

“Treatment strategies for each patient should be individualized and planned carefully, and all of the above factors should be considered when making treatment decisions,” the authors concluded.


Dimopoulos M-A, Richardson P, Lonial S. Treatment options for patients with heavily pretreated relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. Published online January 18, 2022. doi:10.1016/j.clml.2022.01.011

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