Treatments for Subsequent Relapse

For most patients, myeloma is a remitting and relapsing disease: periods of response to treatment and remission are followed by relapse. Most patients will experience several remissions and several relapses throughout their disease course.

Treatments for Subsequent Relapse (or Late Relapse)

The biology of myeloma changes and becomes clonally more complex over time. As successive treatments eliminate all but the most resistant clones, late-stage relapses become more difficult to treat, and require new and more effective therapies. Fortunately, there is a large number of approved treatment guidelines for relapsed and refractory (no longer responsive to prior therapy) myeloma. When those treatments are not effective, many new drugs and immunotherapy approaches are available in clinical trials.

As with treatment of first relapse, effective combination regimens for subsequent relapse are usually selected from the three major classes of drugs:

• proteasome inhibitors (PIs),
• immunomodulatory drugs (IMiDs), and
• monoclonal antibodies (mAbs).

The so-called "platform" drugs that are currently approved for use after 1-3 prior therapies include all of those used for newly diagnosed myeloma:

• Velcade® (bortezomib), a PI
• Revlimid® (lenalidomide), an IMiD
• Cytoxan (cyclophosphamide), an alkylating agent, and
• Thalomid® (thalidomide), an IMiD.

The following drugs may be used in combination with the above drugs in the subsequent relapse setting:

• Pomalyst® (pomalidomide), an IMiD
• Kyprolis® (carfilzomib), a PI
• Darzalex® (daratumumab), a mAb
• Empliciti® (elotuzumab), a mAb, and
• Ninlaro® (ixazomib), a PI.

Darzalex in combination with either Velcade/dexamethasone or Revlimid/dexamethasone is highly effective for patients who have had 1-3 prior lines of therapy. Darzalex/Pomalyst/dexamethasone is approved for patients who have had 2 or more prior lines of therapy.

Many patients eventually become resistant to Velcade or Ninlaro and Revlimid. Options for treatment may then include regimens using the proteasome inhibitor Kyprolis and/or the third-generation IMiD, Pomalyst:

• Pomalyst/Cytoxan/dexamethasone
• Kyprolis/Pomalyst/dexamethasone
• Darzalex/Pomalyst/dexamethasone

Clinical Trials

Patients who have become resistant to, or intolerant of, the approved therapies may consider enrolling in a clinical trial with an experimental agent. Given the continuing rapid rate of development of new therapies for multiple myeloma, as well as investigation of new combinations of existing and new agents, treatment in the context of clinical trials can be an option for patients with relapsed myeloma. Promising agents in early trials include:

• several new CAR T-cell therapy approaches
• the novel combination of approved drugs Darzalex, Kyprolis, and dexamethasone
• the bispecific monoclonal antibody GSK2857916
• several other bispecific monoclonal antibodies, as described in this comprehensive overview

Further along in clinical trials are other promising agents:

• isatuximab, a monoclonal antibody to the CD38 myeloma cell surface antigen
• selinexor, a selective inhibitor of nuclear export (SINE®)
• venetoclax, a BCL-2 inhibitor that specifically targets the t(11;14) cytogenetic abnormality

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