Treatments for Late (or Subsequent) Relapse

Despite advances in treatment, myeloma can be persistent. Myeloma patients may experience periods of response to treatment and even remission, followed by relapse. Most patients will experience several remissions and several relapses throughout their disease course. Late relapse indicates multiple lines of therapy have already been used, and myeloma has become refractory. Refractory means myeloma is no longer responding to treatment. 

Treatments for Late Relapse (or Subsequent Relapse)

The biology of myeloma changes. It becomes more complex over time. The clonal plasma cells can evolve or become resistant. As early-line treatments eliminate all but the most resistant clones, late-stage relapses become more difficult to treat. More therapies are needed. These therapies must be effective against new targets. Fortunately, several treatments for relapsed and refractory myeloma have been approved. Clinical trials continue to explore new drugs, immunotherapies, and combination approaches.  

As with treatment of first relapse, effective combination regimens for late 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 newer generation IMiDs, proteasome inhibitor, and MoAbs. Agents with a new mechanism of action (MOA) are also added to late-line regimens. 

• Pomalyst/Cytoxan/dexamethasone
• Kyprolis/Pomalyst/dexamethasone
• Darzalex/Pomalyst/dexamethasone
• Sarclisa® (isatuximab), a monoclonal antibody to the CD38 myeloma cell surface antigen 
• Xpovio® (selinexor), a selective inhibitor of nuclear export (SINE®) 

In recent years, immunotherapy options have demonstrated significant treatment benefit in the late relapse setting.  Dr. Joseph Mikhael, MD provides a two-part overview of the immune system. He explains how using a person’s own immune system can treat myeloma. (See Using the Immune System to Fight Multiple Myeloma).  

Clinical trials will help answer if immunotherapies can be used in

• an earlier line of therapy
• during early relapse
• as potential frontline treatments

Cellular Therapies

• Chimeric Antigen Receptor T Cell (CAR T) 
• Abecma® (idecabtagene vicleucel) 
• Carvykti® (ciltacabtagene autoleucel) 
• Bispecific Antibodies 
• Tecvayli® (teclistamab) 
• Talvey® (talquetamab) 
• Elrexfio® (elranatamab) 

Clinical Trials

Approved treatments for myeloma are based on results from clinical trials. Continued drug development and investigation of new combinations will come from patient participation in clinical trials. Patients who need to start a new treatment may consider enrolling in a clinical trial.  

With the rapid development of new therapies for multiple myeloma and the investigation of new combinations of existing plus new agents, clinical trials may be an option for patients with relapsed myeloma. Many clinical trials are available clinical trials in the relapse setting. Promising agents in early trials include: 

• several new CAR T-cell therapy approaches 
• novel combinations of already approved drugs such as Darzalex, Kyprolis, and dexamethasone; or Tecvayli and Talvey 
• comparing approved and new drugs (e.g. Iberdomide, Darzalex and dexamethasone versus Darzalex, Velcade,and dexamethasone) 
• the bispecific monoclonal antibody GSK2857916 
• several other bispecific monoclonal antibodies
• Further along in clinical trials are other promising agents: 
• elranatamab, a bispecific antibody to the CD38 myeloma cell surface antigen 
• iberdomide and mezigdomide,  new generation immunomodulatory agents known as CELMoDs 
• venetoclax, a BCL-2 inhibitor that specifically targets the t(11;14) cytogenetic abnormality