All myeloma patients want to avoid relapse. However, even with our best newer options, relapse comes at some point for most patients.
The great news is that first remissions are getting longer and longer— into the 4- to 5-year range or better. The menu for relapse treatment options includes many agents or combinations with the likelihood of long additional remissions.
On top of that, some early interventions are attempting very deep responses and the potential for cure with no indication of residual disease or functional cure with a low level of residual disease, which is in an MGUS-like state.
The initial challenge is to be clear if a relapse is occurring or not. The levels of myeloma proteins can fluctuate from test to test. The first step is to double check for any increased myeloma protein level which might suddenly be much higher than expected.
Don’t hesitate to ask your doctor for a recheck. If the serum protein level goes up on a recheck by 25% and the spike protein is at least 500mg [0.5Gm /dl], this is called biochemical relapse—it may or may not be accompanied by other indicators of disease progression.
The next steps include checking other results for any CRAB features (Calcium elevation, Renal insufficiency, Anemia, and Bone lesions/new or increasing lesions on x-ray or scan).
Follow-up bone marrow sampling may be needed to clarify the situation. If this is done, follow-up genetic FiSH (Fluorescence in situ hybridization) testing should be performed to identify any chromosomal abnormalities in the myeloma cells such as 17p-; t [11 ;14]; 1q + or other changes which may guide treatment selection decisions. The Freelite ratio is checked since any increase of > 100 is considered a myeloma defining event.
The common dilemma is often whether to nip it in the bud and start treatment right away or to wait while closely monitoring to see if the myeloma is really that active or not.
Sometimes, a relapse can evolve very slowly over time and there is no need to rush. However, if high-risk genetic features have been noted and/ or the relapse happens within the first year (called functional high-risk myeloma), then most myeloma experts would recommend starting treatment sooner rather than later.
Shared decision making between the patient and the treating doctor is key at this staging, not just to decide if treatment should be started, but to review results of prior treatments and to consider everything from availability, to costs and potential side effects as well as convenience for the patient and family.
Age and underlying medical conditions can significantly impact the decision-making process. There is an opportunity to discuss the many excellent combinations and new agents available in 2023 to make the best choices.
A full range of treatments are available using agents which are FDA-approved and commercially available.
Many patients have received standard of care first therapy with VRd [Velcade®(bortezomib), Revlimid® (lenalidomide) + dexamethasone] + or - ASCT (autologous stem cell transplant) and relapse after Revlimid maintenance.
In this case, alternative agents are considered such as pomalidomide (a 3rd generation immunomodulatory drug/IMiD) or Kyprolis® (carfilzomib)— a next-generation proteasome inhibitor. There are several very active combinations such as a combination with a newer agent, daratumumab (an anti-CD 38 inhibitor) including:
Daratumumab + pomalidomide and dexamethasone (pom-dex) or KPd (carfilzomib, pomalidomide, and dexamethasone), or combinations still using bortezomib (versus carfilzomib) and/or alternates such as ixazomib, isatuximab, or elotuzumab.
Clearly, there are a lot of options to review in joint discussions. Other agents to consider include selinexor and Cytoxan® (cyclophosphamide) as part of combinations plus venetoclax, which is selectively active in patients with t [11;14].
If it is felt that response can still occur with Revlimid, a variety of combinations can be considered, including triplets (3-drug combinations) which are preferred in all scenarios (Revlimid-resistant and sensitive) to achieve maximum benefit in the relapse setting.
Common regimens are Dara-Rd (MAIA regimen) which has produced excellent remissions (beyond 4-5 years) in relapsing patients or KRd (carfilzomib, lenalidomide, and dexamethasone) for example.
In both situations, autologous stem cell transplantation (ASCT) can be considered in patients who have not received it, as well as those who have achieved a long first remission after frontline ASCT (after induction).
What is considered long is somewhat controversial in 2023 since so many therapies less arduous than ASCT can provide remissions of several years. In general, 2-3 years is considered long, but some would argue for longer—such as 5 years or greater for the first remission, with an expectation of perhaps 3 years with an additional transplant.
What provides a very positive approach in the relapse setting is the availability of many new options. Immune therapies such a CAR T-cells (BCMA targeted: ide-cel and cilta-cel are already FDA-approved in the later relapse setting) and bispecific monoclonal antibodies (BCMA / CD3 targeted: teclistamab is also already approved in later relapse setting) are exciting options, if potentially available in a clinical trial and other therapies are not working.
It is remarkable that response rates between 65-100% have been observed in previously heavily treated patients, providing strong hopes of significant benefit with earlier use. This is especially important in patients who have become resistant to prior daratumumab.
Newer CAR-T cell products and bispecific antibodies are also showing promising results in clinical trials, including talquetamab—a non-BCMA targeted bispecific, which is producing excellent remissions. Other agents, such as the CELMoDs (agents resembling IMiDs) are available in clinical trials and many additional agents are in early development.
Having all this positive information available makes decision making much less frightening. If relapse has occurred, there are really excellent options with the likelihood of years of remission (even many years) with the earlier introduction of newer immune therapies.
Since access to clinical trials can become crucial and necessary, planning ahead is recommended. Which center in your area can give you the strongest menu of options? Are there myeloma experts available?
Consider an appointment and review so that myeloma experts can become familiar with your situation for current and/or potential future choices. This positive approach allows you to have access to agents that will extend your survival—maybe even literally save your life at the right moment or in the future.
Wishing all patients the best choices, as they move positively forward!
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Professor of Medicine, Hematologist/Oncologist, and Honoree MD at the University of Brussels, Dr. Brian G.M. Durie is the Chairman of the Board and Chief Scientific Officer of the IMF. Dr. Durie is also the Chairman of the International Myeloma Working Group (IMWG)—a consortium of more than 250 myeloma experts from around the world—and leads the IMF’s Black Swan Research Initiative® (BSRI).
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