Newly diagnosed patients ask: What is myeloma? What can I expect? Is it treatable? How long will I live? As we struggle to emerge from the COVID -19 pandemic, albeit seeing very encouraging results with many new immune therapies, it is a good time to assess the future for myeloma patients. The future is bright, much brighter than it has ever been in the past. But how is treatment likely to evolve, moving forward?
The history of myeloma treatments
I have witnessed the transition — from old-time chemotherapy to new targeted biologic therapies, and now, to the potential impact of new immune therapies. Up until the late 1990s, chemotherapy — such as alkylating agents (melphalan/cyclophosphamide) and anthracyclines (Adriamycin®) and vincalkaloids (vincristine) — were used to treat myeloma. Very deep responses were rare and there were concerns about both typical chemo side effects and the development of additional second cancers.
IMiDs and proteasome inhibitors
The introduction of immunomodulatory drugs (IMiDs), starting with thalidomide in the late 1990s and proteasome inhibitors starting with VELCADE® (bortezomib) were major steps forward. Suddenly, much deeper responses were achievable, and toxicities were very different, although often still challenging such as with neuropathy.
We learned that the steroid dexamethasone — especially using a low-dose regimen (with a once-per-week schedule) — enhanced overall results and was well tolerated.
We also learned that three-drug combinations such as: Velcade (bortezomib) + REVLIMID® (lenalidomide) + dexamethasone (VRd, a second generation iMiD/dexamethasone) and the drug combination of bortezomib, thalidomide, and dexamethasone (VTd) (which uses thalidomide instead of lenalolidomide) produced remarkably good results and became the new standards of care, with average overall survival almost doubly improving — from 4 years to over 7 years, especially if combined with autologous stem cell transplant (ASCT).
The high dose melphalan (used as part of ASCT) was the first treatment to produce deep responses, as observed by Prof. Timothy John McElwain of the Royal Marsden Hospital outside London in the UK during the late 1980s and early 1990s. The great disappointment for Prof. McElwain and his patients was that relapses occurred, and new therapies were required.
Additionally, we learned that maintenance therapy (which had been a concern with melphalan because of second cancers) really improved outcomes, especially with ongoing Revlimid treatment with a much lower risk of second cancers. Velcade (often used along with Revlimid) is also used as a maintenance approach, especially for patients with higher risk cytogenetic findings on bone marrow samples through abnormalities found in a Flourescent in Situ Hybridization (FiSH) test to improve remission duration in the maintenance setting. Other proteasome inhibitors can also be used in this fashion.
Introduction of new immune therapies
The introduction of immune therapies began with the testing of the anti-CD-38 monoclonal antibody daratumumab (dara). Following the achievement of remarkable results in relapse/refractory myeloma patients, dara was evaluated rapidly in all treatment situations — including as part of first therapy.
The results of the MAIA Trial represent a landmark or benchmark because first remissions greater than 4 years were achieved in the frontline setting for patients not eligible for ASCT using the combination of dara + Revlimid (lenalidomide) and dexamethasone (D-Rd). Thus, three triplets have emerged as important for newly diagnosed patients: VRd, VTd and now, D-Rd. Isatuximab is also available as an alternate anti-CD-38 monoclonal antibody.
The next step has been to assess the added value of dara along with either VRd or VTd or other regimens. Results have shown clear benefits with the four-agent combinations and the results of randomized trials are being awaited to determine if the Dara VRd and Dara VTd regimens can be fully established as new standards of care.
The remarkable good news for newly diagnosed patients is that a vast majority of patients respond very well to these new regimens and can expect (while anticipating longer term results with D-Rd and VTd) long first remissions on average in the 7-10 years range or perhaps greater.
It is important to note the outstanding results in two Black Swan Research Initiative® (BSRI) Cure trials in which KYPROLIS® (carfilzomib) + Revlimid (lenalidomide) + dextamethasone (KRd, using Kyprolis instead of Velcade) plus Dara (ASCENT Trial) as well as KRd + ASCT (CESAR Trial) have produced excellent results in patients with high-risk smoldering multiple myeloma (HR SMM) including high levels (60-70% or better) of MRD negativity (at the 10 to minus 6 level: zero out of a million bone marrow cells counted).
These are important steps in the ongoing search to achieve cure for myeloma patients. Clearly, we are at the brink of achieving this lofty goal with these intensive combination approaches. Toxicities, as well as costs incurred by the use of an increasing number of drugs are obviously causes for concern.
The upcoming role of new immune therapies
In addition to CD 38 (an antigen on the surface of myeloma cells), there other important antigens present and strongly expressed selectively on myeloma cells, including B-Cell Maturation Antigen (BCMA). Treatments directed against BCMA have proven to be very effective, including antibody drug conjugates (belantamab); Chimeric antigen receptor (CAR) T cells (where the patient’s own immune T cells are engineered to target BCMA on the myeloma) and bi-specific monoclonal antibodies which bridge BCMA with CD 3 on the patient’s T cells to enhance the attack against the myeloma.
Early results in relapse/refractory myeloma patients have been very positive especially for CAR T cells with overall response rates in the 70 to greater than 90% range with very deep response being achieved. Especially encouraging were results from the CARTITUDE-1 (CAR T) trial with an overall response rate at 2 years of 98%.
Use of immune therapies in earlier disease
The natural next step is to evaluate these very promising therapies in patients in early or even newly diagnosed settings. As always, there is a balance between expected high-level benefit and potential short- or longer-term toxicities or side effects.
From the history of myeloma therapies, these trade-offs have had the biggest impact on whether a new approach will produce lasting improved outcomes. Nonetheless, there is great anticipation that the new immune therapies will have a major impact and perhaps transform the treatment of myeloma.
Based upon the results with the CESAR and ASCENT trial regimens noted above, in treating patients with HR SMM, it is very reasonable to expect an important impact with CAR T and other newer immune therapies in this setting, as well as in patients with newly diagnosed multiple myeloma (NDMM).
It is especially attractive to consider the impact of a single infusion of CAR T cells with or without other therapies. Will this bring us closer to sustained deep responses at the MRD-negative level that may translate into longer term elimination of the myeloma or a cure? It is too soon to know, but trials using CAR T cells for newly diagnosed myeloma patients (with very promising results) are already ongoing in China and numerous other trials are being planned.
It is likely that myeloma therapy is about to take a major leap forward with the introduction of new immune therapies in patients with earlier disease. If a single infusion of engineered CAR T cells or ongoing use of other immune therapies can produce lasting benefit, this will truly be a quantum leap forward in producing lasting remission — potentially, without the need for additional or ongoing maintenance therapy. The evolution from the introduction of traditional chemo therapies over 50 years ago can be a remarkable achievement which we all await with eager anticipation.
This is definitely good news during these difficult times.
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